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CMOD Week 1 > Cellular Adaptation > Flashcards

Flashcards in Cellular Adaptation Deck (44):
1

What do pathologists do?

ID changes in the gross or microscopic appearance of cells and tissues

2

What is etiology?

the origin of a disease, including the underlying causes and modifying factors: genetic, environmental, multifactorial

3

What is the pathogenesis?

the steps in the development of disease

4

What are physiologic adaptations?

responses of cells to normal stimulation by hormones or endogenous chemical mediators

5

What are pathologic adaptations?

responses to stress that allow cells to modulate their structure and function and thus escape injury

6

What are some examples of cell adaptation responses?

hypertrophy, hyperplasia, atrophy, and metaplasia

7

What is hypertrophy and what is it driven by?

an increase in the size of an individual cell and eventually in the size of the collective organ

Hyperplasia is an adaptive response in cells capable of replication, whereas hypertrophy occurs when cells have a limited capacity to divide

Hypertrophy can be physiologic or pathologic and is caused either by increased functional demand or by growth factor or hormonal stimulation.

In response to increased demand the striated muscle cells in both the skeletal muscle and the heart can undergo only hypertrophy because adult muscle cells have a limited capacity to divide.

8

What is ischemia?

reduced blood flow

9

What is an infarction?

cell death

10

What are the two signal related mechanisms driving cardiac hypertrophy?

An example of pathologic cellular hypertrophy is the cardiac enlargement that occurs with hypertension or aortic valve disease

mechanical triggers, such as stretch

and trophic triggers, which typically are soluble mediators that stimulate cell growth, such as growth factors and adrenergic hormones

These stimuli turn on signal transduction pathways that lead to the induction of a number of genes, which in turn stimulate synthesis of many cellular proteins, including growth factors and structural proteins. The result is the synthesis of more proteins and myofilaments per cell, which increases the force generated with each contraction, enabling the cell to meet increased work demands.

Whatever the exact mechanisms of hypertrophy, a limit is reached beyond which the enlargement of muscle mass can no longer compensate for the increased burden. When this happens in the heart, several “degenerative” changes occur in the myocardial fibers, of which the most important are fragmentation and loss of myofibrillar contractile elements.

11

What is hyperplasia?

increase in the NUMBER of cells (in cells that can replicate/undergo mitosis). Can result in an enlarged organ (can occur with hypertrophy)

Hyperplasia is an adaptive response in cells capable of replication, whereas hypertrophy occurs when cells have a limited capacity to divide.

12

What is atrophy and what are some common causes?

shrinkage in the size of the cell by the loss of cell substance. These are diminished function, but are not dead.

lack of use, loss of innervation, diminished blood supply, inadequate nutrition, loss of endocrine stimulation, and aging (senile atrophy)

NOT DEAD, just smaller

13

What are some possible mechanisms of atrophy?

decreased protein synthesis due to reduced metabolic activity or increased protein degradation

The degradation of cellular proteins occurs mainly by the ubiquitin-proteasome pathway. Nutrient deficiency and disuse may activate ubiquitin ligases, which attach multiple copies of the small peptide ubiquitin to cellular proteins and target them for degradation in proteasomes. This pathway is also thought to be responsible for the accelerated proteolysis seen in a variety of catabolic conditions, including the cachexia associated with cancer.

14

In many situations, atrophy is also accompanied by?

increased autophagy, with resulting increases in the number of autophagic VACUOLES.

Autophagic is the process in which the stavred cells eat their own components in an attempt to survive

15

What is metaplasia?

Metaplasia is a REVERSIBLE change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type.

Metaplasia is thought to arise by reprogramming of stem cells to differ- entiate along a new pathway rather than a phenotypic change (transdifferentiation) of already differentiated cells.

Moreover, the influences that induce metaplastic change, if persistent, may predispose to malignant transformation of the epithelium.

16

What are the differences between hypertrophy, hyperplasia, dysplasia, and neoplasia?

hypertrophy just results in increased cell size and its original organization is maintained

hyperplasia results in increased cell NUMBER, with its original organization retained

dysplasia results in increased cell NUMBER and disruptions in the organization of the cell structure

neoplasia is the uncontrolled growth of cells with increase in cell number

17

In relation to morphologic changes associated with injury, what are two indications of a reversible injury?

swelling and fatty change, with leakage of proteins from the damage

Cellular swelling is the result of failure of energy-dependent ion pumps in the plasma membrane, leading to an inability to maintain ionic and fluid homeostasis.

Fatty change occurs in hypoxic injury and in various forms of toxic or metabolic injury and is manifested by the appearance of small or large lipid vacuoles in the cytoplasm

18

In relation to morphologic changes associated with injury, what are two indications of a irreversible injury?

mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) and

disturbance in membrane function

19

What is the difference regarding change in morphology in cell size between apoptosis and necrosis?

apoptosis- reduced (skrinkage)
necrosis- enlarged swelling

20

What is the difference regarding change in morphology in nucleus appearance between apoptosis and necrosis?

apoptosis- fragmentation into nucleosome size fragments

necrosis-
pyknosis (the irreversible condensation of chromatin in the nucleus),

karyorrhexis (the destructive fragmentation of the nucleus of a dying cell whereby its chromatin is distributed irregularly throughout the cytoplasm. It is usually preceded by pyknosis),

karyolysis- the complete dissolution of the chromatin of a dying cell inside the nucleus due to the enzymatic degradation by endonucleases.

21

What is the difference regarding change in morphology in plasma membrane appearance between apoptosis and necrosis?

apoptosis- intact; altered structure, especially in the orientation of lipids

necrosis-disrupted causing enzyme leakage

22

What is the difference regarding change in morphology in cellular contents between apoptosis and necrosis?

apoptosis- intact, may be released in apoptotic bodies

necrosis- enzymatic digestion that may leak out of the cell (and cause inflammation) OR into the cytoplasm to digest the cell(the definition of necrosis). Necrotic cells show increased
eosinophilia (i.e., pink staining from the eosin dye), attributable in part to increased binding of eosin to denatured cytoplasmic proteins and in part to loss of the basophilia that is normally imparted by the ribonucleic acid (RNA) in the cytoplasm (basophilia is the blue staining from the hematoxylin dye—the H in “H&E”).

Necrosis is the major pathway of cell death in many commonly encountered injuries, such as those resulting from ischemia, exposure to toxins, various infections, and trauma.

When a cell is deprived of growth factors, or the cell’s DNA or proteins are damaged beyond repair, typically the cell kills itself by another type of death, called apoptosis, which is charac- terized by nuclear dissolution without complete loss of membrane integrity.

23

What is the difference regarding change in morphology in adjacent inflammation between apoptosis and necrosis?

apoptosis- no

necrosis- frequent

24

What is the difference regarding change in physiologic or pathogenic role between apoptosis and necrosis?

apoptosis- often physiologic, means of eliminating unwanted cells, may be pathogenic after some forms of cell injury, especially DNA and protein damage

necrosis- invariably pathogenic (culmination fo irreversible injury)

25

What are some common mechanism of cell injury?

-depletion of ATP (death by necrosis),
-mitochondrial damage and dysfunction,
-influx of calcium,
-accumulation of oxygen-derived free radicals, defects in membrane permeability (death by necrosis), and damage to DNA and proteins (death by apoptosis)

Multiple biochemical alterations may be triggered by any one injurious insult

26

What are some of the major consequences of ischemia, damage, etc. to mitochondria (decreased mitochondrial function)?

Does this usually lead to apoptosis or necrosis?

Usually leads to necrosis

Draw out the flowchart
1. decreased oxidative phosphorylation leading to decreased ATP production

2. decreased ATP production causes:
a) decreased Na efflux pump resulting in an influx of calcium, water, and Na and an efflux of potassium, which eventually leads to ER swelling, cellular swelling, blebs, and loss of microvilli

b) anaerobic glycolysis increases leadings to (i) decreased glycogen production, (ii) increased lactic acid production, and (iii) decreased pH, which leads to clumping of nuclear chromatin

c) prolonged ATP depletion causes detachment of ribosomes leading to decreased protein synthesis

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

27

What are some common ways intracellular calcium concentrations can be increased (which is a form of injury to the cell)?

release from intracellular stores and influx across the plasma membrane following injury

28

What are some of the consequences of increased cytosolic Ca2+?

it activates a number of enzymes with potentially deleterious cellular effects and may also activate caspases and by increasing mitochondrial permeability= apoptosis

29

The generation of free radicals is increased under what circumstances?

1. the absorption of radiant energy (e.g. ultraviolet light, x-rays). Ionizing radiation can hydrolyze water into hydroxyl and hydrogen free radicals

2. The enzymatic metabolism of exogenous chemicals (e.g. carbon tetrachloride)

3. Inflammation, in which free radicals are produced by leukocytes

NOTE: ROS are produced normally in small amounts in all cells during reduction-oxidation (redox) reactions that occur during mitochondrial respiration and energy genera- tion. In this process, molecular oxygen is sequentially reduced in mitochondria by the addition of four electrons to generate water. This reaction is imperfect, however, and small amounts of highly reactive but short-lived toxic intermediates are generated when oxygen is only partially reduced. These intermediates include superoxide (O2• ), which is converted to hydrogen peroxide (H2O2) spontaneously and by the action of the enzyme superoxide dismutase. H2O2 is more stable than O2• and can cross biologic membranes. In the presence of metals, such as Fe2+, H2O2 is converted to the highly reactive hydroxyl radical •OH by the Fenton reaction.

ROS are produced in phagocytic leukocytes, mainly neutro- phils and macrophages, as a weapon for destroying ingested microbes and other substances during inflam- mation and host defense. The ROS are generated in the phagosomes and phagolysosomes of leukocytes by the respiratory burst (or oxida- tive burst). In this process, a phagosome membrane enzyme catalyzes the generation of superoxide, which is converted to H2O2. H2O2 is in turn converted to a highly reactive compound hypochlorite (the major component of household bleach) by the enzyme myeloperoxidase, which is present in leukocytes.

• Nitric oxide (NO) is another reactive free radical pro- duced in leukocytes and other cells. It can react with O2• to form a highly reactive compound, peroxynitrite, which also participates in cell injury.

30

How does carbon monoxide affect people?

CO forms a stable complex with hemoglobin that prevents oxygen binding. SaO2 decreases

31

What are the two types of physiologic hyperplasia?

(1) hormonal hyperplasia, exemplified by the proliferation of the glandular epithelium of the female breast at puberty and during pregnancy, and

(2) compensatory hyperplasia, in which residual tissue grows after removal or loss of part of an organ. For example, when part of a liver is resected, mitotic activity in the remaining cells begins as early as 12 hours later, eventually restoring the liver to its normal weight. The stimuli for hyperplasia in this setting are polypeptide growth factors produced by uninjured hepatocytes as well as nonparenchymal cells in the liver. After restoration of the liver mass, cell proliferation is “turned off” by various growth inhibitors.

32

What are most forms of pathologic hyperplasia caused by?

excessive hormonal or growth factor stimulation. For example, after a normal menstrual period there is a burst of uterine epithelial proliferation that is normally tightly regulated by stimulation through pituitary hormones and ovarian estrogen and by inhibition through proges- terone. However, a disturbed balance between estrogen and progesterone causes endometrial hyperplasia, which is a common cause of abnormal menstrual bleeding.

33

What is the difference between pathologic hyperplasia and cancer?

An important point is that in all of these situations, the hyperplastic process remains controlled; if the signals that initiate it abate, the hyperplasia disappears. It is this responsiveness to normal regulatory control mechanisms that distinguishes pathologic hyperplasias from cancer, in which the growth control mechanisms become dysregulated or ineffective. Nevertheless, in many cases, pathologic hyperplasia constitutes a fertile soil in which cancers may eventually arise. For example, patients with hyperplasia of the endometrium are at increased risk of developing endometrial cancer.

34

What stimuli might cause squamous metaplasia in the lungs?

It is thought that cigarette smoking initially causes squamous metaplasia, and cancers arise later in some of these altered foci. Since vitamin A is essential for normal epithelial differentiation, its deficiency may also induce squamous metaplasia in the respiratory
epithelium.

Metaplasia need not always occur in the direction of columnar to squamous epithelium; in chronic gastric reflux, the normal stratified squamous epithelium of the lower esophagus may undergo metaplastic transformation to gastric or intestinal-type columnar epithelium. Metaplasia may also occur in mesenchymal cells but in these situations it is generally a reaction to some pathologic alteration and not an adaptive response to stress. For example, bone is occasionally formed in soft tissues, particularly in foci of injury.

35

T or F. Cell injury results when cells are stressed so severely that they are no longer able to adapt or when cells are exposed to inherently damaging agents or suffer from intrinsic abnormalities (e.g., in DNA or proteins)

T.

36

T or F. Cellular function may be lost long before cell death occurs, and the morphologic changes of cell injury (or death) lag far behind both).

T. For example, myocardial cells become noncontractile after 1 to 2 minutes of isch- emia, although they do not die until 20 to 30 minutes of ischemia have elapsed. These myocytes may not appear dead by electron microscopy for 2 to 3 hours, or by light microscopy for 6 to 12 hours.

37

What is Coagulative necrosis?

a form of necrosis in which the underlying tissue architecture is preserved for at least several days. The affected tissues take on a firm texture. Presumably the injury denatures not only structural proteins but also enzymes, thereby blocking the pro- teolysis of the dead cells; as a result, eosinophilic, anucleate cells may persist for days or weeks. Leukocytes are recruited to the site of necrosis, and the dead cells are digested by the action of lysosomal enzymes of the leukocytes. The cellular debris is then removed by phagocytosis. Coagulative necrosis is characteristic of infarcts (areas of ischemic necrosis) in all of the solid organs except the brain.

38

What is Liquefactive necrosis?

seen in focal bacterial or, occasionally, fungal infections, because microbes stimulate the accumulation of inflammatory cells and the enzymes of leukocytes digest (“liquefy”) the tissue. For obscure reasons, hypoxic death of cells within the central nervous system often evokes liquefactive necrosis. Whatever the pathogenesis, the dead cells are completely digested, transforming the tissue into a liquid viscous mass. Eventually, the digested tissue is removed by phagocytes. If the process was initiated by acute inflammation, as in a bacterial infection, the material is frequently creamy yellow and is called pus

39

What is Caseous necrosis?

encountered most often in foci of tuberculous infection. Caseous means “cheese-like,” referring to the friable yellow-white appearance of the area of necrosis. On microscopic examination, the necrotic focus appears as a collection of fragmented or lysed cells with an amorphous granular pink appearance in the usual H&E-stained tissue. Unlike with coagulative necrosis, the tissue architecture is completely obliterated and cellular outlines cannot be discerned. The area of caseous necrosis is often enclosed within a distinctive inflammatory border; this appearance is characteristic of a focus of inflammation known as a granuloma

40

What is Fat necrosis?

Refers to focal areas of fat destruction, typi- cally resulting from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity. This occurs in the calamitous abdominal emergency known as acute pancreatitis. In this disorder, pancreatic enzymes that have leaked out of acinar cells and ducts liquefy the membranes of fat cells in the peri- toneum, and lipases split the triglyceride esters contained within fat cells. The released fatty acids combine with calcium to produce grossly visible chalky white areas (fat saponification), which enable the surgeon and the pathologist to identify the lesions. On histologic exami- nation, the foci of necrosis contain shadowy outlines of necrotic fat cells with basophilic calcium deposits, sur- rounded by an inflammatory reaction.

41

What is Fibrinoid necrosis?

a special form of necrosis, visible by light microscopy, usually in immune reactions in which complexes of antigens and antibodies are deposited in the walls of arteries. The deposited immune complexes, together with fibrin that has leaked out of vessels, produce a bright pink and amorphous appearance on H&E preparations called fibrinoid (fibrin-like) by pathologists.

42

T or F. The consequences of an injurious stimulus depend on the type, status, adaptability, and genetic makeup of the injured cell.

T. The same injury has vastly different outcomes depending on the cell type; thus, striated skeletal muscle in the leg accommodates complete ischemia for 2 to 3 hours without irreversible injury, whereas cardiac muscle dies after only 20 to 30 minutes.

The nutritional (or hor- monal) status can also be important; clearly, a glycogen- replete hepatocyte will tolerate ischemia much better than one that has just burned its last glucose molecule. Genetically determined diversity in metabolic pathways can contribute to differences in responses to injurious stimuli.

43

What mechanisms do cells have to remove ROSs?

1) Free radicals are inherently unstable and decay spontaneously.

2) superoxide dismutases (SODs)

3) Glutathione (GSH) peroxidases

4) Catalase

etc.

44

Reactive oxygen species cause cell injury by what three main reactions?

• Lipid peroxidation of membranes. Double bonds in mem- brane polyunsaturated lipids are vulnerable to attack by oxygen-derived free radicals. The lipid–radical interac- tions yield peroxides, which are themselves unstable and reactive, and an autocatalytic chain reaction ensues.

• Cross-linking and other changes in proteins. Free radicals promote sulfhydryl-mediated protein cross-linking, resulting in enhanced degradation or loss of enzymatic activity. Free radical reactions may also directly cause polypeptide fragmentation.

• DNA damage. Free radical reactions with thymine in nuclear and mitochondrial DNA produce single-strand breaks. Such DNA damage has been implicated in cell death, aging, and malignant transformation of cells.