wednesday 6/12/19 michelle dolan, m.d. dept. of laboratory ...€¦ · figure 1-17 functional and...
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¡ Normal cells have a fairly narrow range of function or steady state: Homeostasis
¡ Excess physiologic or pathologic stress may force the cell to a new steady state: Adaptation
¡ Too much stress exceeds the cell’s adaptive capacity: Injury
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Figure 1-1 Stages of the cellular response to stress and injurious stimuli.
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Figure 1-7 Sequential development of biochemical and morphologic changes in cell injury. Cells may become rapidly nonfunctional after the onset of injury, although they are still viable, with
potentially reversible damage; a longer duration of injury may eventually lead to irreversible injury and cell death. Note that irreversible biochemical alterations may cause cell death, and typically
this precedes ultrastructural, light microscopic, and grossly visible morphologic changes.
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Figure 1-8 Schematic illustration of the morphologic changes in cell injury culminating in necrosis or apoptosis.
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¡ Cell injury can be reversible or irreversible¡ Reversibility depends on the type, severity
and duration of injury¡ Cell death is the result of irreversible injury
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¡ Four very interrelated cell systems are particularly vulnerable to injury:§ Membranes (cellular and organellar)§ Aerobic respiration§ Protein synthesis (enzymes, structural
proteins, etc)§ Genetic apparatus (e.g., DNA, RNA)
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¡ Loss of calcium homeostasis¡ Defects in membrane permeability¡ ATP depletion¡ Oxygen and oxygen-derived free radicals
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Figure 1-16 The principal mechanisms of cell injury, and their biochemical and functional effects, are shown. These are described in detail in the text.
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¡ Hypoxia§ Ischemia§ Hypoxemia§ Loss of oxygen carrying capacity
¡ Free radical damage¡ Chemicals, drugs, toxins (e.g., acids, bases, organo-
phosphates)¡ Infections¡ Physical agents¡ Immunologic reactions¡ Genetic abnormalities (e.g., storage diseases,
enzyme deficiencies)¡ Nutritional imbalance (e.g., protein or calorie
malnutrition)
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¡ Block in ventilation (e.g., foreign body)¡ Block in diffusion of oxygen (e.g., pneumonia,
pulmonary edema)¡ Block in perfusion (e.g., pulmonary embolus)¡ Decreased cardiac output¡ Decreased oxygen carrying capacity (e.g., anemia)¡ Ischemia (e.g., blockage of blood flow) à oxygen
and glycogen rapidly depleted; metabolites accumulate and are not carried away by circulation (\more rapid and severe acidosis)
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¡ Oxygen tension fallsß
¡ Oxidative phosphorylation disruptedß
¡ ATP levels fallß
¡ Wide ranging effects
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¡ Mitochondrial oxidative phosphorylation is disrupted first àêATP ৠê Na/K ATPase àéintracellular Na à cell swelling§ êATP-dependent Ca pumps àécytoplasmic [Ca]§ Anaerobic respirationàêglycogen § Lactic acid accumulation àê pH§ Detachment of ribosomes from RER àê protein
synthesis¡ End result is cytoskeletal disruption with loss of
microvilli, bleb formation, etc
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Figure 1-17 Functional and morphologic consequences of decreased intracellular ATP during cell injury. The morphologic changes shown here are indicative of reversible cell injury. Further
depletion of ATP results in cell death, typically by necrosis. ER, endoplasmic reticulum.
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¡ Mitochondrial swelling with formation of large amorphous densities in matrix
¡ Lysosomal membrane damage à leakage of proteolytic enzymes into cytoplasm
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¡ Membrane damage and loss of calcium homeostasis are most crucial
¡ Too much cytoplasmic calcium:§ Denatures proteins§ Poisons mitochondria§ Inhibits cellular enzymes
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Figure 1-19 The role of increased cytosolic calcium in cell injury. ER, endoplasmic reticulum.
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Figure 1-21 Mechanisms of membrane damage in cell injury. Decreased O2 and increased cytosolic Ca2+ are typically seen in ischemia but may accompany other forms of cell injury. Reactive oxygen species, which are often produced on reperfusion of ischemic tissues, also
cause membrane damage (not shown).
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¡ Injured membranes are leaky¡ Enzymes and other proteins that escape
through the leaky membranes make their way to the bloodstream, where they can be measured in the serum
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¡ Free radicals have an unpaired electron in their outer orbit
¡ Free radicals cause chain reactions¡ Generated by:
§ Absorption of radiant energy§ Oxidation of endogenous constituents§ Oxidation of exogenous compounds
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¡ Chemical (e.g., CCl4, acetaminophen)¡ Inflammation / Microbial killing¡ Irradiation (e.g., UV rays à skin cancer)¡ Oxygen (e.g., exposure to very high
oxygen tension on ventilator)¡ Age-related changes
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¡ Lipid peroxidation à damage to phospholipids (cellular and organellar membranes) and proteins§ Oxidized phospholipids and proteins are not readily
broken down à\ accumulate and aggregate¡ Protein cross-linking and fragmentation due to
oxidative modification of amino acids and proteins
¡ DNA damage due to reactions of free radicals with thymine
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Rubin Fig 1-11
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¡ Morphologic changes follow functional changes
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Figure 1-7 Sequential development of biochemical and morphologic changes in cell injury. Cells may become rapidly nonfunctional after the onset of injury, although they are still viable, with
potentially reversible damage; a longer duration of injury may eventually lead to irreversible injury and cell death. Note that irreversible biochemical alterations may cause cell death, and typically
this precedes ultrastructural, light microscopic, and grossly visible morphologic changes.
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¡ Light microscopic changes§ Cell swelling (a/k/a hydropic change)§ Fatty change
¡ Ultrastructural changes§ Alterations of cell membrane§ Swelling of and small amorphous deposits in
mitochondria§ Swelling of RER and detachment of ribosomes
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Hydropic change (cell swelling) in hepatocytes
Rubin, Fig 1-1
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Swelling of RER
Disaggregation of ribosomes from RERRubin Figs 1-2, 1-3
Normal Swollen
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Swelling of mitochondria
Rubin Fig 1-4
Normal Swollen
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Rubin
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¡ Light microscopic changes§ Increased cytoplasmic eosinophilia (loss of RNA,
which is more basophilic)§ Cytoplasmic vacuolization§ Nuclear chromatin clumping
¡ Ultrastructural changes§ Breaks in cellular and organellar membranes§ Larger amorphous densities in mitochondria§ Nuclear changes
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¡ Pyknosis§ Nuclear shrinkage and increased basophilia
¡ Karyorrhexis§ Fragmentation of the pyknotic nucleus
¡ Karyolysis§ Fading of basophilia of chromatin
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http://education.vetmed.vt.edu/Curriculum/VM8304/vet%20pathology/CASES/CELLINJURY2/PAGE4-10.htm
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¡ Apoptosis§ Usually a regulated, controlled process
(“programmed cell death”)§ Energy-dependent§ Death of single, isolated cells within a tissue
¡ Necrosis§ Always pathologic – the result of irreversible
injury§ Widespread cell death within a tissue or organ§ Induces inflammatory response
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Figure 1-8 Schematic illustration of the morphologic changes in cell injury culminating in necrosis or apoptosis.
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¡ Involved in many processes, some physiologic, some pathologic§ Programmed cell death during embryogenesis§ Hormone-dependent involution of organs in the
adult (e.g., thymus)§ Cell deletion in proliferating cell populations§ Cell death in tumors§ Cell injury in some viral diseases (e.g., hepatitis)
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Rubin Fig 1-39
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¡ Cell shrinkage with increased cytoplasmic density
¡ Chromatin condensation¡ Formation of cytoplasmic blebs and
apoptotic bodies¡ Phagocytosis of apoptotic cells by adjacent
healthy cells
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Rubin Fig 1-36
Normal cell Apoptotic cell with nuclear fragmentation
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Fig. 1-24
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¡ Controlled by BCL protein family – both pro- and anti-apoptotic§ Pro-apoptotic: BAX, BAK
▪ BAD, BIM, BID, Puma, Noxa: sense cell injury è activate BAX and BAK
▪ BAX and BAK form oligomers that insert into mitochondrial membrane to create channels
§ Simultaneous ê in anti-apoptotic proteins (BCL2, BCL-XL, MCL1), which normally keep mitochondrial outer membrane impermeable
§ Net result: cytoplasmic release of mitochondrial proteins triggers caspase cascade
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Fig. 1-25
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Fig. 1-24
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¡ TNF receptor family members (“death receptors;” e.g., TNFR1, Fas) bind to cell membrane
¡ Fas ligand (FasL) binds to Fas è oligomerization of Fas forms binding site for adapter protein Fas associated death domain (FADD)
¡ FADD binds to inactive caspase-8 which in turn cleaves other nearby caspase-8 molecules to form active form è cascade of caspase activation
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Fig. 1-26
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¡ Caspase cascade initiated by intrinsic and extrinsic pathways è activation of executioner caspases that have wide ranging effects:§ Activate DNases to cleave DNA§ Degrade structural components of nuclear matrix è nuclear fragmentation
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¡ Too little (é cell survival)§ Malignancies (e.g., mutations in TP53 è failure of
cells with damaged DNA to die)§ Autoimmune disorders
¡ Too much (é cell death)§ Neurodegenerative disorders§ Ischemic injury§ Viral infections
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¡ Coagulative (most common)¡ Liquefactive¡ Caseous¡ Fat necrosis¡ Gangrenous necrosis
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¡ Cells’ basic outlines are preserved¡ Homogeneous, glassy eosinophilic
appearance due to loss of cytoplasmic RNA (basophilic) and glycogen (granular)
¡ Nucleus may show pyknosis, karyolysis or karyorrhexis
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Figure 1-11 Coagulative necrosis. A, A wedge-shaped kidney infarct (yellow). B, Microscopic view of the edge of the infarct, with normal kidney (N) and necrotic cells in the infarct (I) showing
preserved cellular outlines with loss of nuclei and an inflammatory infiltrate (which is difficult to discern at this magnification).
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http://www3.dut.ac.za/olympus1/html/myron/PATH%20WEB%20DEVELOPMENT/GENERAL%20PATHOLOGY%20II/PAST%20PRACTICALS/PathPrac_1/Question_4_a.htm
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http://upload.wikimedia.org/wikipedia/commons/8/8e/Acute_myocardial_infarction_with_coagulative_necrosis_(4).JPG&imgrefurl=http://pl.wikipedia.org/wiki/Plik:Acute_myocardial_infarction_with_coagulative_necrosis_(4).JPG&usg=__gN5em-RPMDY1QXzIY8gFTCZ_iNA=&h=376&w=500&sz=99&hl=en&start=66&zoom=1&itbs=1&tbnid=FaENJrUKXB3wkM:&tbnh=98&tbnw=130&prev=/search%3Fq%3Dmyocardial%2Binfarction%26start%3D60%26hl%3Den%26sa%3DN%26ndsp%3D20%26tbm%3Disch&ei=xdzHTZjUFom_gQf4opzOBA
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¡ Usually due to enzymatic dissolution of necrotic cells (usually due to release of proteolytic enzymes from neutrophils)
¡ Most often seen in CNS and in abscesses
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Figure 1-12 Liquefactive necrosis. An infarct in the brain, showing dissolution of the tissue.
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¡ Gross: Resembles cheese¡ Micro: Amorphous, granular eosinophilc
material surrounded by a rim of inflammatory cells§ No visible cell outlines – tissue architecture is
obliterated¡ Usually seen in infections (esp. mycobacterial
and fungal infections)
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Figure 1-13 Caseous necrosis. Tuberculosis of the lung, with a large area of caseous necrosis containing yellow-white and cheesy debris.
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Rubin Fig 1-34
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¡ Results from hydrolytic action of lipases on fat
¡ Most often seen in and around the pancreas; can also be seen in other fatty areas of the body, usually due to trauma
¡ Fatty acids released via hydrolysis react with calcium to form chalky white areas à“saponification”
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Figure 1-14 Fat necrosis. The areas of white chalky deposits represent foci of fat necrosis with calcium soap formation (saponification) at sites of lipid breakdown in the mesentery.
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http://www.udel.edu/biology/Wags/histopage/colorpage/ca/watmv.GIF
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¡ Most often seen on extremities, usually due to trauma or physical injury
¡ “Dry” gangrene – no bacterial superinfection; tissue appears dry
¡ “Wet” gangrene – bacterial superinfection has occurred; tissue looks wet and liquefactive
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http://eso-cdn.bestpractice.bmj.com/best-practice/images/bp/en-gb/1156-3_default.jpg
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¡ Usually seen in the walls of blood vessels (e.g., in vasculitides)
¡ Glassy, eosinophilic fibrin-like material is deposited within the vascular walls
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Figure 1-15 Fibrinoid necrosis in an artery. The wall of the artery shows a circumferential bright pink area of necrosis with inflammation (neutrophils with dark nuclei).
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Rubin Fig 1-35