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Flashcards in Cellular Injury and Adaptation Deck (174):
1

Homeostasis

balance of physiologic and biochemical functions within the body

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Alteration of homeostasis results in

stress to cell, cellular injury or adaptive changes to survive altered environment

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Reversible injury

injury is corrected prior to destruction of cellular repair mechanisms; severity of injury does not exceed the cells ability to repair itself

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Irreversible injury

repair mechanisms are destroyed (removal from altered environment will be insufficient) cell cannot repair itself --> DEATH; injury exceeds the cell's ability for self-repair, resulting in cell death

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Cellular Injury

Hypoxia, Physical agents, chemicals, infectious agents, immune reactions, genetic derangements, nutritional imbalance

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Hypoxia

Decreased supply of O2 to cell or inability to use O2

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Anoxia

Complete absence of O2

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Causes of Hypoxia

Ischemia (decreased BF), decreased oxygenation of blood, decreased O2 carrying capacity, inability to utilize O2

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Examples of Physical injury to cell

mechanical trauma, temperature extremes, atmospheric pressure variation, radiation, electrical injury

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Examples of Chemical Injury to cell

Simple agents (electrolytes, glucose), Poisons, Pollutants, Insecticides, herbicides, industrial products, drugs (therapeutic or recreational), alcohol

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Infectious Causes of cell injury

bacteria, rickettsia, fungi, virus, parasite

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Immune Response Causes of cell injury

Hypersensitivity reaction

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4 Key Signs of REVERSIBLE cell injury

Decreased aerobic respiration, cellular edema, ribosome detachment from RER, ultrastructural morphological changes

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Reversible Injury - Decreased Aerobic Respiration Results in

Decreased ATP production, increased AMP and anaerobic glycolysis, Increased lactate (decreased pH), decreased cellular glycogen, clumping of nuclear chromatin, decreased protein synthesis

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Examples of nutritional variations that cause cellular injury

deficits, excess, malabsorption, altered use

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Sites that are altered in cellular injury

cell membrane integrity, aerobic respiration, enzyme/protein synthesis, genetic apparatus

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What causes cellular edema in reversible cell injury?

Suppression of Na+ pump with increased [Na+] retention; increased intracellular Na+

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Ultrastructural Morphological Changes in reversible cellular injury

Phospholipid membrane alteration, loss of microvilli, myelin figure formation, mitochondrial swelling, RER swelling

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Key Signs of IRREVERSIBLE cellular injury

ATP Depletion, Cell Membrane Damage

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Cell Membrane Damage as a result of irreversible damage

Phospholipid Depletion, Cytoskeletal breakdown, toxic ROS, Lipid breakdown products, amino acid loss

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Structural changes in IRREVERSIBLE cell injury include

vacuolization of mitochondria, PM damage, Lysosomal swelling, Loss of proteins, enzymes, and RNA

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What characterizes cell injure as irreversible?

ATP depletion, cellular edema -> PM tears and damage, mitochondrial dysfunction (high [Ca2+] intracellularly), Membrane phospholipid depletion, cytoskeleton changes, ROS, lipid breakdown products, and amino acid loss

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Irreversible Cellular Damage - What is the determining/most important factor?

Cellular Membrane Dysfunction

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Irreversible Cellular Damage - What results from mitochondrial dysfunction?

ATP depletion -> increased cytosolic [Ca2+] -> mitochondrial phospholipase activation -> phospholipid breakdown + accumulation of FFA -> altered permeability of PM

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Myelin figures are characteristic of

reversible injury

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cellular edema is characteristic of

reversible injury

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Irreversible Cellular Damage - What causes membrane phospholipid depletion?

increase [Ca2+] intracellular activation of phospholipase AND ATP-dependent maintenance and production of phospholipids

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Irreversible Cellular Damage - What causes cytoskeletal abnormalities?

Hypoxia AND activation of proteases by high intracellular levels of [Ca2+]

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Irreversible Cellular Damage - What causes Toxic oxygen radical production?

sudden repercussion of hypoxic tissue

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Irreversible Cellular Damage - What produces Toxic oxygen radicals?

segmented neutrophils

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Reperfusion Injury

sudden reperfusion of ischemic tissue causes toxic oxygen radical production by segmented neutrophils

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Irreversible Cellular Damage - What produces lipid breakdown products?

phospholipase breakdown of pospholipids, high [FFA]

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Irreversible Cellular Damage - What amino acid is protective?

GLYCINE

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GLYCINE's protective feature

allows ATP depleted cells to resist high Ca2+ levels

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decreased aerobic respiration is a characteristic of

reversible injury

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increased intracellular pH is a characteristic of

reversible injury

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Increased intracellular AMP is a characteristic of

reversible injury

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Decreased glycogen stores v

reversible injury

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clumping of nuclear chromatin is a characteristic of

reversible injury due to decreased pH

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Ribosome detachment from RER is a characteristic of

reversible injury

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decreased function of sodium pump is a characteristic of

reversible injury

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Increased intracellular sodium is a characteristic of

reversible injury

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decreased protein synthesis is a characteristic of

reversible injury

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swelling of mitochondria is a characteristic of

reversible injury

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loss of microvilli is a characteristic of

reversible injury

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accumulation of lactate metabolites and phosphate is a characteristic of

reversible injury

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blebs is a characteristic of

reversible edema; due to structural alterations in phospholipid membranes

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myelin figures is a characteristic of

reversible injury

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ATP depletion reversible injury

irreversible injury; suppression of ATP-dependent repair mechanisms

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vacuolization of mitochondria is a characteristic of

irreversible injury

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lysosomal swelling is a characteristic of

irreversible injury

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loss proteins/enzymes and RNA is a characteristic of

irreversible injury

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PM tearing/damage is a characteristic of

irreversible injury

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Increased cytosolic [Ca2+] is a characteristic of

irreversible injury

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Increased [Ca2+] causes

activation of mitochondrial phospholipase and lysosomal proteases, ATPases, endonucleases

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Phospholipase

mitochondrial ([Ca2+] activated) breaks down phospholipids of PM

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Accumulation of FFA's is a characteristic of

irreversible injury

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Permeability changes in PM is a characteristic of

irreversible injury

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Membrane phospholipid depletion is a characteristic of

irreversible injury

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Damage to intermediate cytoskeletal filaments is a characteristic of

irreversible injury; hypoxia induced

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Separation of PM and cytoskeleton is a characteristic of

irreversible injury

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Proteases

lysosomal proteases released and activated by high intracellular [Ca2+]

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Toxic oxygen radicals is a characteristic of

irreversible injury

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reperfusion injury is a characteristic of

irreversible injury

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accumulation of lipid breakdown products is a characteristic of

irreversible injury

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loss of glycine and other amino acids is a characteristic of

irreversible injury

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Glycine

allows ATP depleted cells to resist high Ca2+ levels

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Reason for decreased protein synthesis in cellular injury?

detachment of ribosomes from RER

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Reason for nuclear clumping in cellular injury?

increased anaerobic glycolysis and decreased pH

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Intracellular release of lysosomal enzymes is a characteristic of

irreversible injury

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What is a free radical?

Activated oxygen or carbon species that cause cell damage (ROS, COS)

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Unstable free radicals react with?

inorganic and organic chemicals in membrane lipids and nucleic acids

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What generates free radicals?

autocatalytic reactions within the cell, O2 therapy, radiation, oxidative injury, reperfusion, chemicals, inflammation, microbes, gases, aging

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Free radicals can result in

lipid peroxidation, oxidative protein modification, DNA damage

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Examples of Free radicals

Hydrogen Peroxide (H2O2), Superoxide (O2-), Hydroxyl ions (-OH)

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Superoxide dismutase

converts superoxide (O2-) to hydrogen peroxide (H2O2)

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Radiation creates free radicals by

radiolysing H2O into hydroxyl ions (-OH)

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Aging and free radicals

continuous free radical production, decreased anti-oxidant production, decreased anti-oxidant activity

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Agents that are protective against free radicals

Antioxidants: Vitamin E, Glutathione, D-Penicillamine, serum proteins, flavonoids

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Catalase enzyme converts

H2O2 --> H2O and O2

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Glutathione peroxidase

H2O2 --> H20

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Free radical production increases with

AGE

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Direct acting chemicals induce chemical injury by

DIRECTLY combining with critical components of cellular organelle

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By-products of glycolysis

H2O2 and O2-

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Toxic metabolites of chemicals induce chemical injury by

metabolism of drugs create toxic active metabolites that can either directly bind critical components of cellular organelle or induce freed radical formation

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Lipid peroxidation in the liver due to drug metabolites free radical production result in

lipid peroxidation causing damage to RER and PM -> ribosome detachment and decreased protein synthesis (Fatty liver) OR -> PM damage and increased permeability, cell swelling, influx of Ca, necrosis

87

Viral infections cause cell injury by

causing cytolysis or cytopathic changes (degenerative changes)

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How does a virus directly damage the cell?

viral replication interferes with cellular mechanisms

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How does a virus inadvertently cause cell damage?

induces immunologic response: viral tropism (supporting growth of virus) result in phagocytosis, endocytosis or direct fusion of host cell

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Viral infections may cause host cell

lysis, cytoskeletal alterations, syncytial/giant cell formation, or inclusion formation

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Physiologic and biochemical mechanisms resulting in cellular injury may cause

morphological alterations in the cell

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Ultrastructural morphological changes include

PM alterations: swelling, blood formation, microvilli destruction, myelin figures;
Mitochondria: swelling, densities and granule formation
ER: swelling
Lysosome: swelling, rupture

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What morphological changes may be seen with the LIGHT microscope?

Reversible Injuries: Cellular swelling and intracellular accumulations
Irreversible Injuries: cell death

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Cell Death morphologic changes result from

Progressive degradation: enzyme digestion of cellular components and denaturation of proteins

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Autolysis

cellular digestion and denaturation cause by enzymes produced by necrotic cell

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Heterolysis

cellular digestion and denaturation cause by enzymes produced by cells other than the one affected

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General morphologic appearance of necrotic cell cytoplasm under the microscope?

eosinophilic (pink with H&E), glassy (loss of glycogen), and vacuolated

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General morphologic appearance of necrotic cell nucleus under the microscope?

clumped chromatin, pyknosis (shrunken nucleus), karyolysis (degraded nucleus), karyorrhexis (breakup of nucleus)

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Pyknosis

shrunken nucleus (as seen with necrotic cells)

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Karyolysis

degraded nucleus (as seen with necrotic cells)

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Karyorrhexis

breakup of nucleus (as seen with necrotic cells)

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Apoptosis

type of necrosis of an individual cell death by fragmentation and phagocytosis of fragments

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Coagulation Necrosis

Lose of nucleus due to denaturation of nuclear proteins and lysosomal enzymes (thus preventing proteolysis); cell shape maintained, eosinophila prominent

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Organs typically with coagulation necrosis

heart, kidney, and skeletal muscle

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Liquefeaction Necrosis

affected cell is completely digested by hydrolytic enzymes, resulting in a soft, circumscribed lesion consisting of pus

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Liquefeaction Necrosis hydrolytic enzymes are produced by

autolysis (self) or heterolysis (others)

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Liquefeaction Necrosis occurs primarily in the

brain, abdominal viscera and tissues infected with bacteria

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Liquefeaction Necrosis may result in _________ formation

abscess

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coagulation necrosis may progress to

Liquefeaction Necrosis

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Fat Necrosis

lipases cause saponification of fat -> resultant chalky white consistency

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Fat necrosis may result in ______

calcification

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Fat necrosis primarily occurs in

pancreas (after lipase and amylase release) and trauma to adipose tissue

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Caseation Necrosis is a combination of

coagulation and liquefaction necrosis

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Caseation Necrosis leads to ____ formation

granuloma

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Caseation Necrosis is characterized by

soft, granular, "cheesy" proteinacious material, surrounded by multinucleate giant cells, lymphocytes, and macrophages

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Caseation Necrosis primarily occurs in

any tissue infected with Mycobacterium tuberculosis and certain fungal infections

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Gangrenous Necrosis occurs primarily in

ISCHEMIC necrotic tissues, subsequently infected by anaerobic bacteria (Clostridium)

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Dry Gangrene

ISCHEMIA + necrosis and drying of the tissue -> black, mummified appearance

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Dry gangrene is typically caused by

arterial occlusion

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Dry gangrene microscopically shows ___________ necrosis

COAGULATION

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Wet gangrene is characterized by

soft, green-black, foul smelling purulent consistency

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Wet gangrene microscopically shows ___________ necrosis

Liquefaction following the release of autolytic, heterlytic, and bacterial enzymes

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Wet gangrene is typically caused by

arterial occlusion or traumatic injury

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Intracellular accumulations include

normal substances, abnormal substances, pigments; accumulation within the cell

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Intracellular accumulations may be:

harmful or harmless, within the cytoplasm or nucleus, produced by cell or elsewhere

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Types of intracellular accumulations

lipid, protein, glycogen, complex lipids, complex carbohydrates, pigments

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Lipid intracellular accumulations are characterized by

fatty change (fatty degeneration/infiltration)

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Lipid intracellular accumulations occur in

liver, heart, kidney, or skeletal muscle

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Lipid intracellular accumulations may be composed of

triglycerides, cholesterol, or both

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Protein intracellular accumulations may occur

in any tissue as HYALINE or plasma cells as RUSSELL BODIES

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Russell bodies

protein accumulation in plasma cells

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Protein intracellular accumulations often occur in

kidney, liver, or joints

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Glycogen intracellular accumulations

Common in diabetics (many tissues) and in glycogen storage diseases (specific or many tissues)

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Fatty liver

Fat accumulation in hepatocytes due to metabolic abnormality

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Lysosomal storage disease

accumulation in cells due to lack of enzyme

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Pigment intracellular accumulation

Normal or abnormal, produced endogenously or exogenously (uptake of indigestible material)

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Exogenous pigment accumulation include:

carbon (tattoo, anthracosis)

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Endogenous pigment accumulation include:

melanin, lipofuscin, hemosiderin, bilirubin and carotene

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Subcellular Alterations

changes occurring in the cell at the level of organelle

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Lysosome mechanism

vesicle from RER - Golgi - cytoplasm as primary lysosome fuses with phagosome to become secondary lysosome; hydrolytic enzymes digest phagosome particles

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Heterophagocytosis

type of phagocytosis of a compound outside the cell begin brought into the cell

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Heterophagocytosis is carried out by

neutrophils and macrophages

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Autophagocytosis

type of phagocytosis where lysosomes phagocytose damaged organelle originate ding within the same cell

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SER subcellular alterations due to injury

SR is broken down after PM damage

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Mitochondrial subcellular alterations due to injury

mitchondrial permeability transition pore -> loss of mitochondrial membrane potential -> loss of OXphos and ATP

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Lipofuscin pigment granules

finely granular yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion (aging process)

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What causes mitchondrial permeability transition pore formation?

increased Ca2+, free radicals, toxins, hypoxia

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Cytoskeleton/Cell membrane sub cellular alteration due to injury are characterized by

changes in the filaments and microtubules

149

Damage to cytoskeletal filaments and MT's result in

altered cellular structure, impaired phagocytosis, impaired mitosis, impaired sperm motility

150

Mallory Bodies

characteristic cytoskeletal change (twisted rope appearance) indicative of alcoholic liver disease

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Neurofibrillary tangles

characteristic cytoskeletal change - aggregates of hyperphosphorylated tau protein that are a primary marker of Alzheimer's Disease

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Atrophy - cellular adaptation

decreased cell size due to loss of cell substance

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Atrophy may be caused by

decreased workload (disuse), loss of innervation, decreased blood supply, inadequate nutrition, loss of endocrine stimulation, aging, pressure

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Hypertrophy

increase in cell size; increased demands of cell or increased stimulation by hormones

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Physiologic hypertrophy

uterine and breast enlargement during pregnancy

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Pathologic hypertrophy

cardiac hypertrophy in HTN or valvular incompetence

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Hyperplasia

increase in cell number (with hypertrophy depending on stimulus)

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Hyperplasia cannot occur in

nerve, skeletal, or cardiac muscle

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Physiologic Hyperplasia

Hormonal: epithelium of breast during puberty
Compensatory: to account for damaged tissue

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Pathologic Hyperplasia

Abnormal hormonal stimulation (endometrium, breast, adrenal)

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Metaplasia

Reversible change in cell type as a result of stress, divergent differentiation

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Metaplasia may lead to

pre-malignant (dysplastic) changes

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Dysplasia

Deranged development due to stimulation to proliferate with atypical cytological alterations

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Dysplasia may be

precursor to cancer

165

Calcification

Calcium salt + other ions precipitate and deposit in tissues

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Dystrophic calcification

deposition of calcium as a sequelae to necrosis or tissue injury and inflammation; intra- or extracellular

167

Examples of Dystrophic calcification

arteriosclerosis, fat necrosis

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Metastatic Calcification

Systemic hypercalcemia -> deposition of calcium in viable tissue

169

What condition is known for systemic increased levels of Ca?

Hyperparathyroidism -> systemic metastatic calcification deposition

170

Hyaline

translucent, albuminoid protein which is the product of amyloid degeneration

171

Intracellular hyaline deposition may occur

in plasma cells + viral infection, hepatocytes + chronic alcohol abuse

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Extracellular hyaline deposition may occur

arterial walls and in scar tissue following chronic inflammatory processes

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Desmoplasia

associated with malignant neoplasms, which can evoke a fibrosis response by invading healthy tissue.

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Fibrosis

formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process