Revision: cell injury

Question 1

Causes of cell injury and death

Answer 1

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

Question 2

Hypoxia and types

Answer 2

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

Question 3

examples of toxins

Answer 3

high gluc, salt and O2 levels/concs

insect/herbicides

poisons, pollutants

asbestos

alcohol, narcotic drugs, medicines

Question 4

immune mech.s that cause cell injury/death

Answer 4

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

Question 5

definitions of necrosis and apoptosis

Answer 5

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

Question 6

Reversible sequence of events after hypoxia

Answer 6

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

Question 7

Irreversible tipping point in cell injury and chain of events

Answer 7

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

Question 8

Structural reversible changes (seen down an EM)

Answer 8

blebs

cell swelling

chromatin clumping

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

ribosome dispersal

Question 9

what are blebs?

Answer 9

bumps where the cytokeleton has detached from the cell membrane

Question 10

structural irreversible changes (seen down an EM)

Answer 10

membrane defects (from phospholipase activation) leading to: defects in pm, lysosomal rupture, ER lysis

nuclear changes: pyknosis (swelling) -> karyorrhexis (fragmentation) -> karyolysis (dissolution)

Question 11

types of necrosis

Answer 11

common: liquefactive, coagulative
rarer: fat, caseous

Question 12

coagulative necrosis

Answer 12

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)

Question 13

liquefactive necrosis

Answer 13

enz. release > prot. denaturation

tiss is lysed and disappears

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

Question 14

caseous necrosis

Answer 14

1/2 way between coagulative and liquefactive necrosis

tiss. appears amorphous (‘cheese-like’)

caseous necrosis in lungs -> very likely to be TB

Question 15

fat necrosis

Answer 15

necrosis in adipose tiss.

Question 16

gangrene

Answer 16

grossly visible necrosis

‘Dry’: coagulative eg umbilical cord after death

‘Wet’: liquefactive - infarction -> neutrophils -> proteolytic enz.s are produced

Question 17

infarct

Answer 17

= 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

Question 18

microscopic changes in apoptosis

Answer 18

single/small clusters of cells affected

very eosinophilic (basic)

dense nuclear fragments

cell shrinkage

chromatin condensation

nuclear fragmentation

phagocytosis by macrophages

Question 19

Electron microscopic changes in apoptosis

Answer 19

cytoplasmic blebs form

fragmentation into membrane-bound apoptotic bodies - cytoplasm, organelles, +/- nuclear fragments

Question 20

Aspirin OD

Answer 20

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

Question 21

2 different types and 3 stages of apoptosis

Answer 21

extrinsic/intrinsic

1 initiation, 2 execution, 3 degradation and phagocytosis

Question 22

extrinsic apoptosis

Answer 22

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

Question 23

intrinsic apoptosis

Answer 23

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

Question 24

Normal alcohol metabolism pathway

Answer 24

Ethanol -> Acetaldehyde -> Acetate

1st rxn is catalysed by Alcohol dehydrogenase, CYPZE1 (raised in chronic alcohol consumption), catalase

2nd rxn is catalysed by Aldehyde dehydrogenase

Question 25

Result of chronic alcohol OD

Answer 25

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

Question 26

Normal paracetamol metabolism, and consequences w/in pathway of OD

Answer 26

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

Question 27

result of NAPQI production from paracetamol OD

Answer 27

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

Question 28

significant Free radicals, their generation, damage, removal

Answer 28

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

Question 29

Main mech.s of cell injury

Answer 29

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