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

Revision: cell injury Flashcards by Jack Hasler

Causes of cell injury and death

Hypoxia, toxins, Micro-Os, heat/cold, radiation, trauma, immune mech.s

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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

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examples of toxins

high gluc, salt and O2 levels/concs

insect/herbicides

poisons, pollutants

asbestos

alcohol, narcotic drugs, medicines

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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

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definitions of necrosis and apoptosis

necrosis: changes that occur in a cell AFTER death in living tissue
apoptosis: programmed cell death

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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

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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

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Structural reversible changes (seen down an EM)

blebs

cell swelling

chromatin clumping

autophagy (ie. hydrolysis of cell material by lysosomal enz.s)

ribosome dispersal

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what are blebs?

bumps where the cytokeleton has detached from the cell membrane

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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)

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types of necrosis

common: liquefactive, coagulative
rarer: fat, caseous

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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)

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liquefactive necrosis

enz. release > prot. denaturation

tiss is lysed and disappears

tends to be from infections, or an infarct in the brain

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caseous necrosis

1/2 way between coagulative and liquefactive necrosis

tiss. appears amorphous (‘cheese-like’)

caseous necrosis in lungs -> very likely to be TB

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fat necrosis

necrosis in adipose tiss.

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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