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This refers to the increase in the size of the cells and its functional activity.A. HyperplasiaB. AtrophyC. MetaplasiaD. Hypertrophy

D. Hypertrophy


A branch of pathology that is concerned with the alterations in specialized organs and tissues that are responsible for disorders that involve these organs.

Systemic Pathology


The aspect of a disease process that is the 'main cause' of that disease.A. PathogenesisB. Functional derangementsC. EtiologyD. Molecular and Morphological Changes

C. Etiology


He is known as the father of modern pathology.

Rudolf Virchow


The process in which there is a decrease in size and metabolic activity.A. HypertrophyB. HyperplasiaC. AtrophyD. Metaplasia

C. Atrophy


A process by which cells change its phenotype.



TRUE or FALSE: In the process of hypertrophy, there are new and larger cells.

FALSE. Cells become larger but there are no new cells.


The most common stimulus for hypertrophy of muscle is _________.

Increased workload


The main biochemical pathway that mediates the physiologic muscle hypertrophy is _________.A. GlycolysisB. ETCC. Phosphoinositide 3-kinase/Akt pathwayD. Signaling down stream of G-protein coupled receptors

C. Phosphoinositide 3-kinase/Akt pathway


TRUE or FALSE: The signaling down stream of G-protein couple receptor is the main biochemical pathway for pathologic hypertrophy.



In muscle hypertrophy the alpha myosin heavy chain is converted to its ___________.

Beta isoform


Barbiturates show hypertrophy of this specific cell organelle in hepatocytes.

Smooth Endoplasmic Reticulum (SER)


In the mechanism of muscle atrophy, the degradation of cellular proteins occurs mainly by this pathway.

Ubiquitin-Proteasome Pathway (responsible for accelerated proteolysis)


The process in which starved cells eat its own components in attempt to find nutrients and survive.



The most common epithelial metaplasia is:A. Squamous to cuboidalB. Columnar to squamousC. Squamous to columnarD. Cuboidal to columnar

B. Columnar to squamous


Barrett Esophagus manifests this type of metaplasia.A. Squamous to cuboidalB. Columnar to squamousC. Squamous to columnarD. Cuboidal to columnar

C. Squamous to columnar


Two features of reversible cell injury that can be recognized under the light microscope.

Cellular swelling and fatty change


______________ is the first manifestation of almost all forms of injury to cells.

Cellular swelling


The following statements regarding necrosis are correct EXCEPT:A. Cells are unable to maintain membrane integrity.B. The process may present with inflammation.C. The cells usually enlarge or swell.D. Necrosis is often physiologic to maintain homeostasis.

D. Necrosis is often physiologic to maintain homeostasis.


Necrotic cells show increased __________ in H&E staining.A. BasophilsB. NeutrophilsC. EosinophilsD. Monocytes

C. Eosinophils


The glassy homogenous appearance of a necrotic cell is mainly due to the loss of _________ particles.



The basophilia of the chromatin may fade, a change that presumably reflects loss of DNA because of enzymatic degradation by endonucleases.



This process is characterized by nuclear shrinkage and increased basophilia.



TRUE or FALSE: Pyknosis is also observed in apoptotic cell death.



The process in which pyknotic nucleus undergoes fragmentation.



A localized area of coagulative necrosis is called an ___________.



Type of necrosis that is characterized by digestion of dead cells, resulting in the transformation of the tissue into a liquid viscous mass.

Liquefactive necrosis


Type of necrosis that is often encountered in foci of tuberculous infection.

Caseous ('cheeselike') Necrosis


A special form of necrosis usually seen in immune reactions involving blood vessels.

Fibrinoid necrosis


Most common type of cell injury.

Ischemic and Hypoxic Injury


This term refers reduced oxygen availability.



TRUE or FALSE: Hypoxia is a more rapid and severe cell and tissue injury than does ischemia.



________ arrests the cell cycle at G1 phase and triggers apoptosis if the damage is great.

Gene p53


Most common type of cell injury.

Ischemic and Hypoxic Injury


This term refers reduced oxygen availability.



TRUE or FALSE: Hypoxia is a more rapid and severe cell and tissue injury than does ischemia.



________ arrests the cell cycle at G1 phase and triggers apoptosis if the damage is great.

Gene p53


The four aspects of a disease process that form the core of pathology are:

 its cause (etiology), the mechanisms of its development (pathogenesis), the biochemical and structural alterations induced in the cells and organs of the body (molecular and morphologic changes) ,
and the functional consequences of these changes (clinical manifestations


What are Adaptations?

Adaptations are reversible functional andstructural responses to more severe physiologic stresses and some pathologic stimuli, duringwhich new but altered steady states are achieved, allowing the cell to survive and continue tofunction ( Fig. 1-1 and Table 1-1 ).


The adaptive response may consist of an: 

increase in the size of cells (hypertrophy) and functional activity, an increase in their number (hyperplasia), a decrease in the size and metabolic activity of cells (atrophy), or a change in the phenotype of cells (metaplasia).


ALTERED PHYSIOLOGICAL STIMULI; SOMENONLETHAL INJURIOUS STIMULI • Increased demand, increased stimulation (e.g., bygrowth factors, hormones)• Decreased nutrients, decreased stimulation• Chronic irritation (physical or chemical)

CELLULAR ADAPTATIONS • Hyperplasia, hypertrophy• Atrophy• Metaplasia


REDUCED OXYGEN SUPPLY; CHEMICAL INJURY;MICROBIAL INFECTION • Acute and transient• Progressive and severe (including DNA damage)

• Acute reversible injuryCellular swelling fatty change• Irreversible injury ➙ cell deathNecrosisApoptosis








What is cell injury?

If the limits of adaptive responses are exceeded or if cells are exposed to injurious agents orstress, deprived of essential nutrients, or become compromised by mutations that affectessential cellular constituents, a sequence of events follows that is termed cell injury


_________ may be stages of progressive impairment following different types of insults. 

Adaptation, reversible injury, and cell death
​ For instance, in response to increased hemodynamic loads, the heart muscle becomes enlarged, a form of adaptation, and can even undergo injury. If the blood supply to the myocardium is compromised or inadequate, the muscle first suffers reversible injury, manifested by certain cytoplasmic changes (described later). Eventually, the cells sufferirreversible injury and die


What is cell death?

Cell death, the end result of progressive cell injury, is one of the most crucial events in theevolution of disease in any tissue or organ.  It results from diverse causes, including ischemia(reduced blood flow), infection, and toxins.Cell death is also a normal and essential process inembryogenesis, the development of organs, and the maintenance of homeostasis. 


There are two principal pathways of cell death, ____ and _______ 

necrosis and apoptosis


. Nutrient deprivation triggers anadaptive cellular response called _________ that may also culminate in cell death. We willreturn to a detailed discussion of these pathways of cell death later in the chapter.



Stresses of different types may induce :

changes in cells and tissues other than typical adaptations, cell injury, and death (see Table 1-1 ). Metabolic derangements in cells and sublethal, chronic injury may be associated with intracellular accumulations of a number of substances, including proteins, lipids, and carbohydrates. Calcium is often deposited at sites of cell death, resulting in pathologic calcification. Finally, the normal process of aging itself is accompanied by characteristic morphologic and functional changes in cells.


Adaptations of Cellular Growth and Differentiation 



What is hypertrophy?

Hypertrophy refers to an increase in the size of cells, resulting in an increase in the size of theorgan.The hypertrophied organ has no new cells, just larger cells.


Hypertrophy is due to?

The increased size of thecells is due to the synthesis of more structural components of the cells.Cells capable of divisionmay respond to stress by undergoing both hyperplasia (described below) and hypertrophy,whereas in nondividing cells (e.g., myocardial fibers) increased tissue mass is due tohypertrophy. In many organs hypertrophy and hyperplasia may coexist and contribute toincreased size.


Hypertrophy can be physiologic or pathologic and is caused by ________.

increased functional demand orby stimulation by hormones and growth factors


 The striated muscle cells in the heart andskeletal muscles have only a limited capacity for division, and respond to increased metabolicdemands mainly by undergoing___________ 



The most common stimulus for hypertrophy ofmuscle is___________. 

 increased workload  For example, the bulging muscles of bodybuilders engaged in“pumping iron” result from an increase in size of the individual muscle fibers in response toincreased demand. In the heart, the stimulus for hypertrophy is usually chronic hemodynamicoverload, resulting from either hypertension or faulty valves (see Fig. 1-2 ).In both tissue typesthe muscle cells synthesize more proteins and the number of myofilaments increases. Thisincreases the amount of force each myocyte can generate, and thus increases the strengthand work capacity of the muscle as a whole.


The massive physiologic growth of the uterus during pregnancy is a good example of hormoneinducedincrease in the size of an organ that results mainly from __________ of muscle fibers (Fig. 1-3 ). The cellular enlargement is stimulated by estrogenic hormones acting on smoothmuscle estrogen receptors, eventually resulting in increased synthesis of smooth muscleproteins and an increase in cell size.



What is the mechansm of hypertrophy?

Hypertrophy is the result of increased production of cellular proteins .Much of ourunderstanding of hypertrophy is based on studies of the heart. 


What induce hypertrophy?

Hypertrophy can be induced bythe linked actions of : mechanical sensors (that are triggered by increased work load), growth factors (including TGF-β, insulin-like growth factor-1 [IGF-1], fibroblast growth factor), and vasoactive agents (such as α-adrenergic agonists, endothelin-1, and angiotensin II).


The two main biochemical pathways involved in musclehypertrophy seem to be the :

phosphoinositide 3-kinase/Akt pathway (postulated to be most important in physiologic, e.g., exercise-induced, hypertrophy) and signaling downstream of G protein-coupled receptors (induced by many growth factors and vasoactive agents, and thought to be more important in pathologic hypertrophy). 


What pathway is mainly involved in the physiologic hypertropy?

 phosphoinositide 3-kinase/Akt pathway (postulated to be mostimportant in physiologic, e.g., exercise-induced, hypertrophy) 


What pathway is important for pathologic hypertrophy?

signaling downstream of Gprotein-coupled receptors (induced by many growth factors and vasoactive agents, and thoughtto be more important in pathologic hypertrophy). 


Hypertrophy may also be associated with aswitch of contractile proteins from adult to fetal or neonatal forms.For example, during musclehypertrophy the α isoform of myosin heavy chain is replaced by the β isoform, which has aslower, more energetically economical contraction.In addition, some genes that are expressedonly during early development are re-expressed in hypertrophic cells, and the products of thesegenes participate in the cellular response to stress.For example, the gene for________ is expressed in both the atrium and the ventricle in the embryonic heart, but it isdown-regulated after birth. 

 atrial natriureticfactor (ANF) Cardiac hypertrophy, however, is associated with reinduction of ANFgene expression. ANF is a peptide hormone that causes salt secretion by the kidney, decreasesblood volume and pressure, and therefore serves to reduce hemodynamic load.


What is hyperplasia?

Hyperplasia is an increase in the number of cells in an organ or tissue, usually resulting inincreased mass of the organ or tissue. Although hyperplasia and hypertrophy are distinctprocesses, frequently they occur together, and they may be triggered by the same externalstimulus. 


Hyperplasia takes place if the cell population is capable of ____, and thusincreasing the number of cells.Hyperplasia can be physiologic or pathologic.



Physiologic hyperplasia can be divided into: 

(1) hormonal hyperplasia, which increases thefunctional capacity of a tissue when needed,and (2) compensatory hyperplasia, whichincreases tissue mass after damage or partial resection. 


Hormonal hyperplasia is well illustratedby the _____________ 

proliferation of the glandular epithelium of the female breast at puberty and duringpregnancy, usually accompanied by enlargement (hypertrophy) of the glandular epithelial cells.


The classical illustration of compensatory hyperplasia comes from the myth of Prometheus,which shows that the ancient Greeks recognized the ______

capacity of the liver to regenerate.Aspunishment for having stolen the secret of fire from the gods, Prometheus was chained to amountain, and his liver was devoured daily by an eagle, only to regenerate anew everynight. [1] In individuals who donate one lobe of the liver for transplantation, the remaining cellsproliferate so that the organ soon grows back to its original size. Experimental models of partialhepatectomy have been very useful for defining the mechanisms that stimulate regeneration ofthe liver


Most forms of pathologic hyperplasia are caused by ____________ 

excesses of hormones or growth factorsacting on target cells. Endometrial hyperplasia is an example of abnormal hormone-inducedhyperplasia. Normally, after a menstrual period there is a rapid burst of proliferative activity inthe epithelium that is stimulated by pituitary hormones and ovarian estrogen. It is brought to a


______ is a characteristic response to certain viral infections, such as papillomaviruses,which cause skin warts and several mucosal lesions composed of masses of hyperplasticepithelium. Here, growth factors produced by viral genes or by infected cells may stimulatecellular proliferation



What is the mechanism of Hyperplasia?

Mechanisms of HyperplasiaHyperplasia is the result of growth factor–driven proliferation of mature cells and, in somecases, by increased output of new cells from tissue stem cells.For instance, after partialhepatectomy growth factors are produced in the liver that engage receptors on the survivingcells and activate signaling pathways that stimulate cell proliferation. But if the proliferativecapacity of the liver cells is compromised, as in some forms of hepatitis causing cell injury,hepatocytes can instead regenerate from intrahepatic stem cells.


What is atrophy?

Atrophy is reduced size of an organ or tissue resulting from a decrease in cell size andnumber . Atrophy can be physiologic or pathologic. 


Physiologic atrophy is common during 

normal development. Some embryonic structures, such as the notochord and thyroglossal duct,undergo atrophy during fetal development. The uterus decreases in size shortly afterparturition, and this is a form of physiologic atrophy.


Pathologic atrophy depends on the underlying cause and can be local or generalized. Thecommon causes of atrophy are the following:

* Decreased workload (atrophy of disuse)
* Loss of innervation (denervation atrophy)
* Diminished blood supply
* Inadequate nutrition
* Loss of endocrine stimulation
The fundamental cellular changes associated with atrophy are identical in all of these settings.  


What is the initial response in atrophy?

The initial response is a decrease in cell size and organelles, which may reduce the metabolicneeds of the cell sufficiently to permit its survival. In atrophic muscle, the cells contain fewermitochondria and myofilaments and a reduced amount of rough ER.By bringing into balancethe cell's metabolic demand and the lower levels of blood supply, nutrition, or trophicstimulation, a new equilibrium is achieved. Early in the process atrophic cells may havediminished function, but they are not dead.However, atrophy caused by gradually reducedblood supply may progress to the point at which cells are irreversibly injured and die, often by apoptosis. Cell death by apoptosis also contributes to the atrophy of endocrine organs afterhormone withdrawal.


What is the mechanism of Atrophy?

Atrophy results from decreased protein synthesis and increased protein degradation in cells . Protein synthesis decreases because of reduced metabolic activity.The degradation of cellularproteins occurs mainly by the ubiquitin-proteasome pathway. Nutrient deficiency and disusemay activate ubiquitin ligases, which attach the small peptide ubiquitin to cellular proteins andtarget these proteins for degradation in proteasomes. [3,] [9,] [10] This pathway is also thoughtto be responsible for the accelerated proteolysis seen in a variety of catabolic conditions,including cancer cachexia


In many situations, atrophy is also accompanied by increased ________, with resultingincreases in the number of autophagic vacuoles. 



What is autophagy?

Autophagy (“self eating”) is the process inwhich the starved cell eats its own components in an attempt to find nutrients and survive.Autophagic vacuoles are membrane-bound vacuoles that contain fragments of cellcomponents. The vacuoles ultimately fuse with lysosomes, and their contents are digested bylysosomal enzymes.Some of the cell debris within the autophagic vacuoles may resist digestionand persist as membrane-bound residual bodies that may remain as a sarcophagus in thecytoplasm.An example of such residual bodies is the lipofuscin granules, discussed later in thechapter. When present in sufficient amounts, they impart a brown discoloration to the tissue(brown atrophy). Autophagy is associated with various types of cell injury, and we will discuss itin more detail later.


What is Metaplasia?

Metaplasia is a reversible change in which one differentiated cell type (epithelial ormesenchymal) is replaced by another cell type.It may represent an adaptive substitution ofcells that are sensitive to stress by cell types better able to withstand the adverse environment


What  is the most common type of metaplasia?

The most common epithelial metaplasia is columnar to squamous ( Fig. 1-6 ), as occurs in therespiratory tract in response to chronic irritation. In the habitual cigarette smoker, the normalciliated columnar epithelial cells of the trachea and bronchi are often replaced by stratifiedsquamous epithelial cells.Stones in the excretory ducts of the salivary glands, pancreas, or bileducts may also cause replacement of the normal secretory columnar epithelium by stratifiedsquamous epithelium. A deficiency of vitamin A (retinoic acid) induces squamous metaplasia inthe respiratory epithelium ( Chapter 9 ).In all these instances the more rugged stratifiedsquamous epithelium is able to survive under circumstances in which the more fragilespecialized columnar epithelium might have succumbed. However, the change to metaplasticsquamous cells comes with a price. In the respiratory tract, for example, although the epitheliallining becomes tough, important mechanisms of protection against infection—mucus secretionand the ciliary action of the columnar epithelium—are lost. Thus, epithelial metaplasia is adouble-edged sword and, in most circumstances, represents an undesirable change. Moreover,the influences that predispose to metaplasia, if persistent, may initiate malignant transformationin metaplastic epithelium. Thus, a common form of cancer in the respiratory tract is composedof squamous cells, which arise in areas of metaplasia of the normal columnar epithelium intosquamous epithelium


Metaplasia from squamous to columnar type may also occur, as in __________, in whichthe esophageal squamous epithelium is replaced by intestinal-like columnar cells under theinfluence of refluxed gastric acid.Cancers may arise in these areas; these are typicallyglandular (adeno)carcinomas

Barrett esophagus


What is Connective tissue metaplasia ?

Connective tissue is the formation of cartilage, bone, or adipose tissue(mesenchymal tissues) in tissues that normally do not contain these elements. For example,bone formation in muscle, designated myositis ossificans, occasionally occurs afterintramuscular hemorrhage. This type of metaplasia is less clearly seen as an adaptiveresponse, and may be a result of cell or tissue injury.


What is the mechanism of Metaplasia?

Metaplasia does not result from a change in the phenotype of an already differentiated celltype; instead it is the result of a reprogramming of stem cells that are known to exist in normaltissues, or of undifferentiated mesenchymal cells present in connective tissue.In a metaplasticchange, these precursor cells differentiate along a new pathway.The differentiation of stemcells to a particular lineage is brought about by signals generated by cytokines, growth factors,and extracellular matrix components in the cells' environment. [11,] [12]These external stimulipromote the expression of genes that drive cells toward a specific differentiation pathway.In thecase of vitamin A deficiency or excess, it is known that retinoic acid regulates gene transcriptiondirectly through nuclear retinoid receptors ( Chapter 9 ), which can influence the differentiationof progenitors derived from tissue stem cells. How other external stimuli cause metaplasia isunknown, but it is clear that they too somehow alter the activity of transcription factors thatregulate differentiation.


In Reversible cell injury . In early stages or mild forms of injury, the functional andmorphologic changes are reversible if the damaging stimulus is removed.The hallmarksof reversible injury are _______________ In addition, various intracellularorganelles, such as mitochondria and the cytoskeleton, may also show alterations.

reduced oxidative phosphorylation with resultant depletion ofenergy stores in the form of adenosine triphosphate (ATP), and cellular swelling causedby changes in ion concentrations and water influx.


Cell death. With continuing damage the injury becomes irreversible, at which time thecell cannot recover and it dies. There are two principal types of cell death,____________, which differ in their morphology, mechanisms, and roles in physiology anddisease. [13] [14] [15] 

 necrosis andapoptosis


When damage to membranes is severe, lysosomal enzymesenter the cytoplasm and digest the cell, and cellular contents leak out, resulting in_________. 



In situations when the cell's DNA or proteins are damaged beyond repair, thecell kills itself by ______, a form of cell death that is characterized by nucleardissolution, fragmentation of the cell without complete loss of membrane integrity, andrapid removal of the cellular debris. 



Whereas necrosis is always a pathologic process,apoptosis serves many normal functions and is not necessarily associated with cellinjury. TorF



 Cell death is also sometimes the end result of__________Although it is easier tounderstand these pathways of cell death by discussing them separately, there may bemany connections between them.Both apoptosis and necrosis may be seen inresponse to the same insult, such as ischemia, perhaps at different stages.Apoptosiscan progress to necrosis, and cell death during autophagy may show many of thebiochemical characteristics of apoptosis.



Causes of Cell Injury

* Oxygen Deprivation.
* Physical Agents.
* Chemical Agents and Drugs.
* Infectious Agents.
* Immunologic Reactions.
* Genetic Derangements.
* Nutritional Imbalances.


What is hypoxia?

Hypoxia is a deficiency of oxygen, which causes cell injury by reducing aerobic oxidativerespiration. Hypoxia is an extremely important and common cause of cell injury and cell death. 


Causes of hypoxia include 

reduced blood flow (celled ischemia), inadequate oxygenation of the blood due to cardiorespiratory failure, and decreased oxygen-carrying capacity of the blood, as in anemia or carbon monoxide poisoning (producing a stable carbon monoxyhemoglobin that blocks oxygen carriage) or after severe blood loss.  
 Depending on the severity of the hypoxicstate, cells may adapt, undergo injury, or die. For example, if an artery is narrowed, the tissuesupplied by that vessel may initially shrink in size (atrophy), whereas more severe or suddenhypoxia induces injury and cell death.


What are the morphological alterations in cellular injury? 

Reversible injury is characterized by:
* generalized swelling of the cell and its
* organelles;
* blebbing of the plasma membrane;
* detachment of ribosomes from the ER;
* and clumping of nuclear chromatin.


The morphologic changes of cell injury are associated with 

decreased generation of ATP, loss of cell membrane integrity, defects in protein synthesis, cytoskeletal damage, and DNA damage.
 Within limits, the cell can repair these derangements and, if theinjurious stimulus abates, will return to normalcy.


Severe mitochondrial damage with depletion of ATP and rupture of lysosomal and plasma membranes are typically associated with ___________.

necrosis   Necrosis is the principal outcome in manycommonly encountered injuries, such as those following ischemia, exposure to toxins, variousinfections, and trauma. 


Features of Necrosis

Cell size Enlarged (swelling) Nucleus: Pyknosis ➙ karyorrhexis ➙ karyolysis Cellular contents: Enzymatic digestion; may leak out of cell Adjacent inflammation :Frequent Physiologic or pathologic role :Invariably pathologic (culmination of irreversible cell injury)


Features of Apoptosis

Cell size --Reduced (shrinkage) Nucleus -- Fragmentation into nucleosome-size fragments Plasma membrane - Intact; altered structure, especially orientation of lipids Cellular contents  -Intact; may be released in apoptotic bodies Adjacent inflammation - No Physiologic or pathologic role -  Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury, especially DNA damage


Two features of reversible cell injury can be recognized under the light microscope: ____________. 

cellularswelling and fatty change


__________ appears whenever cells are incapable ofmaintaining ionic and fluid homeostasis and is the result of failure of energy-dependent ionpumps in the plasma membrane. 

Cellular swelling


_________occurs in hypoxic injury and various forms oftoxic or metabolic injury. It is manifested by the appearance of lipid vacuoles in the cytoplasm.It is seen mainly in cells involved in and dependent on fat metabolism, such as hepatocytes andmyocardial cells. The mechanisms of fatty change are discussed later in the chapter.

Fatty change 


__________ is the first manifestation of almost all forms of injury to cells (Fig. 1-9B ). It is a difficult morphologic change to appreciate with the light microscope; it maybe more apparent at the level of the whole organ. When it affects many cells, it causes somepallor, increased turgor, and increase in weight of the organ. On microscopic examination,small clear vacuoles may be seen within the cytoplasm; these represent distended andpinched-off segments of the ER.This pattern of nonlethal injury is sometimes called hydropicchange or vacuolar degeneration.Swelling of cells is reversible. Cells may also showincreased eosinophilic staining, which becomes much more pronounced with progression tonecrosis (described below



The ultrastructural changes of reversible cell injury ( Fig. 1-10B ) include: 

1. Plasma membrane alterations, such as blebbing, blunting, and loss of microvilli2. Mitochondrial changes, including swelling and the appearance of small amorphous densities3. Dilation of the ER, with detachment of polysomes; intracytoplasmic myelin figuresmay be present (see later)4. Nuclear alterations, with disaggregation of granular and fibrillar elements. 


The morphologic appearance of necrosis is the result of _______________ 

denaturation of intracellular proteinsand enzymatic digestion of the lethally injured cell (cells placed immediately in fixative are deadbut not necrotic).  Necrotic cells are unable to maintain membrane integrity and their contents often leak out, a process that may elicit inflammation in the surrounding tissue.The enzymes that digest the necrotic cell are derived from the lysosomes of the dying cells themselves and from the lysosomes of leukocytes that are called in as part of the inflammatory reaction.Digestion of cellular contents and the host response may take hours to develop, and so therewould be no detectable changes in cells if, for example, a myocardial infarct caused suddendeath. The only circumstantial evidence might be occlusion of a coronary artery. The earliest histologic evidence of myocardial necrosis does not become apparent until 4 to 12 hours later.However, because of the loss of plasma membrane integrity, cardiac-specific enzymes andproteins are rapidly released from necrotic muscle and can be detected in the blood as early as2 hours after myocardial cell necrosis. 


What is the microscopic morphology of necrosis?

Necrotic cells show increased eosinophilia in hematoxylin and eosin (H & E)stains, attributable in part to the loss of cytoplasmic RNA (which binds the blue dye,hematoxylin) and in part to denatured cytoplasmic proteins (which bind the red dye, eosin).The necrotic cell may have a more glassy homogeneous appearance than do normal cells, mainly as a result of the loss of glycogen particles ( Fig. 1-9C ). When enzymes havedigested the cytoplasmic organelles, the cytoplasm becomes vacuolated and appears motheaten.Dead cells may be replaced by large, whorled phospholipid masses called myelinfigures that are derived from damaged cell membranes. These phospholipid precipitatesare then either phagocytosed by other cells or further degraded into fatty acids; calcificationof such fatty acid residues results in the generation of calcium soaps.Thus, the dead cellsmay ultimately become calcified. By electron microscopy, necrotic cells are characterized bydiscontinuities in plasma and organelle membranes, marked dilation of mitochondria with theappearance of large amorphous densities, intracytoplasmic myelin figures, amorphousdebris, and aggregates of fluffy material probably representing denatured protein (see Fig.1-10C ).


What is karyolysis?

The basophilia of the chromatin may fade (karyolysis), a change thatpresumably reflects loss of DNA because of enzymatic degradation by endonucleases.


What is pyknosis?

 Asecond pattern (which is also seen in apoptotic cell death) is pyknosis, characterized bynuclear shrinkage and increased basophilia.Here the chromatin condenses into a solid,shrunken basophilic mass.


What is karyorrhexis?

In the third pattern, known as karyorrhexis, the pyknotic nucleusundergoes fragmentation.With the passage of time (a day or two), the nucleus in thenecrotic cell totally disappears.


What are thie patterns of tissue necrosis?

* Coagulative
* Liquefactive
* Gangenous
* Casseous
* Fatty
* Fibrinoid


What is coagulative necrosis?

Coagulative necrosis is a form of necrosis in which the architecture of deadtissues is preserved for a span of at least some days ( Fig. 1-11 ). The affected tissues exhibita firm texture.Presumably, the injury denatures not only structural proteins but also enzymesand so blocks the proteolysis of the dead cells; as a result, eosinophilic, anucleate cells may persist for days or weeks. Ultimately the necrotic cells are removed by phagocytosis of thecellular debris by infiltrating leukocytes and by digestion of the dead cells by the action oflysosomal enzymes of the leukocytes.Ischemia caused by obstruction in a vessel may lead tocoagulative necrosis of the supplied tissue in all organs except the brain. 


What is an infarct?

A localized area ofcoagulative necrosis is called an infarct.


What is liquefactive necrosis?

Liquefactive necrosis, in contrast to coagulative necrosis, is characterized by digestion ofthe dead cells, resulting in transformation of the tissue into a liquid viscous mass.It is seen infocal bacterial or, occasionally, fungal infections, because microbes stimulate theaccumulation of leukocytes and the liberation of enzymes from these cells. 


What is morphologic appearance of Liquefactive necrosis grossly?

The necroticmaterial is frequently creamy yellow because of the presence of dead leukocytes and is calledpus. For unknown reasons, hypoxic death of cells within the central nervous system oftenmanifests as liquefactive necrosis


What is gangrenous necrosis?

Gangrenous necrosis is not a specific pattern of cell death, but the term is commonly usedin clinical practice. It is usually applied to a limb, generally the lower leg, that has lost its bloodsupply and has undergone necrosis (typically coagulative necrosis) involving multiple tissueplanes.When bacterial infection is superimposed there is more liquefactive necrosis becauseof the actions of degradative enzymes in the bacteria and the attracted leukocytes (giving riseto so-called wet gangrene).


What is caseous necrosis?

Caseous necrosis is encountered most often in foci of tuberculous infection ( Chapter 8 ).The term “caseous” (cheeselike) is derived from the friable white appearance of the area ofnecrosis ( Fig. 1-13 ).  


What is the microscopic appearance of caseour necrosis?

On microscopic examination, the necrotic area appears as a collectionof fragmented or lysed cells and amorphous granular debris enclosed within a distinctiveinflammatory border; this appearance is characteristic of a focus of inflammation known as agranuloma ( Chapter 2 ).


What is a granuloma?

On microscopic examination, the necrotic area appears as a collectionof fragmented or lysed cells and amorphous granular debris enclosed within a distinctiveinflammatory border; this appearance is characteristic of a focus of inflammation known as agranuloma ( Chapter 2 ).


Wha is a Fat necrosis ?

is a term that is well fixed in medical parlance but does not in reality denote aspecific pattern of necrosis.Rather, it refers to focal areas of fat destruction, typicallyresulting from release of activated pancreatic lipases into the substance of the pancreas andthe peritoneal cavity.This occurs in the calamitous abdominal emergency known as acute pancreatitis ( Chapter 19 ).In this disorder pancreatic enzymes leak out of acinar cells andliquefy the membranes of fat cells in the peritoneum. The released lipases split thetriglyceride esters contained within fat cells.  


What is the macroscopic appearance of Fat necrosis?

The fatty acids, so derived, combine with calciumto produce grossly visible chalky-white areas (fat saponification), which enable the surgeonand the pathologist to identify the lesions ( Fig. 1-14 ).  


What is the histologic appearance of fat necrosis?.

On histologic examination the necrosistakes the form of foci of shadowy outlines of necrotic fat cells, with basophilic calciumdeposits, surrounded by an inflammatory reaction.


What is a Fibrinoid necrosis?

Fibrinoid necrosis is a special form of necrosis usually seen in immune reactions involvingblood vessels. This pattern of necrosis typically occurs when complexes of antigens andantibodies are deposited in the walls of arteries. Deposits of these “immune complexes,”together with fibrin that has leaked out of vessels, result in a bright pink and amorphousappearance in H&E stains, called “fibrinoid” (fibrin-like) by pathologists ( Fig. 1-15 ). Theimmunologically mediated vasculitis syndromes in which this type of necrosis is seen aredescribed in Chapter 6 .


Ultimately, in the living patient most necrotic cells and their contents disappear by phagocytosisof the debris and enzymatic digestion by leukocytes. If necrotic cells and cellular debris are notpromptly destroyed and reabsorbed, they tend to attract calcium salts and other minerals andto become calcified. This phenomenon, called dystrophic calcification, is considered later in thechapter.

Ultimately, in the living patient most necrotic cells and their contents disappear by phagocytosisof the debris and enzymatic digestion by leukocytes. If necrotic cells and cellular debris are notpromptly destroyed and reabsorbed, they tend to attract calcium salts and other minerals andto become calcified. This phenomenon, called dystrophic calcification, is considered later in thechapter.


What is dystrophic calcification?

If necrotic cells and cellular debris are notpromptly destroyed and reabsorbed, they tend to attract calcium salts and other minerals andto become calcified. This phenomenon, called dystrophic calcification, is considered later in thechapter.


Principles important in the mechanisms of Cell Injury

The cellular response to injurious stimuli depends on the nature of the injury, its duration, and its severity. The consequences of cell injury depend on the type, state, and adaptability of the injured cell. Cell injury results from different biochemical mechanisms acting on several essential cellular components Any injurious stimulus may simultaneously trigger multiple interconnected mechanisms that damage cells.


What are the biochemical mechanisms that may be activated bydifferent injurious stimuli and contribute to cell injury



The major causes of ATP depletionare ____ 

reduced supply of oxygen and nutrients,
mitochondrial damage, and the actions of sometoxins (e.g.,  cyanide). 

 Tissues with a greater glycolytic capacity (e.g., the liver) are able tosurvive loss of oxygen and decreased oxidative phosphorylation better than are tissues withlimited capacity for glycolysis (e.g., the brain).


The major pathway inmammalian cells is 

oxidative phosphorylation of adenosine diphosphate, in a reaction that results in reduction of oxygen by the electron transfer system of mitochondria. The second is the glycolytic pathway, which can generate ATP in the absence of oxygen using glucose derived either from body fluids or from the hydrolysis of glycogen


High-energy phosphate in the form of ATP is required for virtually all synthetic and degradativeprocesses within the cell. These include membrane transport, protein synthesis, lipogenesis,and the deacylation-reacylation reactions necessary for phospholipid turnover. Depletion ofATP to 5% to 10% of normal levels has widespread effects on many critical cellular systems:

The activity of the plasma membrane energy-dependent sodium pump (ouabainsensitive Na + , K + -ATPase) is reduced.
* Cellular energy metabolism is altered Failure of the Ca 2+ pump leads to influx of Ca 2+ , with damaging effects on numerous cellular components, described below.
* With prolonged or worsening depletion of ATP, structural disruption of the protein synthetic apparatus occurs, manifested as detachment of ribosomes from the rough ER and dissociation of polysomes, with a consequent reduction in protein synthesis. In cells deprived of oxygen or glucose, proteins may become misfolded, and misfolded proteins trigger a cellular reaction called the unfolded protein response that may culminate in cell injury and even death.
* Ultimately, there is irreversible damage to mitochondrial and lysosomal membranes, and the cell undergoes necrosis.


What happens when the activity of the plasma membrane energy-dependent sodium pump (ouabainsensitiveNa + , K + -ATPase) is reduced.

 Failure of this active transport system causessodium to enter and accumulate inside cells and potassium to diffuse out. The net gainof solute is accompanied by isosmotic gain of water, causing cell swelling, and dilation ofthe ER.


What happens when the cellular energy metabolism is altered .

 If the supply of oxygen to cells is reduced, as inischemia, oxidative phosphorylation ceases, resulting in a decrease in cellular ATP andassociated increase in adenosine monophosphate. These changes stimulatephosphofructokinase and phosphorylase activities, leading to an increased rate ofanaerobic glycolysis, which is designed to maintain the cell's energy sources bygenerating ATP through metabolism of glucose derived from glycogen. As aconsequence glycogen stores are rapidly depleted . Anaerobic glycolysis results in theaccumulation of lactic acid and inorganic phosphates from the hydrolysis of phosphateesters. This reduces the intracellular pH, resulting in decreased activity of many cellularenzymes


In cells deprived of oxygen or glucose, proteins may become misfolded, and misfoldedproteins trigger a cellular reaction called the _________ response that mayculminate in cell injury and even death.

unfolded protein


Mitochondria are the cell's suppliers of life-sustaining energy in the form of ATP, but they arealso critical players in cell injury and death. [17]Mitochondria can be damaged by:

 increases of cytosolic Ca 2+ , reactive oxygen species (discussed below), and oxygen deprivation, and so they are sensitive to virtually all types of injurious stimuli, including hypoxia and toxins. In addition, mutations in mitochondrial genes are the cause of some inherited diseases


There are two major consequences of mitochondrial damage .

Mitochondrial damage often results in the formation of a high-conductance channel in the mitochondrial membrane, called the mitochondrial permeability transition pore
The mitochondria also sequester between their outer and inner membranes several proteins that are capable of activating apoptotic pathways; these include cytochrome c and proteins that indirectly activate apoptosisinducing enzymes called caspases.


The opening of this conductance channel leads to the loss of mitochondrial membrane potential, resulting in failure of oxidative phosphorylation and progressivedepletion of ATP, culminating in ______. 

necrosis of the cell Note: One of the structural components ofthe mitochondrial permeability transition pore is the protein cyclophilin D, which is atarget of the immunosuppressive drug cyclosporine (used to prevent graft rejection). Insome experimental models of ischemia, cyclosporine reduces injury by preventingopening of the mitochondrial permeability transition pore—an interesting example ofmolecularly targeted therapy for cell injury (although its clinical value is not established).


What are caspases?

cytochrome c and proteins that indirectly activate apoptosisinducing enzymes called caspases.Increased permeability of the outer mitochondrial membrane may result in leakage ofthese proteins into the cytosol, and death by apoptosis


The finding that depleting calcium protects cells from injury induced by a variety of harmful stimuli indicates that calcium ions are important mediators of cell injury. [19]Cytosolic free calcium is normally maintained at very low concentrations (-0.1 μmol) compared with extracellular levels of 1.3 mmol, and most intracellular calcium is sequestered in mitochondria and the ER.Ischemia and certain toxins cause an increase in cytosolic calcium concentration, initially because of_____________, and later resulting from increasedinflux across the plasma membrane ( Fig. 1-19 ). 

 release of Ca 2+ from intracellular stores


Increased intracellular Ca 2+ causes cell injuryby several mechanisms.

The accumulation of Ca 2+ in mitochondria results in opening of the mitochondrial permeability transition pore and, as described above, failure of ATP generation. Increased cytosolic Ca 2+ activates a number of enzymes, with potentially deleterious cellular effects. These enzymes include phospholipases (which cause membrane damage), proteases (which break down both membrane and cytoskeletal proteins), endonucleases (which are responsible for DNA and chromatin fragmentation), and ATPases (thereby hastening ATP depletion). Increased intracellular Ca 2+ levels also result in the induction of apoptosis, by direct activation of caspases and by increasing mitochondrial permeability. [


ACCUMULATION OF OXYGEN-DERIVED FREE RADICALS (OXIDATIVE STRESS)Cell injury induced by free radicals, particularly reactive oxygen species, is an importantmechanism of cell damage in many pathologic conditions, such as :

chemical and radiation injury,
 ischemia-reperfusion injury (induced by restoration of blood flow in ischemic tissue), cellular aging,
and microbial killing by phagocytes.


What are free radicals?

Free radicals are chemical species that have asingle unpaired electron in an outer orbit. Energy created by this unstable configuration isreleased through reactions with adjacent molecules, such as inorganic or organic chemicals—proteins, lipids, carbohydrates, nucleic acids—many of which are key components of cellmembranes and nuclei.Moreover, free radicals initiate autocatalytic reactions, wherebymolecules with which they react are themselves converted into free radicals, thus propagatingthe chain of damage.


What are reactive oxygen species (ROS) ?

are a type of oxygen-derived free radicalwhose role in cell injury is well established. ROS are produced normally in cells duringmitochondrial respiration and energy generation, but they are degraded and removed bycellular defense systems. Thus, cells are able to maintain a steady state in which free radicals may be present transiently at low concentrations but do not cause damage.


What is an oxidative stresS?

When theproduction of ROS increases or the scavenging systems are ineffective, the result is an excessof these free radicals, leading to a condition called oxidative stress.Oxidative stress has beenimplicated in a wide variety of pathologic processes, including cell injury, cancer, aging, and some degenerative diseases such as Alzheimer disease.ROS are also produced in largeamounts by leukocytes, particularly neutrophils and macrophages, as mediators for destroyingmicrobes, dead tissue, and other unwanted substances. Therefore, injury caused by thesereactive compounds often accompanies inflammatory reactions, during which leukocytes arerecruited and activated


Free radicals may be generated within cells in several ways ( Fig. 1-20 ): 

The reduction-oxidation reactions that occur during normal metabolic processes  Absorption of radiant energy Rapid bursts of ROS are produced in activated leukocytes during inflammation Enzymatic metabolism of exogenous chemicals or drugs can generate free radicals that are not ROS but have similar effects Transition metals such as iron and copper donate or accept free electrons during intracellular reactions and catalyze free radical formation, as in the Fenton reaction (H2O2 + Fe 2+ ➙ Fe 3+ + OH + OH-). are not ROS but have similar effects


During this process smallamounts of partially reduced intermediates are produced in which different numbers of electrons have been transferred from O2, these include :

superoxide anion hydrogen peroxide hydroxyl ions


Free radicals are inherently unstable and generally decay spontaneously., for example, is unstable and decays (dismutates) spontaneously into O2 and H2O2 in thepresence of water. In addition, cells have developed multiple nonenzymatic and enzymaticmechanisms to remove free radicals and thereby minimize injury (see Fig. 1-20 ). These includethe following:

* Antioxidants
* iron and copper can catalyze the formation of ROS
* enzymes acts as free radical–scavenging systems and breaks down H2O2 These enzymes are lo-cated near the sites of generation of the oxidants


enzymes acts as free radical–scavenging systems and breaks down H2O2 and O2. These enzymes are lo-cated near the sites of generation of the oxidants and include the following:

* Catalase,
* Superoxide dismutases (SODs)
* Glutathione peroxidase


What is a Catalase?

, present in peroxisomes, decomposes H2O2 (2H2O2 ➙ O2 + 2H2O).


What is Superoxide dismutases (SODs) ?

are found in many cell types and convert O2 to H2O2 (2 + 2H ➙ H2O2 + O2). Thisgroup includes both manganese–SOD, which is localized in mitochondria, andcopper-zinc–SOD, which is found in the cytosol.


What is Glutathione peroxidase?

 also protects against injury by catalyzing free radicalbreakdown (H2O2 + 2GSH ➙ GSSG [glutathione homodimer] + 2H2O, or 2OH +2GSH ➙ GSSG + 2H2O). The intracellular ratio of oxidized glutathione (GSSG)to reduced glutathione (GSH) is a reflection of the oxidative state of the cell andis an important indicator of the cell's ability to detoxify ROS.


Pathologic Effects of Free Radicals.The effects of ROS and other free radicals are wide-ranging, but three reactions areparticularly relevant to cell injury

* Lipid peroxidation in membranes
* Oxidative modification of proteins
* Lesions in DNA


DEFECTS IN MEMBRANE PERMEABILITYEarly loss of selective membrane permeability leading ultimately to overt membrane damage isa consistent feature of most forms of cell injury (except ________) Membrane damage mayaffect the functions and integrity of all cellular membranes



Mechanisms of Membrane Damage.In ischemic cells membrane defects may be the result of ATP depletion and calcium-mediatedactivation of phospholipases (see below).The plasma membrane can also be damaged directlyby various bacterial toxins, viral proteins, lytic complement components, and a variety ofphysical and chemical agents.Several biochemical mechanisms may contribute to membranedamage

* Reactive oxygen species
* Decreased phospholipid synthesis
* Increased phospholipid breakdown
* Cytoskeletal abnormalities


How does Reactive oxygen species damaged the 

. Oxygen free radicals cause injury to cell membranes by lipidperoxidation, discussed earlier


How doeas Decreased phospholipid synthesis damaged the cell membrane?

The production of phospholipids in cells may bereduced as a consequence of defective mitochondrial function or hypoxia, both of whichdecrease the production of ATP and thus affect energy-dependent enzymatic activities.The decreased phospholipid synthesis may affect all cellular membranes, including themitochondria themselves.


How doeas Increased phospholipid breakdown damge the cell membrane?

Severe cell injury is associated with increased degradation of membrane phospholipids, probably due to activation of endogenous phospholipases by increased levels of cytosolic and mitochondrial Ca 2+ . [19]Phospholipid breakdown leads to the accumulation of lipid breakdown products,including unesterified free fatty acids, acyl carnitine, and lysophospholipids, which havea detergent effect on membranes. They may also either insert into the lipid bilayer of the membrane or exchange with membrane phospholipids, potentially causing changes inpermeability and electrophysiologic alterations.


How do cytoskeletal abnormalities damage the cell membrane?

Cytoskeletal abnormalities.Cytoskeletal filaments serve as anchors connecting theplasma membrane to the cell interior. Activation of proteases by increased cytosolic calcium may cause damage to elements of the cytoskeleton. In the presence of cellswelling, this damage results, particularly in myocardial cells, in detachment of the cell membrane from the cytoskeleton, rendering it susceptible to stretching and rupture.


Consequences of Membrane Damage.

* Mitochondrial membrane damage.
* Plasma membrane damage
* Injury to lysosomal membranes


The most important sites of membrane damage during cell injury are the :

mitochondrial membrane, the plasma membrane, and membranes of lysosomes.


What happens when there is mitochondrial membrane damage.?

As discussed above, damage to mitochondrialmembranes results in opening of the mitochondrial permeability transition pore leadingto decreased ATP, and release of proteins that trigger apoptotic death.


What happens when there is Plasma membrane damage? 

Plasma membrane damage results in loss of osmoticbalance and influx of fluids and ions, as well as loss of cellular contents. The cells mayalso leak metabolites that are vital for the reconstitution of ATP, thus further depletingenergy stores.


What happens when there is Injury to lysosomal membranes 

results in leakage of their enzymes into the cytoplasmand activation of the acid hydrolases in the acidic intracellular pH of the injured (e.g.,ischemic) cell. Lysosomes contain RNases, DNases, proteases, phosphatases,glucosidases, and cathepsins. Activation of these enzymes leads to enzymatic digestionof proteins, RNA, DNA, and glycogen, and the cells die by necrosis


the molecular mechanisms connecting most forms of cell injury toultimate cell death have proved elusive, for several reasons. The “point of no return,” at whichthe damage becomes irreversible, is still largely undefined, and there are no reliable morphologic or biochemical correlates of irreversibility.Two phenomena consistentlycharacterize irreversibility—________________________- As mentioned earlier, injury to lysosomal membranesresults in the enzymatic dissolution of the injured cell that is characteristic of necrosis.

the inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) even after resolution of the original injury, and profound disturbances in membrane function.


IThis is the most common type of cell injury in clinical medicine and has been studied extensivelyin humans, in experimental animals, and in culture systems. Hypoxia, referring to reducedoxygen availability, may occur in a variety of clinical settings, described earlier. In ischemia, onthe other hand, the supply of oxygen and nutrients is decreased most often because ofreduced blood flow as a consequence of a mechanical obstruction in the arterial system. It canalso be caused by reduced venous drainage. In contrast to hypoxia, during which energyproduction by anaerobic glycolysis can continue, ischemia compromises the delivery ofsubstrates for glycolysis. Thus, in ischemic tissues, not only is aerobic metabolism compromisedbut anaerobic energy generation also stops after glycolytic substrates are exhausted, orglycolysis is inhibited by the accumulation of metabolites that would have been removedotherwise by blood flow. For this reason, ischemia tends to cause more rapid and severe celland tissue injury than does hypoxia in the absence of ischemia.



What is the mechanism of Mechanisms of Ischemic Cell InjuryThe sequence of events following h

* As the oxygen tension within the cell decreases, there is loss of oxidative phosphorylation and decreased generation of ATP.
* The depletion of ATP results in failure of the sodium pump, with loss of potassium, influx of sodium and water, and cell swelling.
* There is also influx of Ca 2+ , with its many deleterious effects.
* There is progressive loss of glycogen and decreased protein synthesis.  The functional consequences may be severe at this stage. For instance, heart muscle ceases to contract within 60 seconds of coronary occlusion. Note, however, that loss of contractility does not mean
* cell death. If hypoxia continues, worsening ATP depletion causes further deterioration.
* The cytoskeleton disperses, resulting in the loss of ultrastructural features such as microvilli and the
* formation of “blebs” at the cell surface (see Figs. 1-9 and 1-10 )
* . “Myelin figures,” derived from degenerating cellular membranes, may be seen within the cytoplasm (in autophagic vacuoles) or extracellularly. They are thought to result from unmasking of phosphatide groups, promoting the uptake and intercalation of water between the lamellar stacks of membranes.
* At this time the mitochondria are usually swollen, as a result of loss of volume control in these organelles; the
* ER remains dilated; and the entire cell is markedly swollen, with increased concentrations of
* water, sodium, and chloride and a decreased concentration of potassium.
* If oxygen is restored, all of these disturbances are reversible.


 What are myelin figures?

 “Myelin figures,” derived from degenerating cellular membranes, may be seen within the cytoplasm (in autophagic vacuoles) or extracellularly. They are thought to result from unmasking of phosphatide groups, promoting the uptake and intercalation of water between the lamellar stacks of membranes. 


If ischemia persists, irreversible injury and necrosis ensue . Irreversible injury is associatedmorphologically with:

 severe swelling of mitochondria, extensive damage to plasma membranes (giving rise to myelin figures) and swelling of lysosomes (see Fig. 1-10C ). Large, flocculent, amorphous densities develop in the mitochondrial matrix. In the myocardium, these are indications of irreversible injury and can be seen as early as 30 to 40 minutes after ischemia. Massive influx of calcium into the cell then occurs, particularly if the ischemic zone is reperfused. Death is mainly by necrosis, but apoptosis also contributes; the apoptotic pathway is probably activated by release of pro-apoptotic molecules from leaky mitochondria. The cell's components are progressively degraded, and there is widespread leakage of cellular enzymes into the extracellular space and, conversely, entry of extracellular macromolecules from the interstitial space into the dying cells. Finally, the dead cells may become replaced by large masses composed of phospholipids in the form of myelin figures. These are then either phagocytosed by leukocytes or degraded further into fatty acids. Calcification of such fatty acid residues may occur, with the formation of calcium soaps.


Mammalian cells have developed protective responses to hypoxic stress. The best-defined ofthese is induction of a transcription factor called ______________which promotes newblood vessel formation, stimulates cell survival pathways, and enhances anaerobicglycolysis. [27] It remains to be seen if understanding of such oxygen-sensing mechanisms willlead to new strategies for preventing or treating ischemic and hypoxic cell injury.

hypoxia-inducible factor-1, 


Despite many investigations in experimental models there are still no reliable therapeutic approaches for reducing the injurious consequences of ischemia in clinical situations. 

Thestrategy that is perhaps the most useful in ischemic (and traumatic) brain and spinal cord injury is the transient induction of hypothermia (reducing the core body temperature to 92°F). This treatment reduces the metabolic demands of the stressed cells, decreases cell swelling, suppresses the formation of free radicals, and inhibits the host inflammatory response. All ofthese may contribute to decreased cell and tissue injury


What is ischemiareperfusioninjury, is clinically important because it contributes to tissue damage duringmyocardial and cerebral infarction and following therapies to restore blood flow ( Chapters 12and 28 .

Restoration of blood flow to ischemic tissues can promote recovery of cells if they are reversiblyinjured. However, under certain circumstances, when blood flow is restored to cells that have been ischemic but have not died, injury is paradoxically exacerbated and proceeds at anaccelerated pace. As a consequence, reperfused tissues may sustain loss of cells in addition to the cells that are irreversibly damaged at the end of ischemia. This process, called ischemiareperfusion  injury, is clinically important because it contributes to tissue damage during myocardial and cerebral infarction and following therapies to restore blood flow ( Chapters 12and 28 .


How does reperfusion injury occur? The likely answer is that new damaging processes are setin motion during reperfusion, causing the death of cells that might have recoveredotherwise. [29] Several mechanisms have been proposed:

New damage may be initiated during reoxygenation by increased generation of reactive oxygen and nitrogen species from parenchymal and endothelial cells and from infiltrating leukocytes. [ Ischemic injury is associated with inflammation as a result of the production of cytokines and increased expression of adhesion molecules by hypoxic parenchymal and endothelial cells, which recruit circulating neutrophils to reperfused tissue
* Activation of the complement system may contribute to ischemia-reperfusion injury. [


What is apoptosis?

Apoptosis is a pathway of cell death that is induced by a tightly regulated suicide program in which cells destined to die activate enzymes that degrade the cells' own nuclear DNA andnuclear and cytoplasmic proteins.


What are apoptotic bodies?

 Apoptotic cells break up into fragments, called apoptoticbodies, which contain portions of the cytoplasm and nucleus. The plasma membrane of theapoptotic cell and bodies remains intact, but its structure is altered in such a way that thesebecome “tasty” targets for phagocytes.The dead cell and its fragments are rapidly devoured,before the contents have leaked out, and therefore cell death by this pathway does not elicit aninflammatory reaction in the host.The process was recognized in 1972 by the distinctivemorphologic appearance of membrane-bound fragments derived from cells, and named afterthe Greek designation for “falling off.” [37]


CAUSES OF APOPTOSISApoptosis occurs normally both during _________ and  serves to eliminate unwanted, aged or potentially harmful cells.It is also a pathologic event whendiseased cells become damaged beyond repair and are eliminated.

development and throughout adulthood,


Apoptosis in Physiologic SituationsDeath by apoptosis is a normal phenomenon that serves to eliminate cells that are no longerneeded, and to maintain a steady number of various cell populations in tissues. It is importantin the following physiologic situations:

The programmed destruction of cells during embryogenesis , including implantation, organogenesis, developmental involution, and metamorphosis. Involution of hormone-dependent tissues upon hormone withdrawal , such as endometrial cell breakdown during the menstrual cycle, ovarian follicular atresia in menopause, the regression of the lactating breast after weaning, and prostatic atrophy after castration. Cell loss in proliferating cell populations , such as immature lymphocytes in the bone marrow and thymus that fail to express useful antigen receptors ( Chapter 6 ), B lymphocytes in germinal centers, and epithelial cells in intestinal crypts, so as to maintain a constant number (homeostasis).
* Elimination of potentially harmful self-reactive lymphocytes , either before or after they have completed their maturation, so as to prevent reactions against one's own tissues Death of host cells that have served their useful purpose, such as neutrophils in an acute inflammatory response, and lymphocytes at the end of an immune response


Apoptosis in Pathologic Conditions Apoptosis eliminates cells that are injured beyond repair without eliciting a host reaction, thus limiting collateral tissue damage. Death by apoptosis is responsible for loss of cells in a variety of pathologic states:

* DNA damage
* Accumulation of misfolded proteins
* Cell death in certain infections, particularly viral infections Pathologic atrophy in parenchymal organs after duct obstruction , such as occurs in the pancreas, parotid gland, and kidney



* Cell shrinkage
* Chromatin condensation
* Formation of cytoplasmic blebs and apoptotic bodies
* Phagocytosis of apoptotic cells or cell bodies, usually by macrophages
Plasma membranes are thought to remain intact during apoptosis, until the last stages, when they become permeable to normally retained solutes. This classical description is accurate with respect to apoptosis during physiologic conditions such as embryogenesis and deletion pathway when there is advanced ATP depletion and membrane damage.of immune cells. However, forms of cell death with features of necrosis as well as of apoptosis are not uncommon after many injurious stimuli. [39] Under such conditions the severity rather than the nature of the stimulus determines the pathway of cell death, necrosis being the majorpathway when there is advanced ATP depletion and membrane damage.


What is the appearance of apoptosis historlogically?

On histologic examination, in tissues stained with hematoxylin and eosin, the apoptotic cell appears as a round or oval mass of intensely eosinophilic cytoplasm with fragments of densenuclear chromatin ( Fig. 1-22A ).Because the cell shrinkage and formation of apoptoticbodies are rapid and the pieces are quickly phagocytosed, considerable apoptosis may occur in tissues before it becomes apparent in histologic sections.In addition, apoptosis—in contrast to necrosis—does not elicit inflammation, making it more difficult to detecthistologically.


Biochemical Features of Apoptosis

* Activation of Caspases
* DNA and Protein Breakdown.
* Membrane Alterations and Recognition by Phagocytes.


 What are caspases?

A specific feature of apoptosis is the activation of several members of a family of cysteine proteases named caspases. [40]The term caspase is based on two properties of this family ofenzymes: the “c” refers to a cysteine protease (i.e., an enzyme with cysteine in its active site), and “aspase” refers to the unique ability of these enzymes to cleave after aspartic acid residues. 


The caspase family, now including more than 10 members, can be divided functionallyinto two groups—_________—depending on the order in which they are activatedduring apoptosis.

initiator and executioner


 Initiator caspases include ________. 

caspase-8 and caspase-9


Several other caspases,including _______, serve as executioners. Like many proteases, caspasesexist as inactive pro-enzymes, or zymogens, and must undergo an enzymatic cleavage tobecome active. The presence of cleaved, active caspases is a marker for cells undergoingapoptosis ( Fig. 1-22C ). We will discuss the roles of these enzymes in apoptosis later in thissection.

caspase-3 and caspase-6


The plasma membrane of apoptotic cells changes in ways that promote the recognition of the dead cells by phagocytes.One of these changes is ____________

the movement of some phospholipids(notably phosphatidylserine) from the inner leaflet to the outer leaflet of the membrane, wherethey are recognized by a number of receptors on phagocytes. These lipids are also detectable by binding of a protein called annexin V; thus, annexin V staining is commonly used to identifyapoptotic cells. The clearance of apoptotic cells by phagocytes is described later.


MECHANISMS OF APOPTOSIS All cells contain intrinsic mechanisms that signal death or survival, and apoptosis results froman imbalance in these signals

* The Intrinsic (Mitochondrial) Pathway of Apoptosis
* The Extrinsic (Death Receptor–Initiated) Pathway of Apoptosis
* The Execution Phase of Apoptosis
* Removal of Dead Cells


The process of apoptosis may be divided into an ___________ and _______________.

initiation phase, during which some caspases become catalytically active,
 and an execution phase, during which other caspases trigger the degradation of critical cellular components


 Initiation of apoptosis occurs principally by signalsfrom two distinct pathways:________________-( Fig. 1-24 ). [42]These pathways are induced by distinct stimuliand involve different sets of proteins, although there is some cross-talk between them. Both pathways converge to activate caspases, which are the actual mediators of cell death.

 the intrinsic, or mitochondrial, pathway, and the extrinsic, or death receptor–initiated, pathway 


The Intrinsic (Mitochondrial) Pathway of Apoptosis

The mitochondrial pathway is the major mechanism of apoptosis in all mammalian cells, and its role in a variety of physiologic and pathologic processes is well established. This pathway of apoptosis is the result of increased mitochondrial permeability and release of pro-apoptotic molecules (death inducers) into the cytoplasm ( Fig. 1-25 ). [42]
Mitochondria are remarkable organelles in that they contain proteins such as cytochrome c that are essential for life, but
some of the same proteins, when released into the cytoplasm (an indication that the cell is not healthy), initiate the suicide program of apoptosis.


How is apoptosis regulated?

 There are more than20 members of the Bcl family, and most of them function to regulate apoptosis. The release of these mitochondrial proteinsis controlled by a finely orchestrated balance between pro- and anti-apoptotic members of theBcl family of proteins. [43] This family is named after Bcl-2, which was identified as an oncogenein a B-cell lymphoma and is homologous to the C. elegans protein Ced-9. There are more than20 members of the Bcl family, and most of them function to regulate apoptosis.Growth factorsand other survival signals stimulate production of anti-apoptotic proteins, the main ones beingBcl-2, Bcl-x, and Mcl-1. These proteins normally reside in the cytoplasm and in mitochondrialmembranes, where they control mitochondrial permeability and prevent leakage ofmitochondrial proteins that have the ability to trigger cell death


When cells are deprived of survival signals or their DNA is damaged, or misfolded proteins induce ER stress,sensors of damage or stress are activated.These sensors are also members of the Bcl family,and they include proteins called __________that contain a single “Bcl-2 homologydomain” (the third of the four such domains present in Bcl-2) and are called “BH3-onlyproteins.”The sensors in turn activate two critical (proapoptotic) effectors, Bax and Bak, whichform oligomers that insert into the mitochondrial membrane and create channels that allowproteins from the inner mitochondrial membrane to leak out into the cytoplasm. BH3-onlyproteins may also bind to and block the function of Bcl-2 and Bcl-x.

Bim, Bid, and Bad 


The sensors in turn activate two critical (proapoptotic) effectors, _____, whichform oligomers that insert into the mitochondrial membrane and create channels that allowproteins from the inner mitochondrial membrane to leak out into the cytoplasm. BH3-onlyproteins may also bind to and block the function of Bcl-2 and Bcl-x.

Bax and Bak,


  What is the role of cytochrom c in apoptosis?  

The net result of Bax-Bak activation coupled with lossof the protective functions of the anti-apoptotic Bcl family members is the release into the cytoplasm of several mitochondrial proteins that can activate the caspase cascade ( Fig. 1-25B). One of these proteins is cytochrome c, well known for its role in mitochondrial respiration. Once released into the cytosol, cytochrome c binds to a protein called Apaf-1 (apoptosisactivating factor-1, homologous to Ced-4 in C.elegans), which forms a wheel-like hexamer that has been called the apoptosome. [44]This complex is able to bind caspase-9, the critical initiator caspase of the mitochondrial pathway, and the enzyme cleaves adjacent caspase-9 molecules, thus setting up an auto-amplification process. 


What is caspase 9?

the critical initiator caspase of the mitochondrial pathway, and the enzyme cleaves adjacent caspase-9 molecules, thus setting up an auto-amplification process. 


What are the Other mitochondrial proteins, ___________, enter the cytoplasm, where they bind to and neutralizecytoplasmic proteins that function as physiologic inhibitors of apoptosis (called IAPs).Thenormal function of the IAPs is to block the activation of caspases, including executioners likecaspase-3, and keep cells alive. [45,] [46] Thus, the neutralization of these IAPs permits theinitiation of a caspase cascade.

arcane names like Smac/DIABLO


There is some evidence that the intrinsic pathway of apoptosis can be triggered without a role or mitochondria. [47]T or F

TApoptosis may be initiated by caspase activation upstream ofmitochondria, and the subsequent increase in mitochondrial permeability and release of proapoptoticmolecules serve to amplify the death signal. However, mechanisms of apoptosisinvolving mitochondria-independent initiation are not well defined.


What is the The Extrinsic (Death Receptor–Initiated) Pathway of Apoptosis)?

This pathway is initiated by engagement of plasma membrane death receptors on a variety ofcells. [48] [49] [50]


Death receptors are members of the _________ that contain acytoplasmic domain involved in protein-protein interactions that is called the death domainbecause it is essential for delivering apoptotic signals.

TNF receptor family  Some TNF receptor family members donot contain cytoplasmic death domains; their function is to activate inflammatory cascades [Chapter 2 ], and their role in triggering apoptosis is much less established.)


 (The best-knowndeath receptors are the___________ and a related protein called ____________,but several others have been described.

 type 1 TNF receptor (TNFR1) Fas (CD95)


What is FasL?

The ligand for Fas is called Fas ligand (FasL).FasL is expressed on T cells that recognize selfantigens (and functions to eliminate self-reactive lymphocytes), and on some cytotoxic T lymphocytes (which kill virus-infected and tumor cells)


The Extrinsic (Death Receptor–Initiated) Pathway of Apoptosis is inhibited by?

This pathway of apoptosis can be inhibited by a protein calledFLIP, which binds to pro-caspase-8 but cannot cleave and activate the caspase because itlacks a protease domain. [51] Some viruses and normal cells produce FLIP and use this inhibitor to protect themselves from Fas-mediated apoptosis.


What happens when Fas binds to FasL?

When FasL binds to Fas, three or moremolecules of Fas are brought together, and their cytoplasmic death domains form a binding sitefor an adapter protein that also contains a death domain and is called FADD (Fas-associateddeath domain). FADD that is attached to the death receptors in turn binds an inactive form of caspase-8 (and, in humans, caspase-10), again via a death domain.


We have described the extrinsic and intrinsic pathways for initiating apoptosis as distinctbecause they involve fundamentally different molecules for their initiation, but there may be interconnections between them.For instance, in hepatocytes and several other cell types, Fassignaling activates a BH3-only protein called ______, which then activates the mitochondrialpathway.



What happens in the Execution Phase of Apoptosis?

The two initiating pathways converge to a cascade of caspase activation, which mediates thefinal phase of apoptosis. As we have seen, the mitochondrial pathway leads to activation of theinitiator caspase-9, and the death receptor pathway to the initiators caspase-8 and -10. After aninitiator caspase is cleaved to generate its active form, the enzymatic death program is set in motion by rapid and sequential activation of the executioner caspases. Executioner caspases,such as caspase-3 and -6, act on many cellular components. For instance, these caspases,once activated, cleave an inhibitor of a cytoplasmic DNase and thus make the DNaseenzymatically active; this enzyme induces the characteristic cleavage of DNA into nucleosomesizedpieces, described earlier. Caspases also degrade structural components of the nuclearmatrix, and thus promote fragmentation of nuclei. Some of the steps in apoptosis are not fullydefined. For instance, we do not know how the structure of the plasma membrane is changed inapoptotic cells, or how membrane blebs and apoptotic bodies are formed.


What is the caspase of mitochondrial pathway or intrinsic pathway?

mitochondrial pathway leads to activation of theinitiator caspase-9


, death receptor pathway to the initiators. After aninitiator caspase is cleaved to generate its active form, the enzymatic death program is set in motion by rapid and sequential activation of the executioner caspases

 caspase-8 and -10


Executioner caspases, such as ________, act on many cellular components. For instance, these caspases,once activated, cleave an inhibitor of a cytoplasmic DNase and thus make the DNaseenzymatically active; this enzyme induces the characteristic cleavage of DNA into nucleosomesizedpieces, described earlier. Caspases also degrade structural components of the nuclear matrix, and thus promote fragmentation of nuclei. Some of the steps in apoptosis are not fully refined. For instance, we do not know how the structure of the plasma membrane is changed inapoptotic cells, or how membrane blebs and apoptotic bodies are formed.

caspase-3 and -6


How does removal of cell is done in apoptosis?

The formation of apoptotic bodies breaks cells up into “bite-sized” fragments that are edible forphagocytes.Apoptotic cells and their fragments also undergo several changes in their membranes that actively promote their phagocytosis so they are cleared before they undergosecondary necrosis and release their cellular contents (which can result in injurious inflammation). In healthy cells phosphatidylserine is present on the inner leaflet of the plasma membrane, but in apoptotic cells this phospholipid “flips” out and is expressed on the outerlayer of the membrane, where it is recognized by several macrophage receptors.Cells that aredying by apoptosis secrete soluble factors that recruit phagocytes. [52]Some apoptotic bodiesexpress thrombospondin, an adhesive glycoprotein that is recognized by phagocytes, and macrophages themselves may produce proteins that bind to apoptotic cells (but not to live cells) and thus target the dead cells for engulfment. Apoptotic bodies may also become coated withnatural antibodies and proteins of the complement system, notably C1q, which are recognized by phagocytes. [53] Thus, numerous receptors on phagocytes and ligands induced onapoptotic cells are involved in the binding and engulfment of these cells.This process ofphagocytosis of apoptotic cells is so efficient that dead cells disappear, often within minutes,without leaving a trace, and inflammation is absent even in the face of extensive apoptosis.


CLINICO-PATHOLOGIC CORRELATIONS: APOPTOSIS IN HEALTH AND DISEASE Examples of ApoptosisCell death in many situations is known to be caused by apoptosis, and the selected exampleslisted below illustrate the role of this death pathway in normal physiology and in disease.

* Growth Factor Deprivation.
* DNA Damage.
* Protein Misfolding.
* Apoptosis Induced By the TNF Receptor Family.
* Cytotoxic T Lymphocyte–Mediated Apoptosis.


Which cells are affected of growth hormone deprivaption that leads to apoptosis?

* Hormone-sensitive cells deprived of the relevant hormone,
* lymphocytes that are not stimulated by antigens and cytokines,
* and neurons deprived of nerve growth factor die by apoptosis.
 In all these situations, apoptosis is triggered by the intrinsic (mitochondrial) pathway and is attributable to decreased synthesis of Bcl-2 and Bcl-x and activation of Bim and other proapoptotic members of the Bcl family.


Exposure of cells to radiation or chemotherapeutic agents induces apoptosis by a mechanismthat is initiated by DNA damage (genotoxic stress) and that involves the _____________ [55] 

tumor-suppressor genep53.p53 protein accumulates in cells when DNA is damaged, and it arrests the cell cycle (at the G1 phase) to allow time for repair ( Chapter 7 ).However, if the damage is too great to be repaired successfully, p53 triggers apoptosis. When p53 is mutated or absent (as it is in certain cancers), it is incapable of inducing apoptosis, so that cells with damaged DNA are allowed to survive. In such cells the DNA damage may result in mutations or translocations that lead to neoplastic transformation ( Chapter 7 ). Thus, p53 serves as a critical “life or death” switch following genotoxic stress. The mechanism by which p53 triggers the distal death effector machinery—the caspases—is complex but seems to involve its function in transcriptional activation. Among the proteins whose production is stimulated by p53 are several pro-apoptotic members of the Bcl family, notably Bax, Bak, and some BH3-only proteins, mentioned earlier. 


What is an unfolded protein response

Chaperones in the ER control the proper folding of newly synthesized proteins, and misfolded polypeptides are ubiquitinated and targeted for proteolysis in proteasomes. If, however,unfolded or misfolded proteins accumulate in the ER, because of inherited mutations or stresses, they trigger a number of cellular responses, collectively called the unfolded proteinresponse. [56,] [57]This unfolded protein response activates signaling pathways that increasethe production of chaperones, enhance proteasomal degradation of abnormal proteins, andslow protein translation, thus reducing the load of misfolded proteins in the cell ( Fig. 1-27 ).


What is the ER stress?

However, if this cytoprotective response is unable to cope with the accumulation of misfolded proteins, the cell activates caspases and induces apoptosis. [58] [59] [60] This process is called ER stress.Intracellular accumulation of abnormally folded proteins, caused by genetic utations, aging, or unknown environmental factors, is now recognized as a feature of a umber of neurodegenerative diseases, including Alzheimer, Huntington, and Parkinsondiseases ( Chapter 28 ), and possibly type 2 diabetes. [61] Deprivation of glucose and oxygen,and stress such as heat, also result in protein misfolding, culminating in cell injury and death.


What are chaperones?

Chaperones, such as heat shock proteins (Hsp), protect unfolded or partially folded proteins from degradation and guide proteins into organelles. B


The cytokine__________is an important mediator of the inflammatory reaction ( Chapter 2 ), but it is also capable ofinducing apoptosis.TNF-mediated death is readily demonstrated in cell cultures, but its physiologic or pathologic significance in vivo is not known.In fact, the major physiologicfunctions of TNF are mediated not by inducing apoptosis but by activating the important transcription factor NF-κB (nuclear factor-κB), which promotes cell survival by stimulatingsynthesis of anti-apoptotic members of the Bcl-2 family and, as we shall see in Chapter 2 ,activates a number of inflammatory responses. Since TNF can induce cell death and promotecell survival, what determines this yin and yang of its action? The answer is unclear, but itprobably depends on which signaling proteins attach to the TNF receptor after binding of thecytokine.

 TNF (The name “tumor necrosis factor” arose not because the cytokine kills tumor cells directly but because it induces thrombosis of tumor blood vessels, resulting inischemic death of the tumor.) 


W hat are granzymes?

Cytotoxic T lymphocytes (CTLs) recognize foreign antigens presented on the surface of infected host cells ( Chapter 6 ). Upon activation, CTLs secrete perforin, a transmembranepore-forming molecule, which promotes entry of the CTL granule serine proteases called granzymes. Granzymes have the ability to cleave proteins at aspartate residues and thusactivate a variety of cellular caspases. [63] In this way the CTL kills target cells by directlyinducing the effector phase of apoptosis. CTLs also express FasL on their surface and may killtarget cells by ligation of Fas receptors.


Disorders Associated with Dysregulated ApoptosisDysregulated

Disorders associated with defective apoptosis and increased cell survival .
* mutations in p53 are subjected to DNA damage, the cells not only fail to die but are susceptible to the accumulation of mutations because of defective DNA repair, and these abnormalities can give rise to cancer
* autoimmune disorders
* Disorders associated with increased apoptosis and excessive cell death


Disorders associated with increased apoptosis and excessive cell death . Thesediseases are characterized by a loss of cells and include

 (1) neurodegenerative diseases, manifested by loss of specific sets of neurons, in which apoptosis is causedby mutations and misfolded proteins ( Chapter 28 );(2) ischemic injury, as in myocardialinfarction ( Chapter 12 ) and stroke ( Chapter 28 ); and (3) death of virus-infected cells ,in many viral infections ( Chapter 8 ).


What is autophagy?

Autophagy is a process in which a cell eats its own contentsIt is a survival mechanism in timesof nutrient deprivation, when the starved cell lives by cannibalizing itself and recycling thedigested contents.


What happens in autophagy?

In this process intracellular organelles and portions of cytosol are first sequestered from the cytoplasm in an autophagic vacuole, which subsequently fuses with lysosomes to form an autophagolysosome, and the cellular components are digested by lysosomal enzymes ( Fig. 1-28 ). [64,] [65] Interest in autophagy has been spurred by the finding that it is regulated by a defined set of “autophagy genes” (called Atgs) in single-celled organisms and mammalian cells. The products of many of these genes function in the creationof the autophagic vacuole, but how they do so is unknown. It has also been suggested that autophagy triggers cell death that is distinct from necrosis and apoptosis. [66]However, the mechanism of this type of cell death is not known, nor is it clear that the cell death is caused by autophagy rather than by the stress that triggers autophagy. Nevertheless, autophagy has been invoked as a mechanism of cell loss in various diseases, including degenerative diseasesof the nervous system and muscle; in many of these disorders, the damaged cells containabundant autophagic vacuoles.


One of the manifestations of metabolic derangements in cells is the intracellular accumulation ofabnormal amounts of various substances.The stockpiled substances fall into two categories: 

1) a normal cellular constituent , such as water, lipids, proteins, and carbohydrates, that accumulates in excess; or (2) an abnormal substance, either exogenous, such as a mineral or products of infectious agents, or endogenous, such as a product of abnormal synthesis or metabolism.  Note : These substances may accumulate either transiently or permanently, and they maybe harmless to the cells, but on occasion they are severely toxic. The substance may belocated in either the cytoplasm (frequently within phagolysosomes) or the nucleus. In someinstances the cell may be producing the abnormal substance, and in others it may be merelystoring products of pathologic processes occurring elsewhere in the body.


Many processes result in abnormal intracellular accumulations, but most accumulations areattributable to four types of abnormalities

1. A normal endogenous substance is produced at a normal or increased rate, but the rate of metabolism is inadequate to remove it. Examples of this type of process are fattychange in the liver and reabsorption protein droplets in the tubules of the kidneys (seelater).2. An abnormal endogenous substance, typically the product of a mutated gene, accumulates because of defects in protein folding and transport and an inability to degrade the abnormal protein efficiently. Examples include the accumulation of mutated α1-antitrypsin in liver cells ( Chapter 18 ) and various mutated proteins in degenerative disorders of the central nervous system ( Chapter 28 ).3. A normal endogenous substance accumulates because of defects, usually inherited, in enzymes that are required for the metabolism of the substance. Examples includediseases caused by genetic defects in enzymes involved in the metabolism of lipid and carbohydrates, resulting in intracellular deposition of these substances, largely inlysosomes. 4. An abnormal exogenous substance is deposited and accumulates because the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites. Accumulations of carbon particles and nonmetabolizable chemicals suchas silica are examples of this type of alteration.


Intracellular Accumulations



What is steatosis?

The terms steatosis and fatty change describe abnormal accumulations of triglycerides within parenchymal cells. Fatty change is often seen in the liver because it is the major organ involved in fat metabolism, but it also occurs in heart, muscle, and kidney.


The causes of steatosis include :

toxins, protein malnutrition, diabetes mellitus, obesity, and anoxia.


In developed nations the most common causes of significant fatty change in the liver (fatty liver) are:

 alcohol abuse and nonalcoholic fatty liver disease, which is often associated with diabetes and obesity


What are the mechanism that account for the accumution of TG in liver?

Different mechanisms account for triglyceride accumulation in the liver. 
* Free fatty acids from adipose tissue or ingested food are normally transported into hepatocytes. In the liver they are esterified to triglycerides, converted into cholesterol or phospholipids, or oxidized to ketone bodies.
* Some fatty acids are synthesized from acetate as well. Release of triglycerides from the hepatocytes requires association with apoproteins to form lipoproteins, which may then be transported from the blood into the tissues ( Chapter 4 ).
* Excess accumulation of triglycerides within the liver may result from excessive entry or defective metabolism and export of lipids ( Fig. 1-30A ).
* Several such defects are induced by alcohol, a hepatotoxin that alters mitochondrial and microsomal functions, leading to increased synthesis and reduced breakdown of lipids ( Chapter 18 ).
* CCl4 and protein malnutrition cause fatty change by reducing synthesis of apoproteins, hypoxia inhibits fatty acid oxidation, and starvation increases fatty acid mobilization from peripheral stores.


The significance of fatty change depends on the cause and severity of the accumulation. Whenmild it may have no effect on cellular function. More severe fatty change may impair cellularfunction and may be a harbinger of cell death. T or F



What is the morphology of fatty change?

Fatty change is most often seen in the liver and heart. In all organs fatty change appears as clear vacuoles within parenchymal cells.Intracellular accumulations ofwater or polysaccharides (e.g., glycogen) may also produce clear vacuoles. 


The identification of lipids requires the avoidance of fat solvents commonly used in paraffinembedding for routine hematoxylin and eosin stains.To identify the fat, it is necessary to prepare frozen tissue sections of either fresh or aqueous formalin-fixed tissues. The sectionsmay then be stained with___________ both of which impart an orange-red color tothe contained lipids. 

 Sudan IV or Oil Red-O,


The periodic acid-Schiff (PAS) reaction, coupled with digestion by the enzyme diastase, is used to identify___ although it is not specific.When neither fatnor polysaccharide can be demonstrated within a clear vacuole, it is presumed to containwater or fluid with a low protein content.



What is the morpthological appearance of fat in the liver?

Liver. In the liver, mild fatty change may not affect the gross appearance.With progressive accumulation, the organ enlarges and becomes increasingly yellow until, in extremeinstances, the liver may weigh two to four times normal and be transformed into a brightyellow, soft, greasy organ.


How does fatty change begins?

Fatty change begins with the development of minute, membrane-bound inclusions(liposomes) closely applied to the ER. Accumulation of fat is first seen by light microscopy assmall vacuoles in the cytoplasm around the nucleus.As the process progresses thevacuoles coalesce, creating cleared spaces that displace the nucleus to the periphery of thecell ( Fig. 1-30B ).Occasionally contiguous cells rupture and the enclosed fat globulescoalesce, producing so-called fatty cysts.


What is the morphological appearance of fat in the heart?

Heart. Lipid is found in cardiac muscle in the form of small droplets, occurring in two patterns.  In one, prolonged moderate hypoxia, such as that produced by profound anemia, causes intracellular deposits of fat, which create grossly apparent bands of yellowed myocardium alternating with bands of darker, red-brown, uninvolved myocardium (tigered
effect). 2. The other pattern of fatty change is produced by more profound hypoxia or by some forms of myocarditis (e.g., diphtheria infection) and shows more uniformly affected myocytes.


The cellular metabolism of cholesterol (discussed in detail in Chapter 5 ) is tightly regulatedsuch that most cells use cholesterol for the synthesis of cell membranes without intracellularaccumulation of cholesterol or cholesterol esters. Accumulations manifested histologically byintracellular vacuoles are seen in several pathologic processes.

* Atherosclerosis
* Xanthomas.
* Cholesterolosis.
* Niemann-Pick disease, type C.


What are xanthomas?

Xanthomas.Intracellular accumulation of cholesterol within macrophages is also characteristic of acquired and hereditary hyperlipidemic states.Clusters of foamy cellsare found in the subepithelial connective tissue of the skin and in tendons, producingtumorous masses known as xanthomas.


What is cholesterolosis?

Cholesterolosis.This refers to the focal accumulations of cholesterol-ladenmacrophages in the lamina propria of the gallbladder ( Fig. 1-31 ). The mechanism ofaccumulation is unknown.


What is Niemann-Pick disease, type C?.

 This lysosomal storage disease is caused by mutationsaffecting an enzyme involved in cholesterol trafficking, resulting in cholesterolaccumulation in multiple organs


Intracellular accumulations of proteins usually appear as ___________ 

rounded, eosinophilic droplets,vacuoles, or aggregates in the cytoplasm. By electron microscopy they can be amorphous,fibrillar, or crystalline in appearance. In some disorders, such as certain forms of amyloidosis,abnormal proteins deposit primarily in extracellular spaces


Excesses of proteins within the cells sufficient to cause morphologically visible accumulationhave diverse causes.

* Reabsorption droplets in proximal renal tubules are seen in renal diseases associated with protein loss in the urine (proteinuria). The proteins that accumulate may be normal secreted proteins that are produced in excessive amounts, as occurs in certain plasma cells engaged in active synthesis of immunoglobulins.
* Defective intracellular transport and secretion of critical proteins
* Accumulation of cytoskeletal proteins
* Aggregation of abnormal proteins


Indisorders with heavy protein leakage across the glomerular filter there is increased reabsorption of the protein into vesicles, and the protein appears as_________( Fig. 1-32 ).The process is reversible; ifthe proteinuria diminishes, the protein droplets are metabolized and disappear.

 pink hyalinedroplets within the cytoplasm of the tubular cell 


What are russell bodies?.

The ER becomes hugely distended, producing large, homogeneous eosinophilic inclusions called Russell bodies


Give an example of Defective intracellular transport and secretion of critical proteins

In α1-antitrypsindeficiency, mutations in the protein significantly slow folding, resulting in the buildup of partially folded intermediates, which aggregate in the ER of the liver and are notsecreted.The resultant deficiency of the circulating enzyme causes emphysema (Chapter 15 ). In many of these diseases the pathology results not only from loss ofprotein function but also ER stress caused by the misfolded proteins, culminating inapoptotic death of cells (discussed above).


There are several types of cytoskeletal proteins,including microtubules (20–25 nm in diameter), thin actin filaments (6–8 nm), thickmyosin filaments (15 nm) and intermediate filaments (10 nm). Intermediate filaments,which provide a flexible intracellular scaffold that organizes the cytoplasm and resistsforces applied to the cell, [68] are divided into five classes – 

keratin filaments (characteristic of epithelial cells), neurofilaments (neurons), desmin filaments (muscle cells), vimentin filaments (connective tissue cells), and glial filaments (astrocytes).
  Accumulations of keratin filaments and neurofilaments are associated with certain types of cell injury.Alcoholic hyaline is an eosinophilic cytoplasmic inclusion in liver cells that is characteristic of alcoholic liver disease, and is composed predominantly of keratin intermediate filaments ( Chapter 18 ). The neurofibrillary tangle found in the brain in Alzheimer disease contains neurofilaments and other proteins.


 Certain forms of amyloidosis ( Chapter 6 ) fall in this category of diseases. These disorders are sometimes called proteinopathies or protein-aggregationdiseases.

Aggregation of abnormal proteins . Abnormal or misfolded proteins may deposit in tissues and interfere with normal functions. The deposits can be intracellular,extracellular, or both, and the aggregates may either directly or indirectly cause the pathologic changes. 


What is a hyaline change?

The term hyaline usually refers to an alteration within cells or in the extracellular space that gives a homogeneous, glassy, pink appearance in routine histologic sections stained withhematoxylin and eosin.It is widely used as a descriptive histologic term rather than a specific marker for cell injury.This morphologic change is produced by a variety of alterations and does not represent a specific pattern of accumulation.Intracellular accumulations of protein,described earlier (reabsorption droplets, Russell bodies, alcoholic hyaline), are examples ofintracellular hyaline deposits.


What are glycogen storage diseases, or glycogenoses?

Glycogen is a readily available energy source stored in the cytoplasm of healthy cells.Excessive intracellular deposits of glycogen are seen in patients with an abnormality in either glucose or glycogen metabolism. Whatever the clinical setting, the glycogen masses appear as clear vacuoles within the cytoplasm. Glycogen dissolves in aqueous fixatives; for its localization,tissues are best fixed in absolute alcohol.Staining with Best carmine or the PAS reactionimparts a rose-to-violet color to the glycogen, and diastase digestion of a parallel section before staining serves as a further control by hydrolyzing the glycogen.Diabetes mellitus is the prime example of a disorder of glucose metabolism.In this diseaseglycogen is found in renal tubular epithelial cells, as well as within liver cells, β cells of the isletsof Langerhans, and heart muscle cells.Glycogen accumulates within the cells in a group of related genetic disorders that are collectively referred to as the glycogen storage diseases, or glycogenoses ( Chapter 5 ). Inthese diseases enzymatic defects in the synthesis or breakdown of glycogen result in massiveaccumulation, causing cell injury and cell death.


The most common exogenous pigment is___________), a ubiquitous air pollutant of urbanlife. 

 carbon (coal dust


When coal dust is inhaled it is picked up by macrophages within the alveoli and is then transported through lymphatic channels to the regional lymph nodes in the tracheobronchial region.Accumulations of this pigment blacken the tissues of the lungs ____________and the involvedlymph nodes.In coal miners the aggregates of carbon dust may induce a fibroblastic reaction oreven emphysema and thus cause a serious lung disease known as coal worker's pneumoconiosis ( Chapter 15 ).



_______ is a form of localized, exogenous pigmentation of theskin.  The pigments inoculated are phagocytosed by dermal macrophages, in which they residefor the remainder of the life of the embellished (sometimes with embarrassing consequences forthe bearer of the tattoo!). The pigments do not usually evoke any inflammatory response.



Endogenous igments

* Lipofuscin
* Melanin
* Hemosiderin


What is lipofuscin?

Lipofuscin is an insoluble pigment, also known as lipochrome or wear-and-tear pigment.Lipofuscin is composed of polymers of lipids and phospholipids in complex with protein, suggesting that it is derived through lipid peroxidation of polyunsaturated lipids of subcellular membranes.Lipofuscin is not injurious to the cell or its functions. Its importance lies in its being a telltale sign of free radical injury and lipid peroxidation. The term is derived from the Latin(fuscus, brown), referring to brown lipid.  


What is the appearance of lipofuscin?

In tissue sections it appears as a yellow-brown, finelygranular cytoplasmic, often perinuclear, pigment ( Fig. 1-33 ). It is seen in cells undergoing slow,regressive changes and is particularly prominent in the liver and heart of aging patients orpatients with severe malnutrition and cancer cachexia.


What is melanin?

Melanin, derived from the Greek (melas, black), is an en-dogenous, non-hemoglobin-derived,brown-black pigment formed when the enzyme tyrosinase catalyzes the oxidation of tyrosine todihydroxyphenylalanine in melanocytes.  


.For practicalpurposes _________- is the only endogenous brown-black pigment .The only other that could beconsidered in this category is homogentisic acid, a black pigment that occurs in patients withalkaptonuria, a rare metabolic disease.Here the pigment is deposited in the skin, connectivetissue, and cartilage, and the pigmentation is known as ochronosis



What is hemosiderin?

Hemosiderin is a hemoglobin-derived, golden yellow-to-brown, granular or crystalline pigmentthat serves as one of the major storage forms of iron.Iron metabolism and hemosiderin areconsidered in detail in Chapters 14 and 18 . Iron is normally carried by specific transport proteins, transferrins. In cells, it is stored in association with a protein, apoferritin, to form ferritinmicelles. Ferritin is a constituent of most cell types. When there is a local or systemic excess of iron, ferritin forms hemosiderin granules, which are easily seen with the light microscope ( Fig.1-34 ). Hemosiderin pigment represents aggregates of ferritin micelles. Under normal conditions small amounts of hemosiderin can be seen in the mononuclear phagocytes of the bone marrow, spleen, and liver, which are actively engaged in red cell breakdown.


Local or systemic excesses of iron cause hemosiderin to accumulate within cells.Localexcesses result from hemorrhages in tissues. The best example of localized hemosiderosis isthe _________

common bruise.Extravasated red blood cells at the site of injury are phagocytosed overseveral days by macrophages, which break down the hemoglobin and recover the iron. Afterremoval of iron, the heme moiety is converted first to biliverdin (“green bile”) and then tobilirubin (“red bile”). In parallel, the iron released from heme is incorporated into ferritin and eventually hemosiderin.These conversions account for the often dramatic play of colors seen in a healing bruise, which typically changes from red-blue to green-blue to golden-yellow beforeit is resolved.


When there is systemic overload of iron hemosiderin may be deposited in many organs andtissues, a condition called hemosiderosis.The main causes of hemosiderosis are (

1) increased absorption of dietary iron,(2) hemolytic anemias, in which abnormal quantities of iron arereleased from erythrocytes, and(3) repeated blood transfusions because the transfused redcells constitute an exogenous load of iron


How does an iron pigment appears?

Iron pigment appears as a coarse, golden, granular pigment lying within the cell's cytoplasm ( Fig. 1-34A ).It can be visualized in tissues by the Prussian bluehistochemical reaction, in which colorless potassium ferrocyanide is converted by iron to blue-black ferric ferrocyanide ( Fig. 1-34B ).When the underlying cause is the localizedbreakdown of red cells, the hemosiderin is found initially in the phagocytes in the area.Insystemic hemosiderosis it is found at first in the mononuclear phagocytes of the liver, bonemarrow, spleen, and lymph nodes and in scattered macrophages throughout other organssuch as the skin, pancreas, and kidneys.With progressive accumulation, parenchymal cellsthroughout the body (principally in the liver, pancreas, heart, and endocrine organs) becomepigmented.


In most instances of systemic hemosiderosis the pigment does not damage the parenchymal cells or impair organ function.The more extreme accumulation of iron, however, in aninherited disease called ___________, is associated with liver, heart, and pancreaticdamage, resulting in liver fibrosis, heart failure, and diabetes mellitus (



________- is the normal major pigment found in bile. It is derived from hemoglobin but contains no iron. Its normal formation and excretion are vital to health, and jaundice is a commonclinical disorder caused by excesses of this pigment within cells and tissues



What is Pathologic calcification?

 is the abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other mineral salts. 


There are two forms of pathologiccalcification. 

When the deposition occurs locally in dying tissues it is known as dystrophic​ calcification; it occurs despite normal serum levels of calcium and in the absence of derangements in calcium metabolism. In contrast, the deposition of calcium salts in otherwise normal tissues is known as metastatic calcification, and it almost always results from hypercalcemia secondary to some disturbance in calcium metabolism.


What is dystrophic calcification?.

Dystrophic calcification is encountered in areas of necrosis, whether they are of coagulative, caseous, or liquefactive type, and in foci of enzymatic necrosis of fat. Calcification is almostalways present in the atheromas of advanced atherosclerosis. It also commonly develops inaging or damaged heart valves, further hampering their function ( Fig. 1-35 ). Whatever the site of deposition, the calcium salts appear macroscopically as fine, white granules or clumps, oftenfelt as gritty deposits. Sometimes a tuberculous lymph node is virtually converted to stone


Histologically, with the usual hematoxylin and eosin stain, calcium salts have a 

basophilic, amorphous granular, sometimes clumped appearance. They can be intracellular


What is cellular aging?

Cellular aging is the result of a progressive decline in cellular function and viability caused by genetic abnormalities and the accumulation of cellular and molecular damage due to theeffects of exposure to exogenous influences


The known changes that contribute to cellular aging include the following.

* Decreased cellular replication
* Accumulation of metabolic and genetic damage


The concept that most normal cells have a limitedcapacity for replication was developed from a simple experimental model for aging.Normal human fibroblasts, when placed in tissue culture, have limited division potential. [71] After a fixed number of divisions all somatic cells become arrested in a terminally nondividing state, known as__________.Cells from children undergo morerounds of replication than do cells from older people ( Fig. 1-37 ).



What is Werner's syndrome?

 cells frompatients with Werner syndrome, a rare disease characterized by symptoms of premature aging, are defective in DNA replication and have a markedly reducedcapacity to divide.


It is still not known why aging is associated with progressive senescence of cells. [72]One probable mechanism in human cells is that with each cell division there is _________

in omplete replication of chromosome ends (telomere shortening), which ultimately results in cell cycle arrest.  Note :Telomeres are short repeated sequences of DNA (TTAGGG) present at the linear ends of chromosomes that are important for ensuring the complete replication of chromosomal ends and for protecting chromosomal termini from fusion and degradation. [73]When somatic cells replicate, a small section of the telomere isnot duplicated and telomeres become progressively shortened. As the telomeres become shorter the ends of chromosomes cannot be protected and are seen as broken DNA, which activates the DNA damage response and signals cell cycle arrest. Telomerelength is normally maintained by nucleotide addition mediated by an enzyme calledtelomerase. Telomerase is a specialized RNA-protein complex that uses its own RNA as a template for adding nucleotides to the ends of chromosomes ( Fig. 1-38A ). Theactivity of telomerase is repressed by regulatory proteins, which provide a mechanism for sensing telomere length and restrict unnecessary elongation. Telomerase activity ishighest in germ cells and present at lower levels in stem cells, but it is usually undetectable in most somatic tissues ( Fig. 1-38B ). Therefore, as somatic cells divide, their telomeres become shorter, and they exit the cell cycle, resulting in an inability to generate new cells to replace damaged ones. Thus, both accumulation of senescent cells and depletion of stem cell pools via senescence contribute to aging. Conversely, inimmortal cancer cells telomerase is reactivated and telomeres are stable, suggesting that maintenance of telomere length might be an important—possibly essential—step intumor formation ( Chapter 7 ). Despite such alluring observations, however, the relationship of telomerase activity and telomeric length to aging and cancer still must befully established


Replicative senescence can also be induced by________________ (discussed further below). How these factorscontribute to normal aging is not known

 increased expression of the cell cycleinhibitor p16INK4a and by DNA damage


Consistent with this proposal are the following observations:  [77] 

(1) variation in longevity among different species is inversely correlated with the rates of mitochondrial generation ofanion radical, and (2) overexpression of the antioxidative enzymesSOD and catalase extends life span in transgenic forms of Drosophila. Free radicals may have deleterious effects on DNA, leading to breaks and genome instability, thusaffecting all cellular functions.


Several protective responses counterbalance progressive damage in cells, and a important one is the____________Although most DNAdamage is repaired by endogenous DNA repair enzymes, some persists and accumulates as cells age.Several lines of evidence point to the importance of DNArepair in the aging process. Patients with Werner syndrome show premature aging, and the defective gene product is a DNA helicase—a protein involved in DNA replication andrepair and other functions requiring DNA unwinding. [78] 

 recognition and repair of damaged DNA. 


A defect in this enzyme causesrapid accumulation of chromosomal damage that may mimic the injury that normally accumulates during cellular aging.Genetic instability in somatic cells is alsocharacteristic of other disorders in which patients display some of the manifestations of aging at an increased rate, such as ataxia-telangiectasia, in which the mutated geneencodes a protein involved in repairing double-strand breaks in DNA ( Chapter 7 ).Thus, the balance between cumulative metabolic damage and the response to that damage could determine the rate at which we age. In this scenario aging can bedelayed by decreasing the accumulation of damage or by increasing the response tothat damage.Not only damaged DNA but damaged cellular organelles also accumulate as cells age.In part this may be the result of declining function of the proteasome, the proteolyticmachine that serves to eliminate abnormal and unwanted intracellular proteins.

DNA helicase


Studies in model organisms, from yeast to mammals, have shown that the most effective way ofprolonging life span is __________.How this works is still not established, but the effect ofcalorie restriction on longevity appears to be mediated by a family of proteins calledsirtuins.

calorie restriction


What are sirtuins?

Sirtuins have histone deacetylase activity, and are thought to promote the expression of several genes whose products increase longevity.These products includeproteins that increase metabolic activity, reduce apoptosis, stimulate protein folding, and inhibit the harmful effects of oxygen free radicals. [81]Sirtuins also increase insulin sensitivity andglucose metabolism, and may be targets for the treatment of diabetes. Not surprisingly,optimistic wine-lovers have been delighted to hear that a constituent of red wine may activate sirtuins and thus increase life span! Other studies have shown that growth factors, such as insulin-like growth factor, and intracellular signaling pathways triggered by these hormones alsoinfluence life span. [69]Transcription factors activated by insulin receptor signaling may induce genes that reduce longevity, and insulin receptor mutations are associated with increased life span.The relevance of these findings to aging in humans is an area of active investigation. It should be apparent that the various forms of cellular derangements and adaptationsdescribed in this chapter cover a wide spectrum, ranging from adaptations in cell size, growth, and function; to the reversible and irreversible forms of acute cell injury; to the regulated type of cell death represented by apoptosis; to the pathologic alterations in cell organelles; and to the less ominous forms of intracellular accumulations, including pigmentations.Reference is madeto all these alterations throughout this book, because all organ injury and ultimately all clinicaldisease arise from derangements in cell structure and function.