Topics A1-5 - General Necrosis, Infarction, Apoptosis Flashcards
First 3 steps of necrosis cell death (3 of 6 steps)
- Damage to mitochondria: toxins, ROS, etc. attack mitochondria
- MTC damage -> ATP depletion
- Na+/K+ pump has low E, functions poorly, so sodium builds in the cell and water follows, causing cellular swelling
Last 3 steps (of 6) of necrosis cell death
- Anaerobic glycolysis -> lactic acid increase -> pH drops, protein synthesis reduced
- Ca2+ ATPase impairment -> High intracellular [Ca2+] (“Point of No Return!”). Calcium activates many cell death mechanisms.
- Membrane integrity is lost, cell lyses
5 ways that increased cytosolic Ca2+ causes cell death (try to name at least 4…)
- Phospholipases activated -> destroys membrane
- Proteases activated -> destroys cytoskeleton
- Endonucleases activated -> karyolysis
- Caspases activated -> apoptosis
- ATPase activated -> decreased ATP
Key histo features of necrotic cell
Eosinophilic (eosin binds denatured proteins, loss of DNA/RNA), glassy/homogenous “moth-eaten appearance,” nucleus karylosis, pyknotic or karyorrhexic
How does a pyknotic nucleus look?
Nucleus shrinks, more basophilic
How does karyorrhexis look?
The nucleus fragments
How does karyolysis look?
Nucleus fades, due to fading of nuclear chromatin via endonuclease activity
6 morphological types of cell necrosis
- Fat necrosis
- Gangrene
- Liquefactive
- Coagulative
- Caseatio/”cheesy”
- Fibrinoid necrosis
“Fat gangs lick coagulating cheese fibers”
What is the order of the breakdown of the nucleus during necrosis? (histologically)
Pyknosis -> karyorrhexis -> karyolysis
“Pick Rex’s lice”
How is the nucleus different in necrosis versus apoptosis?
Necrosis: it’s pyknotic, karyorrhexic, or karyolytic.
Apoptosis: It’s fragmented into nucleosome-size pieces
How is the cell size different in necrosis versus apoptosis?
Necrosis: cell is enlarged
Apoptosis: cell shrinks
What happens to the cellular components in necrosis vs apoptosis?
Necrosis: cellular components leak out, including enzymes - causes enzymatic digestion/damage
Apoptosis: cellular contents are kept intact in apoptotic bodies
What is characteristic of coagulative necrosis?
Outlines of cells are still there. Dominating morphological event is that the proteins are denatured. The structure is preserved bc autolytic enzymes are inactivated. Cell becomes firm and acidophilic. Macrophages/neutrophils required to clear them.
Which organs are more prone to coagulative necrosis?
All solid organs EXCEPT the brain, which is liquefactive
Coagulative necrosis mainly in kidney, heart, liver, adrenal glands, spleen
What usually causes coagulative necrosis?
Infarction: sudden occlusion of vessel
What are the 2 types of infarctions?
- Ischemic: pale infarct. Happens in denser tissues (kidney, heart, spleen) that prevents RBCs from damaged vessels from diffusing through necrotic tissue
- Hemorrhagic: red infarct. Lungs, small bowel, testicle. Caused by dual blood supply, venous occlusion, or reperfusion.
What type of infarcts are gangrena humida and pulmonary abcesses?
Anemic liquefactive
What are the anemic types of cerebral infarct called, based on various appearances (reminder that they’re liquefactive)
“Encephalomalacia alba” (white necrosis) = earlier infarct
Becomes “flava” (yellow) after 36 hours due to microglial digestion
If they survive and heal, it becomes “cysta post-encephalomalacia” with cyst + glial tissue
What is the hemorrhagic type of cerebral infarct called?
Encephalomalacia rubra - occurs from reperfusion injury.
Why is reperfusion dangerous?
In what situation is a medical treatment a major risk for reperfusion injury?
Enzymes that neutralize ROS are missing, and so many free radicals are generated.
Reperfusion is associated with fibrinolytic therapy after AMI
What is characteristic of liquefactive necrosis?
Tissue becomes soft and leaky. Transformation is due to autolytic enzymes, either from necrotic cell enzymes or neutrophils.
What cells mediate liquefactive necrosis in a CNS infarction?
What about in abscesses due to bacterial infection?
CNS: microglial cells release hydrolytic enzymes
Abscess: microbes stimulate neutrophils to liquefy dead tissue, produce cavity filled with pus
What is gangrene? What are the 2 types?
Not distinct pattern of cell death, but term still used. Usually refers to necrosis of extremities. Black due to Hb + H2S -> black iron sulphide
Gangrena sicca (dry) - coagulative necrosis. Arterial blockage -> hypoxia.
Gangrena humida (wet) - liquefactive due to bacterial infection, venous blockage.
What is a major symptom that gangrene may occur in the leg due to poor blood supply?
Intermittent claudication (limp and have to stop walking frequently to let blood supply catch up to leg)
How does caseous necrosis appear, both grossly and under a microscope? (keep it simple, not the full description for histo exam)
Gross: “Friable, yellow-white” appearance due to excess lipids from TB
With H-E stain appears as a collection of fragmented/lysed cells with amorphous granular pink appearance. Enclosed with a distinct inflammatory border: granuloma
What are the 2 types of fat necrosis?
- Enzymatic: i.e. pancreas. Activation of lipases -> fats combine with calcium -> saponification. Makes chalky white areas, dystrophic calcification
- Traumatic: injury to fatty tissue like breast. Not enzyme mediated
What is fibrinoid necrosis?
Not a real necrosis but called one in patho anyway, only visible under microscope. Immune complexes (Ag + Ab) are deposited in walls of arteries with fibrin. Makes eosinophilic amorphous shape called fibrinoid.
Where does fibrinoid necrosis usually occur?
Glomerular capillaries, small muscular arteries and arterioles, venules, valve leaflets, myocardium, subQ tissue
What may cause fibrinoid necrosis?
Immune vasculitis (e.g. Henoch-Schoenlein purpura), malignant hypertension, rheumatic fever
What are 3 ways that the extrinsic pathway to apoptosis can be activated? (no details, just names)
- Fas Ligand
- TNF-alpha
- Cytotoxic T cell (perforins, granzymes)
In general, what is the mechanism that the different initiators use in the extrinsic pathway of apoptosis? (again, very general.. need to know more than this)
- Mediator binds to death receptor, activates initiator caspases
- Initiator caspases turn to executioner caspases (proteases and nucleases)
- Proteases destroy cytoskeleton, endonucleases destroy nucleus
What is general layout of the intrinsic pathway to apoptosis?
- Cell injury, DNA damage, misfolded proteins -> BCL-2 sensor genes activated
- Activation of BAX and BAK genes produce mitochondrial channels that cause leakage of cytochrome C into cytosol
- Cytochrome C complexes lead to activation of Caspase 9, which activates other caspases (proteases, endonucleases)
Deficiency in apoptosis can cause what diseases?
Excessive apoptosis can cause what diseases?
Deficiency -> cancer, autoimmune diseases, atresia
Excessive -> sepsis, AMI, ischemia, neurodegenerative diseases, diabetes mellitus
What are 4 examples of anemic coagulative necrosis?
Kidney infarct, splenic infarct, non-reperfusion AMI, and gangrena sicca
What are 3 examples of hemorrhagic coagulative necrosis?
Reperfusion AMI, pulmonary infarct, intestinal infarct
What normally causes renal and splenic infarcts?
Thrombosis or emboli, mostly coming from the heart (more commonly from A-fib, but also maybe embolism arising from endocarditis or AMI)
What, morphologically do you see in both renal and splenic infarcts? (prototypical coagulative infarcts)
Beginning has wedge-shaped anemic pale yellowish tissue, after a day surrounded by red hyperemic ring, then necrotic tissue digested -> fibroblasts come -> scar tissue that contracts to make “flower-bed” depressed tissue.
The functional parenchyma does not recover
What does p53 do in relation to apoptosis? How can it be activated?
p53 is a tumor suppressor gene that can activate apoptosis. Activated by:
- DNA damage
- hypoxia
- aberrant oncogene expression
What does p53 promote? (3 things)
- cell-cycle checkpoints
- DNA repair
- cellular sensecence and apoptosis
How does gangrena sicca usually progress?
Which blood supply blockage is it associated with?
Distal-to-proximal
Associated with arterial blockage
How does gangrena humida result from venous blockage?
Affected limb is saturated with stagnant blood, allowing for proliferation of bacteria
What allows a pulmonary infarct to have reperfusion injury?
Although the pulmonary artery is obstructed, the bronchial arteries allow oxygenation and bleeding into the area
What are 4 major sources of embolism? (will be in later topics too, but ties in here and it’s essential)
- Deep veins
- Periprostatic veins
- Perimetrial veins
- Auricles of heart (left auricle from A-fib, right auricle embolism origin more common in IV drug users)
How does a hemorrhagic infarct in the lungs appear as it progresses?
Usually affects lower lobes. Wedge-shaped, apex pointing towards hilus. First appears as red-blue area.
After 48 hours, infarct becomes pale, then red-brown as hemosiderin accumulates
Why do hemorrhagic infarcts occur in the intestines?
Mesenteric arteries have anastomoses, and so the double circulation means there can be hemorrhage and reperfusion injury
Cerebral infarcts are often prevented, but can still be hemorrhagic because of what mechanism?
The circle of Willis anastomoses system allows oxygenation, often life-saving but can allow reperfusion injury too
What type of blood supply is involved in encephalomalacia rubra?
Venous thrombosis or “borderline” between 2 areas of arterial blood supply
What are emollition cysts?
“Pseudocysts” that occur in the brain after liquefactive necrosis. Don’t have epithelial lining, so they’re not real cysts but just necrotic material
What type of necrosis is a pulmonary abscess? What occurs?
Liquefactive anemic necrosis.
Bacterial infection causes immune cells to kill large amount of parenchyma and form an abscess
What is the Wave-Front Theory?
Myocardial infarctions start at the subendocardial area, then progress to the transmural area step-by-step as a “wave-front.” Fast treatment limits extent of necrosis.
What are the 3 reasons behind the Wave-Front Theory?
- Coronaries run in the subepicardium, and the endocardium only gets the distal branches
- Myocardial fibers twist like a spiral, and subendocardium works harder (more sensitive to O2 deprivation)
- Ventricle has higher pressure, which compresses the subendocardium more than subepicardium
What enzyme reaction can be used to detect an early myocardial infarction?
Diaphorase: bc dehydrogenases are the first enzymes disrupted during an infarct
What is the first morphological sign you see of myocardial infarction? When do you see it?
Dilated cells under a microscope. Seen 30 minutes to 4 hours after infarction (before that it’s not clearly different)
When do you start seeing evidence of full-blown myocardial infarction? What are the major morphological changes?
12-24 hours after infarct. See pale, firm tissue
What do you see at 1-2 days after a myocardial infarction has occurred?
Degeneration: Reddish hyperemic ring around pale area. Enzymatic leakage makes the tissue necrotic tissue soft.
What occurs 3-12 days after a myocardial infarction?
Capillarization of tissue: endothelial cells grow into tissue, change into fibroblasts, produce collagen. May also see myocardial rupture during this period..
From 12 to 20 days, what occurs morphologically after a myocardial infarction?
The whole necrotic tissue is replaced by scar tissue, which is white/ “egg shell” colored
When is the ideal time for reperfusion therapy in myocardial infarction? Why?
(4 specific effects are listed)
3-6 hours after infarction. Effects:
- Free radicals are produced after reperfusion, damaging myocytes
- Myocyte hypercontracture: ischemia caused high intracellular calcium levels, impaired calcium cycling and sarcolemma damage. Reperfusion causes uncontrolled contraction because they lack ATP to undergo relaxation. Can also kill myocytes
- Leukocytes aggregate + platelets and complement are activated, injuring tissue and the microvasculature
- Vascular injury/leakiness can cause bleeding into necrotic area (major risk)
What are 5 consequences of myocardial infarction?
- Pump failure / heart failure: can cause hypotension, pulmonary edema, cardiogenic shock
- Arrythmias: conducting system impaired
- Myocardial rupture: usually 5-6 days after due to inflammatory cells digesting tissue. May cause hemiparcardium, cardiac tamponade
- Aneurysm: soft infarct tissue bulges from pressure
- Chronic ischemic heart disease: heart failure in long run, hypertrophy
Note that MIs are covered again (and more thoroughly) in topic B2
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