Cell Injury Flashcards
hypoxia
oxygen deprivation due to inadequate oxygenation of the blood (cardiorespiratory failure, CO poisoning)
Ischemia
loss of blood supply. more rapidly injurious than hypoxia bc of loss of both oxygen and nutrients. No glycolytic energy production can occur (as in hypoxia)
cellular adaptations
physiologic and morphologic cellular changes leading to a new but altered steady state. caused by excessive stress or pathologic stimuli. REVERSIBLE
four types of cellular adaptations
hyperplasia, hypertrophy, atrophy, metaplasia
hyperplasia
an increase in the number of cells in an organ or tissue due to an increased demand for function
types of hyperplasia
normal hormonal (uterus during pregnancy), compensatory (regeneration), pathologic (excessive hormonal stimulation to divide)
hypertrophy
an increase in cell size due to increased protein synthesis (not due to cell swelling). caused by in increased demand for function, mechanically or hormonally.
types of hypertrophy
skeletal muscle (exercise, steroids), cardiac (hypertension, valvular stenosis)
atrophy
decrease in cell size. caused by decreased workload, decreased blood supply, inadequate nutrition, loss of endocrine stimulation, denervation
metaplasia
a reversible change in the differentiation program of tissue stem cells to a different mature cell type
classic example of metaplasia
protective change from psuedostratified to squamous metaplasia of the respiratory tract due to smoking. loss of mucus production/cilia. also metaplasic changes may predispose to neoplastic formation and cancer
which cells are most susceptible to ischemic injury?
neurons>myocardium, hepatocytes, renal epithelia>fibroblast, epidermis, skeletal muscle
consequences of ischemia
decreased oxphos=decreased ATP=decreased Na pump (swelling), increased glycolysis (acidosis), decreased protein synthesis (lipid deposition)
what is generally indicative of irreversible cell injury
large increase in intracellular Ca2+ (after damage to membrane. activates proteases and leads to lysosomal lysis which damages membranes)
how does mitochondrial dysfunction lead to cell injury?
via formation of free radicals
defenses against free radicals
antioxidants, superoxide dismutase, catalase, glutathione peroxidase, ferritin
ferritin
an iron is an iron storage and detoxifying protein. limits toxicity due to iron donating electrons to H2O2–> OH*
which nucleic bases do free radicals react with?
A & T, cause single chain breaks
lipid peroxidation
free radicals interact with the double bonds in poly-unsaturated fatty acids resulting in lipid peroxides, which react with O2 which ultimately produces lipid hydroperoxides. (chain rxn of radical formation)
carbon tetrachloride
dry cleaning solvent. converted by cytochrome P-450 to highly reactive free radical. Causes lipid peroxidation (a chain rxn). ER in liver is affected=decreased protein synthesis and fat export (hepatocyte fat accumulation=cell death)
necrosis
morphological changes that follow cell death due to the degradative actions of enzymes and protein denaturation
three types of necrosis
coagulative, caseous, liquefactive
coagulative necrosis
most common type of necrosis, proteins denature & coagulate, cytoplasm becomes eosinophilic, cellular architecture is preserved. characteristic pattern of irreversible ischemic injury to solid organs.
why is coagulative necrosis surrounded by red border?
RBCs pile up since their entry into the necrotic area is impaired
liquefactive necrosis
hydrolytic enzymes predominate over protein denaturation. rapid softening with loss of cell outlines. characteristic of brain tissue and inflammatory rxns.
caseous necrosis
combination of coagulative and liquefactive. principally associated with TB. cells aren’t totally liquefied, but outlines are not preserved and necrotic areas is surrounded by granulomatous inflammatory wall.
apoptosis
morphological manifestation of programmed cell death, which is designed to eliminate unwanted cells through the activation of a coordinated set of regulatory and effector proteins
morphological changes associated with apoptosis
cell shrinks, chromatin condenses, cytoplasmic blebs break off, macrophages phagocytose blebs, membrane remains in tact, doesn’t elicit inflammation
p53
normally delays cell cycle allowing for DNA damage repair, but stimulates apoptosis when repair fails. mutated in tumors
extrinsic pathway of apoptosis (death receptor pathway)
initiated by binding of FasL from CTLs to Fas death receptor. multimerization in induced and activates FADD protein, which activates pro-caspase 8, the executioner proteins.
Bcl-2 protein family function
regulates outer membrane permeability. consist of BH genes
apoptotic mitochondrial pathway
outer mitochondrial membrane becomes permeable and pro-apoptotic proteins (cytochrome c) are released, which neutralize apoptotic inhibitors in cytosol. Forms apoptosome, which activates caspases
caspase
the executioner proteins of apoptosis that process substrates leading to DNA degradation, chromatin condensation, and membrane blebbing
what is required for the apoptosome formation?
ATP
multi domain, anti apoptotic protein in Bcl-2 family
Bcl-2 (inhibits permeability)
which Bcl-2 gene on its own is pro-apoptotic?
BH3 (enhances permeability)
multi-domain, pro apoptotic protein in Bcl-2 family
Bak, Bax (enhances permeability)
what sets the threshold of susceptibility to apoptosis for the mitochondrial/intrinsic pathway?
ratio of anti to pro apoptotic proteins in the membrane
