Cellular Injury and Adaptation Flashcards
Homeostasis
balance of physiologic and biochemical functions within the body
Alteration of homeostasis results in
stress to cell, cellular injury or adaptive changes to survive altered environment
Reversible injury
injury is corrected prior to destruction of cellular repair mechanisms; severity of injury does not exceed the cells ability to repair itself
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
Cellular Injury
Hypoxia, Physical agents, chemicals, infectious agents, immune reactions, genetic derangements, nutritional imbalance
Hypoxia
Decreased supply of O2 to cell or inability to use O2
Anoxia
Complete absence of O2
Causes of Hypoxia
Ischemia (decreased BF), decreased oxygenation of blood, decreased O2 carrying capacity, inability to utilize O2
Examples of Physical injury to cell
mechanical trauma, temperature extremes, atmospheric pressure variation, radiation, electrical injury
Examples of Chemical Injury to cell
Simple agents (electrolytes, glucose), Poisons, Pollutants, Insecticides, herbicides, industrial products, drugs (therapeutic or recreational), alcohol
Infectious Causes of cell injury
bacteria, rickettsia, fungi, virus, parasite
Immune Response Causes of cell injury
Hypersensitivity reaction
4 Key Signs of REVERSIBLE cell injury
Decreased aerobic respiration, cellular edema, ribosome detachment from RER, ultrastructural morphological changes
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
Examples of nutritional variations that cause cellular injury
deficits, excess, malabsorption, altered use
Sites that are altered in cellular injury
cell membrane integrity, aerobic respiration, enzyme/protein synthesis, genetic apparatus
What causes cellular edema in reversible cell injury?
Suppression of Na+ pump with increased [Na+] retention; increased intracellular Na+
Ultrastructural Morphological Changes in reversible cellular injury
Phospholipid membrane alteration, loss of microvilli, myelin figure formation, mitochondrial swelling, RER swelling
Key Signs of IRREVERSIBLE cellular injury
ATP Depletion, Cell Membrane Damage
Cell Membrane Damage as a result of irreversible damage
Phospholipid Depletion, Cytoskeletal breakdown, toxic ROS, Lipid breakdown products, amino acid loss
Structural changes in IRREVERSIBLE cell injury include
vacuolization of mitochondria, PM damage, Lysosomal swelling, Loss of proteins, enzymes, and RNA
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
Irreversible Cellular Damage - What is the determining/most important factor?
Cellular Membrane Dysfunction
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
Myelin figures are characteristic of
reversible injury
cellular edema is characteristic of
reversible injury
Irreversible Cellular Damage - What causes membrane phospholipid depletion?
increase [Ca2+] intracellular activation of phospholipase AND ATP-dependent maintenance and production of phospholipids
Irreversible Cellular Damage - What causes cytoskeletal abnormalities?
Hypoxia AND activation of proteases by high intracellular levels of [Ca2+]
Irreversible Cellular Damage - What causes Toxic oxygen radical production?
sudden repercussion of hypoxic tissue
Irreversible Cellular Damage - What produces Toxic oxygen radicals?
segmented neutrophils
Reperfusion Injury
sudden reperfusion of ischemic tissue causes toxic oxygen radical production by segmented neutrophils
Irreversible Cellular Damage - What produces lipid breakdown products?
phospholipase breakdown of pospholipids, high [FFA]
Irreversible Cellular Damage - What amino acid is protective?
GLYCINE
GLYCINE’s protective feature
allows ATP depleted cells to resist high Ca2+ levels
decreased aerobic respiration is a characteristic of
reversible injury
increased intracellular pH is a characteristic of
reversible injury
Increased intracellular AMP is a characteristic of
reversible injury
Decreased glycogen stores v
reversible injury
clumping of nuclear chromatin is a characteristic of
reversible injury due to decreased pH
Ribosome detachment from RER is a characteristic of
reversible injury
decreased function of sodium pump is a characteristic of
reversible injury
Increased intracellular sodium is a characteristic of
reversible injury
decreased protein synthesis is a characteristic of
reversible injury
swelling of mitochondria is a characteristic of
reversible injury
loss of microvilli is a characteristic of
reversible injury
accumulation of lactate metabolites and phosphate is a characteristic of
reversible injury
blebs is a characteristic of
reversible edema; due to structural alterations in phospholipid membranes
myelin figures is a characteristic of
reversible injury
ATP depletion reversible injury
irreversible injury; suppression of ATP-dependent repair mechanisms
vacuolization of mitochondria is a characteristic of
irreversible injury
lysosomal swelling is a characteristic of
irreversible injury
loss proteins/enzymes and RNA is a characteristic of
irreversible injury
PM tearing/damage is a characteristic of
irreversible injury
Increased cytosolic [Ca2+] is a characteristic of
irreversible injury
Increased [Ca2+] causes
activation of mitochondrial phospholipase and lysosomal proteases, ATPases, endonucleases
Phospholipase
mitochondrial ([Ca2+] activated) breaks down phospholipids of PM
Accumulation of FFA’s is a characteristic of
irreversible injury
Permeability changes in PM is a characteristic of
irreversible injury
Membrane phospholipid depletion is a characteristic of
irreversible injury
Damage to intermediate cytoskeletal filaments is a characteristic of
irreversible injury; hypoxia induced
Separation of PM and cytoskeleton is a characteristic of
irreversible injury
Proteases
lysosomal proteases released and activated by high intracellular [Ca2+]
Toxic oxygen radicals is a characteristic of
irreversible injury
reperfusion injury is a characteristic of
irreversible injury
accumulation of lipid breakdown products is a characteristic of
irreversible injury
loss of glycine and other amino acids is a characteristic of
irreversible injury
Glycine
allows ATP depleted cells to resist high Ca2+ levels
Reason for decreased protein synthesis in cellular injury?
detachment of ribosomes from RER
Reason for nuclear clumping in cellular injury?
increased anaerobic glycolysis and decreased pH
Intracellular release of lysosomal enzymes is a characteristic of
irreversible injury
What is a free radical?
Activated oxygen or carbon species that cause cell damage (ROS, COS)
Unstable free radicals react with?
inorganic and organic chemicals in membrane lipids and nucleic acids
What generates free radicals?
autocatalytic reactions within the cell, O2 therapy, radiation, oxidative injury, reperfusion, chemicals, inflammation, microbes, gases, aging
Free radicals can result in
lipid peroxidation, oxidative protein modification, DNA damage
Examples of Free radicals
Hydrogen Peroxide (H2O2), Superoxide (O2-), Hydroxyl ions (-OH)
Superoxide dismutase
converts superoxide (O2-) to hydrogen peroxide (H2O2)
Radiation creates free radicals by
radiolysing H2O into hydroxyl ions (-OH)
Aging and free radicals
continuous free radical production, decreased anti-oxidant production, decreased anti-oxidant activity
Agents that are protective against free radicals
Antioxidants: Vitamin E, Glutathione, D-Penicillamine, serum proteins, flavonoids
Catalase enzyme converts
H2O2 –> H2O and O2
Glutathione peroxidase
H2O2 –> H20
Free radical production increases with
AGE
Direct acting chemicals induce chemical injury by
DIRECTLY combining with critical components of cellular organelle
By-products of glycolysis
H2O2 and O2-
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
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
Viral infections cause cell injury by
causing cytolysis or cytopathic changes (degenerative changes)
How does a virus directly damage the cell?
viral replication interferes with cellular mechanisms
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
Viral infections may cause host cell
lysis, cytoskeletal alterations, syncytial/giant cell formation, or inclusion formation
Physiologic and biochemical mechanisms resulting in cellular injury may cause
morphological alterations in the cell
Ultrastructural morphological changes include
PM alterations: swelling, blood formation, microvilli destruction, myelin figures;
Mitochondria: swelling, densities and granule formation
ER: swelling
Lysosome: swelling, rupture
What morphological changes may be seen with the LIGHT microscope?
Reversible Injuries: Cellular swelling and intracellular accumulations
Irreversible Injuries: cell death
Cell Death morphologic changes result from
Progressive degradation: enzyme digestion of cellular components and denaturation of proteins
Autolysis
cellular digestion and denaturation cause by enzymes produced by necrotic cell
Heterolysis
cellular digestion and denaturation cause by enzymes produced by cells other than the one affected
General morphologic appearance of necrotic cell cytoplasm under the microscope?
eosinophilic (pink with H&E), glassy (loss of glycogen), and vacuolated
General morphologic appearance of necrotic cell nucleus under the microscope?
clumped chromatin, pyknosis (shrunken nucleus), karyolysis (degraded nucleus), karyorrhexis (breakup of nucleus)
Pyknosis
shrunken nucleus (as seen with necrotic cells)
Karyolysis
degraded nucleus (as seen with necrotic cells)
Karyorrhexis
breakup of nucleus (as seen with necrotic cells)
Apoptosis
type of necrosis of an individual cell death by fragmentation and phagocytosis of fragments
Coagulation Necrosis
Lose of nucleus due to denaturation of nuclear proteins and lysosomal enzymes (thus preventing proteolysis); cell shape maintained, eosinophila prominent
Organs typically with coagulation necrosis
heart, kidney, and skeletal muscle
Liquefeaction Necrosis
affected cell is completely digested by hydrolytic enzymes, resulting in a soft, circumscribed lesion consisting of pus
Liquefeaction Necrosis hydrolytic enzymes are produced by
autolysis (self) or heterolysis (others)
Liquefeaction Necrosis occurs primarily in the
brain, abdominal viscera and tissues infected with bacteria
Liquefeaction Necrosis may result in _________ formation
abscess
coagulation necrosis may progress to
Liquefeaction Necrosis
Fat Necrosis
lipases cause saponification of fat -> resultant chalky white consistency
Fat necrosis may result in ______
calcification
Fat necrosis primarily occurs in
pancreas (after lipase and amylase release) and trauma to adipose tissue
Caseation Necrosis is a combination of
coagulation and liquefaction necrosis
Caseation Necrosis leads to ____ formation
granuloma
Caseation Necrosis is characterized by
soft, granular, “cheesy” proteinacious material, surrounded by multinucleate giant cells, lymphocytes, and macrophages
Caseation Necrosis primarily occurs in
any tissue infected with Mycobacterium tuberculosis and certain fungal infections
Gangrenous Necrosis occurs primarily in
ISCHEMIC necrotic tissues, subsequently infected by anaerobic bacteria (Clostridium)
Dry Gangrene
ISCHEMIA + necrosis and drying of the tissue -> black, mummified appearance
Dry gangrene is typically caused by
arterial occlusion
Dry gangrene microscopically shows ___________ necrosis
COAGULATION
Wet gangrene is characterized by
soft, green-black, foul smelling purulent consistency
Wet gangrene microscopically shows ___________ necrosis
Liquefaction following the release of autolytic, heterlytic, and bacterial enzymes
Wet gangrene is typically caused by
arterial occlusion or traumatic injury
Intracellular accumulations include
normal substances, abnormal substances, pigments; accumulation within the cell
Intracellular accumulations may be:
harmful or harmless, within the cytoplasm or nucleus, produced by cell or elsewhere
Types of intracellular accumulations
lipid, protein, glycogen, complex lipids, complex carbohydrates, pigments
Lipid intracellular accumulations are characterized by
fatty change (fatty degeneration/infiltration)
Lipid intracellular accumulations occur in
liver, heart, kidney, or skeletal muscle
Lipid intracellular accumulations may be composed of
triglycerides, cholesterol, or both
Protein intracellular accumulations may occur
in any tissue as HYALINE or plasma cells as RUSSELL BODIES
Russell bodies
protein accumulation in plasma cells
Protein intracellular accumulations often occur in
kidney, liver, or joints
Glycogen intracellular accumulations
Common in diabetics (many tissues) and in glycogen storage diseases (specific or many tissues)
Fatty liver
Fat accumulation in hepatocytes due to metabolic abnormality
Lysosomal storage disease
accumulation in cells due to lack of enzyme
Pigment intracellular accumulation
Normal or abnormal, produced endogenously or exogenously (uptake of indigestible material)
Exogenous pigment accumulation include:
carbon (tattoo, anthracosis)
Endogenous pigment accumulation include:
melanin, lipofuscin, hemosiderin, bilirubin and carotene
Subcellular Alterations
changes occurring in the cell at the level of organelle
Lysosome mechanism
vesicle from RER - Golgi - cytoplasm as primary lysosome fuses with phagosome to become secondary lysosome; hydrolytic enzymes digest phagosome particles
Heterophagocytosis
type of phagocytosis of a compound outside the cell begin brought into the cell
Heterophagocytosis is carried out by
neutrophils and macrophages
Autophagocytosis
type of phagocytosis where lysosomes phagocytose damaged organelle originate ding within the same cell
SER subcellular alterations due to injury
SR is broken down after PM damage
Mitochondrial subcellular alterations due to injury
mitchondrial permeability transition pore -> loss of mitochondrial membrane potential -> loss of OXphos and ATP
Lipofuscin pigment granules
finely granular yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion (aging process)
What causes mitchondrial permeability transition pore formation?
increased Ca2+, free radicals, toxins, hypoxia
Cytoskeleton/Cell membrane sub cellular alteration due to injury are characterized by
changes in the filaments and microtubules
Damage to cytoskeletal filaments and MT’s result in
altered cellular structure, impaired phagocytosis, impaired mitosis, impaired sperm motility
Mallory Bodies
characteristic cytoskeletal change (twisted rope appearance) indicative of alcoholic liver disease
Neurofibrillary tangles
characteristic cytoskeletal change - aggregates of hyperphosphorylated tau protein that are a primary marker of Alzheimer’s Disease
Atrophy - cellular adaptation
decreased cell size due to loss of cell substance
Atrophy may be caused by
decreased workload (disuse), loss of innervation, decreased blood supply, inadequate nutrition, loss of endocrine stimulation, aging, pressure
Hypertrophy
increase in cell size; increased demands of cell or increased stimulation by hormones
Physiologic hypertrophy
uterine and breast enlargement during pregnancy
Pathologic hypertrophy
cardiac hypertrophy in HTN or valvular incompetence
Hyperplasia
increase in cell number (with hypertrophy depending on stimulus)
Hyperplasia cannot occur in
nerve, skeletal, or cardiac muscle
Physiologic Hyperplasia
Hormonal: epithelium of breast during puberty
Compensatory: to account for damaged tissue
Pathologic Hyperplasia
Abnormal hormonal stimulation (endometrium, breast, adrenal)
Metaplasia
Reversible change in cell type as a result of stress, divergent differentiation
Metaplasia may lead to
pre-malignant (dysplastic) changes
Dysplasia
Deranged development due to stimulation to proliferate with atypical cytological alterations
Dysplasia may be
precursor to cancer
Calcification
Calcium salt + other ions precipitate and deposit in tissues
Dystrophic calcification
deposition of calcium as a sequelae to necrosis or tissue injury and inflammation; intra- or extracellular
Examples of Dystrophic calcification
arteriosclerosis, fat necrosis
Metastatic Calcification
Systemic hypercalcemia -> deposition of calcium in viable tissue
What condition is known for systemic increased levels of Ca?
Hyperparathyroidism -> systemic metastatic calcification deposition
Hyaline
translucent, albuminoid protein which is the product of amyloid degeneration
Intracellular hyaline deposition may occur
in plasma cells + viral infection, hepatocytes + chronic alcohol abuse
Extracellular hyaline deposition may occur
arterial walls and in scar tissue following chronic inflammatory processes
Desmoplasia
associated with malignant neoplasms, which can evoke a fibrosis response by invading healthy tissue.
Fibrosis
formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process
