Lecture 2 - Cell Injury Flashcards by Aly Johns

Be able to describe the different types of cellular adaptation to stress or injury listed below. Describe both anatomical changes and mechanisms of adaptation and be prepared to give examples of each type of
adaptation.

Atrophy

Atrophy: shrinkage of the cell size, this can result in shrinking of the whole organ

Causes a decrease in:

a) mitochondria
b) myofilaments (cytoskeleton)
c) ER

Causes:

a) Decreased workload
b) Decrease use
c) Decrease blood supply (chronic ischemia/hypoxia)
d) Decrease nutrition status (autophagic vacuoles)
e) Decrease neuronal stimulation
f) Decrease hormonal stimulation

ex) mm. due to disuse, brain due to aging, gonads due to decreased hormone secretion by the brain

Mechanisms:

Decreased ATP production
Decreased amino acid uptake
Increased protein catabolism (umbiquitin proteosome pathway)
Increased autophagic vacuoles…for malnutrition

Autophagic vaculoes - these digest worn out or damaged/inoperable organelles; digestive enzymes are maintained in these vacuoles to prevent cell injury

Lipofuscin - some parts of the cell resist autophagic destruction and form residual bodies…develop yellow/brown pigment and become age spots

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Hypertrophy

Increase in the cell size and consequently the organ!

Causes:

a) increased work load –> skeletal and cardiac mm.
b) increased stimulation by hormones –> gonads and thyroid, mammary glands, skeletal mm. to testosterone

ex) Skeletal mm…. in response to increased work load and testosterone stimulation

Cardiac mm…..in response to increased work load, pressure load, and volume load

Kidney….increased work load due to removal of one kidney, the other hypertrophies to adapt to increased demand on other kidney

Uterus and Mammary Glands…. in response to increased estrogen during pregnancy

Mechanism:

–> increased a.a. uptake and increased protein synthesis. there is decreased protein catabolism and increased DNA synthesis.

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Hyperplasia

Increased number of cells due to increased cell division

Cause: Injury to cells is severe enough to cause cell death

ex) Epithelial tissue due to an injury
Liver after 70% removed. Regeneration will occur within 2 weeks.

Mechanism: GF production and release

–> note: hypertrophy and hyperplasia can occur at the same time due to increased DNA synthesis

Types of Hyperplasia:

Compensatory - Enables come organs to regenerate ex) liver; Hepatocyte Growth Factor

–> regeneration doesn’t occur with heart mm., neurons, skeletal mm, and eye lens cells

–> significant hyperplasia compensatory occurs with the bone marrow, epithelial tissue, hepatocytes, fibroblasts, and intestinal epithelium

–> occurs to a lesser degree is bone, cartilage, and smooth mm.

Hormonal Hyperplasia - nuclear enlargement, clumping of chromatin, enlargement of nucleoli

–> endometrium of uterus, if GF control fails, can turn malignant

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Dyplasia

Abnormal changes in size, shape, and organization of mature cells. NOT A TRUE ADAPTIVE PROCESS.

Known as atypical hyperplasia

Found next to or near cancerous cells. Precursors to neoplastic growth (Pre-cancerous)

Cause: abnormal response to growth factors

ex) found in the epithelium of the respiratory tract or the cervix where they are strongly associated with neoplastic growths

Mechanisms: Probably what causes a cell to become cancerous - increased sensitivity to GF by mutations or carcinogens

DYSPLASIA DOESN’T MEAN CANCER AND MAY NEVER LEAD TO CANCER

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Metaplasia

Reversible replacement of one type of mature cell by another.

Replacement is usually less mature, less differentiated.

Cause: Usually induced by an exogenous stimulus ex) cigarette smoke –> though to be reprogramming of stem cells

ex) Ciliated pseudostratified columnar epithelium of respiratory tract by a stratified squamous epithelium

These neither secrete mucus not have cilia thus the loss of the protective mechanism of the mucociliary elevator

note: bronchial metaplasia will reverse to some degree is smoking is stopped otherwise it is permanent and can turn neoplastic

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Describe the general or common mechanisms causing cell injury cellular injury and cell death.

Cell injury: when the cell is unable to maintain homeostasis (maintain internal environment)

Reversible - cell can still mend the injury and return to homeostasis

Irreversible - cannot mend, cell death ensues

Mechanisms:

**Hypoxia - THE MOST COMMON CAUSE
Free radicals
Infectious agents
Immunological
Genetic
Nutritional

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Outline in detail the steps and mechanisms of reversible and nonreversible cell injury due to hypoxia. Be prepared to describe 5 different causes of hypoxic injury to cells and point out the most common cause
of tissue hypoxia.

Reversible:

a) Na/K pump fails due to lack of O2 and ATP production
b) Na+ and Ca+ accumulate in the cell and water follows
c) Vacuolation occurs - water is separated to avoid diluting cytoplasmic components
d) ER swells and ribosomes detach –> decreased protein synthesis
e) Cell swells
f) Rupture of membrane
g) Ca+ still enters with more Na+

Still reversible at this point!!!

Irreversible:
Mitchondrial damage
a) Ca+ accumulates in cell
b) Activates digestive enzymes in cytosol
c) More vacuolation occurs, lysozymes swell
d) Rupture of lysozymes releases DIG enzymes that begin to digest the cell
e) Ca+ accumulates in the mitochondria which causes it to swell and burst
f) Free radicals are produced
g) Rapid cell death!!

Different causes of hypoxic injury:

Decreased O2 in atmosphere
- -> decreasing barometric pressure (altitude)
Decreased Hb, Fe+, or RBC production
CO binding to Hb
Respiratory diseases that decrease ability for diffusion
CV disease that decrease cardiac output, or narrow vessels making it harder to deliver blood to tissues
THE MOST COMMON CAUSE OF TISSUE HYPOXIA IS ISCHEMIA

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Define and describe the mechanism of “Reperfusion injuries”.

Reperfusion injuries: re-establishing O2 and blood after mitochondria has been damaged

a) Xanthene dehydrogenase takes O2 –> Xanthene oxidase
b) Increased production of free radicals!!
c) Further damage occurs
d) Superoxide dismutase, Vit C/E are antioxidants that prevent free radical damage

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Define “Free Radical” and “reactive oxygen species” be prepared to identify the free radicals listed in
table 2.3 page 62.

Free radical - an atom or groups of atoms with an unpaired electron

–> it wants to either give its electron away or bind with something else

Types:

ROS
Superoxide (O2-) –> oxidase (O2-)
H2O2
Hydroxyl (OH)
NO

Source:

UV, Gamma rays
Endogenous processess –> end of ETC in the absence of O2
Reactions with exogenous chemicals (CCl4 and CCl3)

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Describe the mechanism of cell injury caused by oxygen free radicals. Identify biological macromolecules
that may be damaged by free radicals and the general the consequences of each one.

Mechanisms:

Lipid peroxidation: free radicals bind to the unsaturated fatty acids causing damage and oxidation along the entire cell membrane
Binds to a.a. and proteins and causes fragmentation
Damages DNA structure

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Name the substances and enzymes used by human cells to inactivate free radicals. (Note: How does this
list compare with commercial substances available?

Antioxidants:

vit c
vit e
superoxide dismutase
cysteine
glutathione
albumin
ceruloplasmin
transferrin

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Describe the mechanism for the injury induced by the following chemicals.

Lead

Lead based paint has a sweet taste to it so children eat it

Targets:

a) Nervous system
b) Bone marrow
c) Kidney

Will lead to nerve hyper-excitability, convulsions, delirium by interfering with nerve transmission
Lead exposure later in life will lead to learning disorders, hyper-activity, attention deficit disorders
Lead prevents Hb synthesis in the bone marrow –> anemia
Lead to renal tubular damage –> proteinuria (aminoaciduria) and glycosuria

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Describe the mechanism for the injury induced by the following chemicals.

Carbon Monoxide

Results from complete or incomplete combustion
–> odorless and undetectable

Primary target: BINDS TO HB 300X THAT OF 02

-> binds to myoglobin and neuroglobin
-> binds to cytochromes at the end of the ETC
-> causes hypoxic injury and death to tissues

S/S: Tinnitus, HA, giddiness, n/v, weakness

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Describe the mechanism for the injury induced by the following chemicals.

Ethanol

Primary target is the CNS: alters its function and causes slowed transmission

–> also targets the liver for detoxification

Detoxification:

Hepatic Alcohol Dehydrogenase
- -> converts ETHANOL to ACETYLALDEHIDE
Hepatic Microsomal Ethanol Oxidizing System (MEOS) requires high levels of ethanol to activate
Genetic differences exist in ability to metabolize alcohol

Acute alcohol:

a) Ethanol is a CNS depressing agent. It causes reduced activation of the brain stem and RAS –> decreased motor skills and intellectual ability
b) Acetylaldehide causes hepatic changes
c) Reduces lipid oxidation in the mitochondria
d) Fat deposition and enlarged liver
e) Interruption of microtubule transport and secretion of proteins (clotting factors, albumin)
f) Increased intracellular swelling

Chronic alcohol:
a) Structural damage in almost all organs

–> primarily the liver, brain, and heart

b) Reduces regeneration capacity by blocking endothelial growth factor production
c) Inhibits ganglioside production –> reduces nerve transmission and leads to mental retardation of fetuses
d) Increased incidence of HTN, CAD, and CA

All this is due primarily to excessive levels of acetylaldehide!!!

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Describe the mechanism for the injury induced by the following chemicals.

a) cocaine
b) marijuana
c) heroine
d) methamphetamine

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Describe the mechanism for the injury induced by the following chemicals.

Infectious Injury

Invade and destroy human cells
Produce toxins (endo/exo) that disrupt cell membranes or enzyme action
Causes hypersensitivity

Describe the mechanism for the injury induced by the following chemicals.

Immunological/Inflammatory

Causes release of histamine

-> H20 in
-> K+ out

Complement creates holes in membrane
Antibodies can block receptors or prevent the formation of cell to cell junctions thus preventing cell to cell communication

List the general physiological responses and consequences of the following nutritional imbalances:

Protein Deficiency

Decreased protein synthesis
Decreased exocrine function (DIG enzymes)
Decreased liver function ( low amount of clotting factors, albumin, plasminogen, alpha/beta globulins, angiotensinogen)
Decreased absorption in intestine

List the general physiological responses and consequences of the following nutritional imbalances:

Hyperglycemia

Increased Insulin
Storage of glucose as glycogen in the liver and skeletal and cardiac mm.
Stimulates lipogenesis and adipose cell growth factor release
Obesity

List the general physiological responses and consequences of the following nutritional imbalances:

Hypoglycemia

Decreased insulin and increased Glucagon and epinephrine
Mobilization of FFA from adipose cells
Production of ketone bodies (acetone and 2 others)
Increased mitochondrial FFA oxidation for ATP production
Weight loss
Release of cortisol, stimulates protein catabolism
Triggers gluconeogenesis from 6 AA
Gluconeogenesis maintains blood glucose for CNS use

List the general physiological responses and consequences of the following nutritional imbalances:

Hypolipidemia

Stimulates release of FFA from adipose cells
Increased ketone production and excretion from kidney
Increased H20 loss in urine (ketones > urine osmotic pressure)
Decreased cell membrane synthesis, decreased cell mitosis
Decreased wound healing and tissue replacement

List the general physiological responses and consequences of the following nutritional imbalances:

Hyperlipidemia

Increased Lipoproteins in the blood
Increased cholesterol and arteriosclerosis
Increased obesity
Increased fat deposition in the liver, heart, and mm.

Ionizing radiation: Name the types of radiation that might cause ionization of organic molecules. When is a cell most vulnerable to ionizing radiation? What are the direct and indirect mechanisms for cell injury?

Ionizing radiation is radiation capable of removing orbital electrons

ex) X-ray, Gamma ray, Alpha and Beta radiation

Sources: environmental or occupational (hospitals), war (uranium, thorium, and K+)

Mechanism: removes electrons from DNA (most vulnerable during meiosis), most sensitive during the G2 phase prior to mitosis or meiosis

Breaks - resulting in:

-> translocation
-> substitutions - point mutations
-> deletions - reading frame shifts

Often injured cells manifest injuries by accumulating substances within the cell due a reduced capacity to metabolize these substances properly. Cell accumulations also result in the enlargement of the organ whose cells are accumulating the substances. Describe the cause or mechanisms for the accumulation of
the following molecules and name a tissue or organ where this usually occurs.

Water

MOST COMMON DEGENERATIVE CHANGE!!!

Definition: Shift of extracellular fluid from the ECF to the ICF

Causes: a disruption in cell’s ability to maintain osmotic balance with electrolytes due to failure of metabolism and inability to produce ATP

-> loss of ATP
-> Hypoxia
-> Free radicals
-> Ionizing radiation, DNA affecting membrane pumps
-> cisternae of ER become distended, rupture, and for vacuolation
-> vacuoles store and separate water from cytoplasm

Often injured cells manifest injuries by accumulating substances within the cell due a reduced capacity to metabolize these substances properly. Cell accumulations also result in the enlargement of the organ whose cells are accumulating the substances. Describe the cause or mechanisms for the accumulation of the following molecules and name a tissue or organ where this usually occurs. Lipid accumulation

Especially in Liver disease! 1. Increased movement of free fatty acids from adipose cells ex) starvation, diabetes 2. Failure of synthesis of phospholipids. FFA --> Triglycerides 3. Increased synthesis of triglycerides 4. Decreased synthesis of apoproteins (DNA defect or low protein diet or damaged rough ER) 5. Failure of lipids to bind to apoproteins 6. Failure of exocytosis mechanism to transport lipoproteins out of the cell 7. Direct damage or the ER by free radicals or acetylaldehyde

Often injured cells manifest injuries by accumulating substances within the cell due a reduced capacity to metabolize these substances properly. Cell accumulations also result in the enlargement of the organ whose cells are accumulating the substances. Describe the cause or mechanisms for the accumulation of the following molecules and name a tissue or organ where this usually occurs. Glycogen

Disorders of glucose or glycogen metabolism Causes: a) DM I/II b) Glucose binding to proteins causes glycosylation associated with decreased function of proteins ex) cataracts, aging of heart, and skeletal mm.

Often injured cells manifest injuries by accumulating substances within the cell due a reduced capacity to metabolize these substances properly. Cell accumulations also result in the enlargement of the organ whose cells are accumulating the substances. Describe the cause or mechanisms for the accumulation of the following molecules and name a tissue or organ where this usually occurs. Melanin

Black/brown pigment synthesized by melanocytes that is then transferred to keratinocytes. Accumulates in epithelial cells of skin and retina. May also accumulate in the phagocytic cells. Function: acts as a protectant against UV light Mechanism: synthesis is stimulated by exposure to UV light . Melanin may also trap exposure to free radicals. Melanoma: cancerous cells originating from melanocytes synthesize varying amounts of melanin. This results in a dark mole or growth.

Often injured cells manifest injuries by accumulating substances within the cell due a reduced capacity to metabolize these substances properly. Cell accumulations also result in the enlargement of the organ whose cells are accumulating the substances. Describe the cause or mechanisms for the accumulation of the following molecules and name a tissue or organ where this usually occurs. Bilirubin

Bilirubin - yellow green pigment derived from the porphyrin part of Hgb. Levels in blood > 1.5-2.0 mg/dl is referred to as JAUNDICED Mechanisms: a) Excessive RBC destruction (Hemolytic toxins from infections) b) Liver disease, slowing the metabolism of bilirubin to conjugated bilirubin and secretion in to bile c) obstruction of the bile duct (conjugated bilirubin can't be converted to urobilirubin) Toxic Effects: 1. Uncoupling of oxidative phosphorylation in mitochondira 2. Loss of cellular proteins

Often injured cells manifest injuries by accumulating substances within the cell due a reduced capacity to metabolize these substances properly. Cell accumulations also result in the enlargement of the organ whose cells are accumulating the substances. Describe the cause or mechanisms for the accumulation of the following molecules and name a tissue or organ where this usually occurs. Calcium

Accumulation of Ca++ salts in injured and dead tissues Mechanisms: --> influx of Ca++ into injured mitochondria --> combo with 2 OH- ions in areas where H+ secretion is occuring --> Dystrophic Calcification in dead or dying tissues --> Metastatic calcification: mineral deposits in normal tissues due to hypercalcemia Effects: a) uncontrolled activation of protein kinases --> phosphorylation of protein, abnormal inactivation of inactivated metabolic pathways b) inadvertent activation of phospholipases --> destruction of membranes c) inadvertent activation of proteases, cytoskeletal disassembly

CELL DEATH: Define, differentiate and indicate what tissue the following forms of necrosis occurs. Coagulative Necrosis Karyolysis: autodigestion of nucleus, becomes small dense matter of nuclear material

Necrosis is when the cell swells and lyses --> causes cell self-digestion which is ALWAYS PATHOLOGICAL Will always trigger and inflammatory response in the surrounding tissue Coagulative occurs primarily in the kidney, heart, and adrenal glands - -> result of hypoxia, ischemia, or chemical injury - -> protein denaturation, albumin changes from gelatinous to firm opague state - -> believed to be caused by calcium SAME AS ALBUMIN CHANGING TO COOKED EGG WHITE

CELL DEATH: Define, differentiate and indicate what tissue the following forms of necrosis occurs. Liquefaction Necrosis

Occurs primarily to neurons and glial cells ---> hypoxic ischemia --> brain cells are rich in hydrolytic enzymes and lipids but low in connective tissue --> when membrane disruption occurs, cells are digested by their own enzymes --> neutrophils cause liquefaction of bacterial cells and human thus creating pus

CELL DEATH: Define, differentiate and indicate what tissue the following forms of necrosis occurs. Caseous Necrosis

Seen in TB combo of liquefation and coagulative necrosis --> hydrolysis is incomplete due to c.t. pressent (cottage cheese)

CELL DEATH: Define, differentiate and indicate what tissue the following forms of necrosis occurs. Fat necrosis

Occurs in the breast and pancreas and other abdominal structures Due to release of lipases --> digest lipids and phospholipids which then combine with Ca++, Mg++, and Na+ to form soaps. Appears opaque and chalk white.

CELL DEATH: Define, differentiate and indicate what tissue the following forms of necrosis occurs. Gangrene

Death by hypoxic injury with subsequent bac. infection Dry gangrene = coagulation necrosis Wet gangrene = neutrophils invade the area and cause liquifaction Gas gangrene = toxins produces by clostridium bacteria, bubbled form and may be fatal

Define and list when and under what circumstances Apoptosis occurs. Recognize the pathways and genes involved in Apoptosis

Distinct type of cell death which is an active process of cell auto-destruction May be normal or pathological Mechanism: --> Normal: suicide program, DNA signals usually triggered by a lack of nerve innervation or lack of sufficient colonizing factors or GF --> provides a way to eliminate cells without causing collateral damage --> necrosis causes collateral damage!!! Indicated in alzheimers Can occur in malignant tumors

Describe the general theories of aging and explain the basis for these theories. Understand the basic premise of the following theories: 1. Random accumulation of injuries 2. Genetic and environmental factors 3. Neuroendocrine and Immunity alterations in aging.

Theories on Mechanism of Aging: 1. Random accumulation of small injurious events: a) accumulation of errors in DNA, resulting in errors in both protein structure and function b) accumulation of mutations in somatic cells c) accumulation of metabolic wastes that can't be eliminated from cells d) free radical damage from normally produced reactive free radical intermediates 2. Genetic and Environmental factors a) wear and tear that causes functional changes b) limited number of times a cell can divide (telomere length) c) cells preprogrammed at birth to cause errors in mitotic division d) each cell may have a finite DNA programmed life span e) Decline in the immune system with age f) increase in number of autoantibodies produced 3. Neuroendocrine theory a) decrease in hormone synthesis and secretion b) increase in the rate of hormone degradation c) decrease in the target organ sensitivity * lose elastin with age which causes wrinkles * increase in lipofuscin in cells and other waste products that can't be eliminated from cells * glycosylation of proteins (cataract, heart mm., and skeletal mm.)