Cell injury and necrosis Flashcards
(21 cards)
Causes of cell injury (broad)
• Hypoxia (deficiency of tissue oxygen) • Chemicals and drugs • Micro-organisms • Immunological and allergic reactions • Genetic diseases • Nutritional imbalance * Metabolic abnormalities
Mechanisms of cell injury (more specific) (4)
- mitochondria damage : depletion of ATP and increased production of reactive oxygen species (ROS) - depletion of ATP - failure of ATP-dependent pumps etc - disturbance of calcium homeostasis -> entry of Ca2+ into cell - damage to cell membranes (plasma membrane and lysosomal membrane) - damage to DNA and misfolding of proteins
How does disturbance of calcium homeostasis lead to cell injury?
(1) increase mitochondrial permeability - lead to ROS, and decreased ATP (2) active cell enzymes (ATP-ase, phospholipse, protease, endonuclease) End up with: - decreased ATP - membrane damage - nuclear damage
Features of reversible cell injury
- cell swelling (due to failure of energy-dependant pumps) - accumulation of lipid in cells that normally metabolise it (hepatocytes, myocardial cells) - livery - shows Mallory-Denk body (cell injury seen in alcholoic poisoning)
How does reversible cell injury -> irreversible cell injury How can you tell which way an injured cell will go?
- uncorrectable mitochondrial dysfunction (can’t get ATP via oxidative phosphorylation - loss of cell membrane integrity Can’t tell by looking which way a cell will no (no identified biochem or str change)
When can you see microscopic change of cell injury
Biochemical changes occur before structural changes cell can be dead without any microscopic change - so it takes a while eg in ischaemia - myocytes die within 30min, but no change in H&E for 12hrs
Necrosis - nucleus changes - cytoplasm changes
Nucleus - breakdown of DNA/proteins (1) pyknosis = shrinkagge + increased basophilia (cessation of DNA transcription) (2) karyorrhexis = fragmentation of nucleus (3) karyolysis = total dissolution of nucleus - ghost outline => hypereosinophilia cytoplasm - increased eosinophilia due to increased eosin binding to damaged protein + loss of ribosomes
Apoptosis process
Terminally injured cells activate caspases that degrade DNA/proteins caspases = mediators of cell death Signal is sent Loss of surface specialisations/connections Cell shrinks Degradation + breakdown of cell Cell splits into apoptotic bodies Bodies are phagocytosed
Is there a reversible stage of apoptosis? Necrosis?
Apoptosis - no Necrosis -there is reverssible cell injury, if irreversible then it progresses to necrosis
What are the 2 pathways of apoptosis? Describe them
Intrinsic (mt) and Extrinsic (death receptor) Intrinsic - normally the Bcl-2 family of sensors receives survival signals (eg growth factors) - produce anti-apoptotic proteins (Bcl2,Bclx) - if there is no survival signal, or there is DNA damage, the sensors are activated - the Bcl2 family of effectors (Bax, Bak) then stimulate the Bax/Bak channel of mitochondria -> leakage of cytc/other pro-apoptotic proteins from mt - these stimulate initiator caspases, which stimulate executioner caspases -> common pathway Extrinsic - Receptor-ligand interaction (ligands eg - FasL on CD8, TNF) - stimulation of adapter protein - these stimulate initiator caspases -> stimulate executioner caspases Common pathway - executioner caspase effects: - endonucelase activation -> DNA fragmentation - breakdown of cytoplasm -> formation of apoptotic bodies
What are some patterns of tissue necrosis
Coagulative Caseous Liquefactive Fibrinoid (fat necrosis)
Coagulative necrosis - morphology - under what circumstances does it occur (broad) - examples
Morph: ghost outlines persist - tissue keeps its cell/tissue architecture for a few days Occurs where enzyme dissolution is slow Examples: infarction in solid organs (except brain = liquefactive)
Liquefactive necrosis - morphology - examples
Tissue becomes viscous liquid mass/cavity due to digestion of cells Examples: cerebrain infarction; abscess -> pus
Caseous necrosis - morphology - examples
Morph: macro - “cheesy” histo - amorphous granular debris (pink); with no distinct cell borders Examples: TB - necrotising granulomatous inflammation
Fibrinoid necrosis - morphology - how does it occur - examples
Morphology - is only seen at microscopic level - bright pink (fibrin) Occurs due to deposition of immune complexes -> leakage of fibrin Examples - immune reactions involving blood vessels - vasculitis, serum sickness, malignant hypertension
Fat necrosis - what is it - how does it happen - histology
Destruction of fat Is classicaly the result of lipases (eg in acute pancreatitis) - lipases digest cell membrane, release TAGs, these are converted to FAs - FAs combine with Ca2+ - deposits Histology - large fat droplets with n nuclei - granular pink material - later on: foamy macrophages Morphology: chalky white deposits (FA + Ca2+)
Pigments - what do these look like, where are they found, what do they mean: - Carbon - Lipofuschin - Melanin - Haemosiderin
Carbon - eg in lung macrophages; means smoking etc. Lipofuschin - “wear and tear” pigment - accumulate as you age - yellow-brown on H&E, near nucleus - see in brain, heart, liver - complexes of lipid + protein, formed through oxidative injury - no pathological significance Melanin - dark - in melanocytes/keratinocytes - tumours - naevi, melanoma Haemosiderin - large brown granules on H&E - stain blue with Prussian blue - large aggregates of ferritin molecules - pathologic
Why might you have intracellular accumulations?
- less removal of normal substance - accumulation of an abnormal substance - genetic defect (eg alpha1 antitrypsin deificiency, can’t export a1 antytripsin) - failure to degrade metabolite - genetic deficiency (eg glycogen storage disease) - deposition of exogeneous substance which can’t be degraded (carbon, silica)
Pathological calcifications - what does it look like - what are the 2 types, what do they form as a result of
Abnormal deposition of ca salts, see on histology in ECM - rounded, deep purple bodies with layers (1) Dystrophic - occur in degenerate, necrotic tissue (atherosclerotic plaques, necrotic tumour, aortic stenosis) (2) Metastatic - as a result of high blood Ca (hyperparathyroid, chronic renal failure, hypercalcaemia of malignancy)
What is autolysis?
Cell breakdown when removed from body - due to lysosome enzymes - must fix with formalin, cool in order to retain cell/tissue structure
Necrosis v. apoptosis
- causes
- extent
- histology
- plasma membrane changes
- inflammation
- markers
Apoptosis
Necrosis
Causes
- normal physiological processes
- infection
- immunological disease
- drug interactions etc
Always pathological
Extent of effect
Cell by cell
Involves whole tissue area
Histology
- shrinks, breaks into apoptotic bodies with nuclear fragments (eosinophilic)
- cell breaks down due to loss of plasma membrane
- leakage of enzymes
- change in nucleus
- eosinophilia of cytoplasm (increased eosin binding to damaged protein, loss of ribosomes)
Plasma membrane changes
Stay intact
Loss of integrity → leak enzymes
Inflammation?
None
Yes
Markers
Leaked cellular components appear in blood
- hepatitis: transaminases
- AMI: cardiac enzymes
