Revision: cell injury Flashcards
Causes of cell injury and death
Hypoxia, toxins, Micro-Os, heat/cold, radiation, trauma, immune mech.s
Hypoxia and types
reduced O2 use in cells
Hypoxaemic -> arterial content of O2 is low:
- reduced inspired O2 eg at high altitude
- reduced absorption eg secondary to lung disease
Anaemic -> decreased ability of Hb to carry O2:
- eg anaemia, CO poisoning
Ischaemic -> reduced blood flow:
- egblockage, cardiac failure
Histiocytic -> inability of cells to utilise the O2 in OxPhos
- eg cyanide poisoning
examples of toxins
high gluc, salt and O2 levels/concs
insect/herbicides
poisons, pollutants
asbestos
alcohol, narcotic drugs, medicines
immune mech.s that cause cell injury/death
Hypersensitive: host tiss is damaged secondarily to an overly vigorous immune rxn eg hives
Auto Immune Rxn: IS fails to recognise tiss as host tiss eg Hashimoto’s disease
definitions of necrosis and apoptosis
necrosis: changes that occur in a cell AFTER death in living tissue
apoptosis: programmed cell death
Reversible sequence of events after hypoxia
dec. OxPhos -> dec. ATP:
- > detachment of ribosomes from RER-> dec. prot. synth. -> lipid deposition
- > inc. glycolysis -> dec. pH and glycogen -> clumping of nuclear chromatin
- > dec Na/K ATPase functionality -> inc. Na, Ca, water inside cell and dec. K -> cell swells, loss of microvilli, blebs, ER swells, myelin figures
Irreversible tipping point in cell injury and chain of events
There is a massive influx of Ca into the cell from the mitochondria and ER stores, as well as from outside the cell, leading to the activation of various enzs:
ATPase -> breakdown of ATP
Phospholipase -> breakdown of phospholipids
Protease -> disruption of membrane and cytoskeletal proteins
Endonuclease -> chromatin damage
Structural reversible changes (seen down an EM)
blebs
cell swelling
chromatin clumping
autophagy (ie. hydrolysis of cell material by lysosomal enz.s)
ribosome dispersal
what are blebs?
bumps where the cytokeleton has detached from the cell membrane
structural irreversible changes (seen down an EM)
membrane defects (from phospholipase activation) leading to: defects in pm, lysosomal rupture, ER lysis
nuclear changes: pyknosis (swelling) -> karyorrhexis (fragmentation) -> karyolysis (dissolution)
types of necrosis
common: liquefactive, coagulative
rarer: fat, caseous
coagulative necrosis
prot. denaturation > enz. release
cellular architecture is somewhat preserved, leading to a ‘ghost outline’
tends to occur from infarcts (but if an infarct occurs in the brain it is liquefactive)
liquefactive necrosis
enz. release > prot. denaturation
tiss is lysed and disappears
tends to be from infections, or an infarct in the brain
caseous necrosis
1/2 way between coagulative and liquefactive necrosis
tiss. appears amorphous (‘cheese-like’)
caseous necrosis in lungs -> very likely to be TB
fat necrosis
necrosis in adipose tiss.
gangrene
grossly visible necrosis
‘Dry’: coagulative eg umbilical cord after death
‘Wet’: liquefactive - infarction -> neutrophils -> proteolytic enz.s are produced
infarct
= ischaemic necrosis
Can be white/red depending on haemorrhaging
White: end artery is occluded, no blood supply as there are no collateral arteries/ioles, leaves area w/o blood
Red: occlusion -> sudden haemorrhaging into vessel -> inc. pressure -> dec. blood flow -> ischaemia and infarction
microscopic changes in apoptosis
single/small clusters of cells affected
very eosinophilic (basic)
dense nuclear fragments
cell shrinkage
chromatin condensation
nuclear fragmentation
phagocytosis by macrophages
Electron microscopic changes in apoptosis
cytoplasmic blebs form
fragmentation into membrane-bound apoptotic bodies - cytoplasm, organelles, +/- nuclear fragments
Aspirin OD
aspirin = acetylsalicylic acid
OD -> respiratory centre stimulated to increase pH -> respiratoy alkalosis
compensatory mechanism, interfering w/ carb, fat and prot metab and OxPh leading to inc. lactate, pyruvate and ketones -> metabolic acidosis
can cause acute corrosive gastritis -> GI bleeding
inhibits platelet cyclo-oxygenase -> dec. platelet aggregation -> petechiae (pic) - red/purple spots on body from haemorrhaging
2 different types and 3 stages of apoptosis
extrinsic/intrinsic
1 initiation, 2 execution, 3 degradation and phagocytosis
extrinsic apoptosis
Initiation: Death ligand eg TRAIL binds to Death receptor eg TRAIL-R
Execution: Activation of caspases (enz.s that mediate cellular effects of apoptosis) independently of mitochondria
Degradation and phagocytosis: cell breaks up into fragments, these apoptotic bodies may express prot.s that enable phagocytosis by neighboring cells, they are then taken up by neighboring cells or phagocytes
intrinsic apoptosis
Initiation: eg DNA damage -> activation of p53
Execution: Inc. membrane permeability -> release of cytochrome C -> interacts w/ APAF1 and caspase 9 that then forms an apoptosome -> activation of more caspases
Degradation and phagocytosis: breakdown of cell into apoptotic bodies (may express prot.s on outside that enable uptake by neighboring cells), these are then phagocytosed or taken up by neighboring cells
Normal alcohol metabolism pathway
Ethanol -> Acetaldehyde -> Acetate
1st rxn is catalysed by Alcohol dehydrogenase, CYPZE1 (raised in chronic alcohol consumption), catalase
2nd rxn is catalysed by Aldehyde dehydrogenase
Result of chronic alcohol OD
Biochemical: raised CYPZE1, AST, ALT, MCV (mean corpuscular volume, the avg. RBC volume, this effect is due to toxic effects on bone marrow/folate deficiency), Gamma-GT (the latter is only present in CHRONIC consumption)
Histological: Liver - cirrhosis (regenerating hepatocytes are surrounded by bands of collagen)
CVS - cardiomyopahty from toxicity leading to cardiac dilatation
NS - Thiamine deficiency -> Wernicke syndrome -> degeneration of nerve cells, gliosis (proliferation of glial cells eg oligodendrocytes in response to damage to CNS), atrophy of cerebellum and peripheral nerves
Reproductive system - atrophy of testes, spontaneous abortion (NSWhy for both)
Foetal alcohol syndrome - from toxicity and acetaldehyde crossing placenta and damaging foetal brain -> growth and mental retardation, birth defects such as in brain, CVS
Normal paracetamol metabolism, and consequences w/in pathway of OD
paracetamol is aka acetaminophen
Normal: conjugation w/ sulphide/glucuronide
Abnormal: raised levels lead to entering into 1st stage of drug metabolism and P450 catalysing its conversion to NAPQI
NAPQI is toxic and requires glutathione to neutralise it, turning it to cysteine and mercapturic acid conjugates that are non-toxic
result of NAPQI production from paracetamol OD
NAPQI binds with sulphydryl groups on hepatocyte membranes -> necrosis -> liver failure
Acute renal failure secondary to tubular necrosis also occurs
Testing for OD: after 24 hrs, PT/INR (prothrombin time/international normalised ratio) - determines the clotting time of blood and therefore liver function (as liver produces the factors and enz.s responsible for blood clotting)
-also test serum creatinine levels and blood pH (in severe cases acidosis may be seen)
Antidote: NAC (N-acetylcysteine) inc.s the availability of glutathione to neutralise the toxic NAPQI
significant Free radicals, their generation, damage, removal
OH.(hydroxyl) is the most dangerous, O2-(Superoxide) and H2O2 are also important
generation: Fenton and Haber-Weiss Rxn, OxPhos, Cytosolic Rxns and p450 enz.s, metabolism of exogenous chemicals eg to CCl4
damage: Lipids: peroxidation of phopholipids in pm, autocatalytic rxn -> damage to pm
- Prots: prot. fragmentation and X-links formed
- DNA: single strand breaks formed, both in mitochondrial and nuclear
Removal: SOD turns SOR to hydrogen peroxide, catalase and peroxidases turn that to oxygen and water
- FR scavengers eg Vit C, E and A
- Storage prot.s sequester transition metals eg Fe, used in Fenton rxn
Main mech.s of cell injury
1 production of free radicals
2 derangement of metabolism eg cyanide poisoning
3 insufficient quantities of metab. intermediates eg glutathione
4 Alterations of Ca2+ homeostasis
5 Depletion of mitochondrial DNA and ATP
