Term
| Essential event in irreversible cell injury --> necrosis |
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Definition
1. Lysosomal
2. Mitochondrial
3. Protein denaturation
4. Arrested protein denaturation
5. Loss of pot. and influx of sod.
6. Influx of calcium
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Term
Necrosis
-Influx of calcium |
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Definition
Intracellular after increased membrane permeability
Activates phospholipases --> membrane damage
Mitochondrial membranes injured
MPT
outer membrane injury
-*Nucleus Chromatin Damage
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Term
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Definition
–Membrane dysfunction -->
--Ca2+ influx -->
--Activation of phospholipases -->
–Cell membrane damage and dysfunction -->
–More Ca2+ influx --> etc.
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Term
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Definition
–Reactive molecular species
–Often derived from O2
–Contain a single, unpaired electron
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Term
OXYGEN --> FREE RADICALS 1
MECHANISMS
FENTON REACTION
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Definition
Oxygen --> water by stepwise reduction using mitochondrial transport system
Oxygen can accept four electrons
Accept one --> superoxide ( O2 )
Accept two --> hydrogen peroxide
Hydrogen peroxide in presence of divalent Fe -->
hydroxyl radical
Fe++ + H2O2 - --> • Fe+++ + OH • + OH
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Term
OXYGEN FREE RADICALS
Superoxide anion: O2-·
Hydrogen peroxide: H2O2
Hydroxyl Radical: OH ·
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Definition
INJURIES
Disruption of structure and function by combining with other molecules e.g. phospholipids, nucleic acids
Destruction of protein backbone
Breaks in single stranded DNA
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Term
| PATHOLOGY AND FREE RADICALS |
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Definition
LEUKOCYTES USE THEM FOR KILLING BACTERIA
LEUKOCYTES RELEASE THEM àTISSUE DAMAGE
INJURYà SPILT BLOODàIRON (A CATALYST)
METABOLISM OF RELEASED ARACHIDONIC ACIDàFREE RADICALS
OXYGEN RICH BLOOD IN REPERFUSIONàFREE RADICALS
DAMAGE BY SUNLIGHTà FREE RADICALS
X-RAY DAMAGE( GOOD AND BAD) KILLS WITH FREE RADICALS
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Term
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Definition
•Resumption (get again) of blood supply and oxygenation to ischemic tissue may --> further injury and tissue destructiion.
MECHANISM OF FURTHER IMJURY
1. IschemiA --> inflammation which may further damage tissues
2. Oxygen free radicals
3. The complement system is activated which may increase inflammation
4. Cytokines generated which --> vasoconstriction and adherance of inflammatory cells
5. Oxygen supplied which is required for some enzyme action
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Term
| CCl4 must be altered to damage cells |
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Definition
CCl4 acted upon by P450 oxidases of smooth endoplasmic reticulum forms the reactive radical CCl3·
– Inhibits protein synthesis by damaging the Rough Endoplasmic Reticulum
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–Inhibits apoprotein synthesis by liver cellsà steatosis
Products of lipid peroxidation à plasma membrane damage à calcium influx à cell death
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Term
| CONTROL OF FREE RADICAL INJURY |
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Definition
Cellular antioxidant molecules like Vit E and A(retinoids)
–Act as scavengers for loose free radicals
–May be inserted in cell membranes where they can stop autocatalytic peroxidation
Sequestration of molecules that propagate free radical production
–Fe bound by transferrin and ferritin
–Cu bound by ceruloplasmin
NO-decreases uptake of cellular Fe by
transferrin
Detoxifying enzymes
Superoxide dismutase(SOD)—mitochondria and cytosol
Catalase—in peroxisomesàH2O
Glutathione peroxidase(GPX)-in mitochondria and cytosol—reduces H2O2
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Term
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Definition
Response to dead cells.
DETERMINANTS
1.Protein denaturation
2.Enzymatic digestion—by cell’s own lysosomes (autolysis) or from inflammatory cells
Specific morphology depends on which process is dominant.
MORPHOLOLOGIC FEATURES
Nuclear changes: karyolysis, karyorrhexis, pyknosis
Cytoplasmic eosinophilia is due to
–Loss of basophilia of ribosomes
–Take-up of eosin dye by denatured proteins
Subcellular changes such as:
–Swelling of mitochondria with dense Ca2+ containing bodies
–Breaks in the cell membranes
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Term
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Definition
1. COAGULATIVE NECROSIS e.g. myocardial infarction
2. LIQUEFACRIVE NECROSIS e.g. abscess
3. CASEOUS NECROSIS e.g. tuberculosis
4. FIBRINOID NECROSIS (like Fibrin, and other things), e.g. *hypertension / immune complex disease
5. FAT NECROSIS (a bad term, really Necrosis of Fat, they digest the fat within the area, often in alcoholics) e.g. acute pancreatitis
Must know all these.
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Term
Coagulative Necrosis
-(Ischemic Necrosis)
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Definition
1.a complex process by which blood forms clots. Can cause
Edema, Inflammatory Cells
Denaturation (coagulation) of cellular proteins predominates
Cell outlines and tissue architecture are preserved, at least for a time
e.g. infarct = circumscribed area of an organ undergoing coagulation necrosis due to ischemia – two types
1.Pale or “anemic” infarct (white infarct). No secondary blood supply. A small infarct, so you're not dead. (ex: In heart and spleen).
2.Hemorrhagic or “red” infarct – seen in organs with dual blood supply, or with large amounts of loose connective tissue into which hemorrhage may occur. (Only in Lungs).
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Term
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Definition
-Can't tell the details at the Necrosis (can't see cells).
Lung, Abscess: Inflammatory Exudate at site of necrosis.
Tissues in which the initial digestion of cells and tissue predominates, with loss of structure—due to enzymes from PMNs
–Necrosis due to bacterial infection – substances released by bacteria and by PMN’s attracted to the area result in rapid dissolution of the tissue = Pus!
–Brain – infarction of brain tissue is followed by rapid dissolution, resulting in a liquid filled space. Reason is not clear
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Term
Liquefactive Necrosis
-GANGRENE |
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Definition
Gangrene = not a distinctive pattern of cell death—often begins as coagulative necrosis
e.g. Gradual ischemia of distal extremities, especially the foot and leg
–“dry” = black-brown, mummified appearance
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–“wet” = bacterial superinfection of the necrotic material = LIQUEFACTIVE NECROSIS (term wet gangrene is also used with infarction of the bowel, since rapid bacterial superinfection occurs, for obvious reason)
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Term
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Definition
Tissue necrosis due to Mycobacteria or some fungal infections
Necrotic tissue transformed into granular, “cheesy” material
No residual cell or tissue structure by light microscopy
Difficult to reabsorb by the body. Caseous necrosis areas are surrounded by numerous macrophages, giant cells (granulomatous inflammation) and fibrosis.
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Term
Granuloma with Caseous Necrosis
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Definition
Granuloma: a tumor composed of granulation tissue (secretory vesicles) resulting from injury, inflammation, or infection.
-Inflammatory response with the giant cells.
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Term
Caseous Necrosis
-Miliary tuberculosis
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Definition
1.A romantic way to die....NOT!
2. Miliary tuberculosis of the spleen. The cut surface shows numerous gray-white granulomas.
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Term
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Definition
-Can cause Tuberculosis
-plentiful RBC’s.
-An inflammatory response that becomes a scar. |
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Term
Fibrin(oid) Necrosis (Fibrin like)
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Definition
Special type of necrosis occurring in arteriolar walls
Caused by extreme hypertension or immune complex deposits in arteriolar walls
Necrosis and damage to vesselà
Leakage of Fibrin and other plasma proteins ( e.g.immune complexes) into vessel wall
(Bright pink color by H&E stain)
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Term
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Definition
1. You see a lot of fat destroyed.
2. A difficult disease to deal with.
Necrosis of pancreatic cells which contain large amounts of hydrolytic enzymes including lipase
Lipase acts on adjacent adipocytes (type of cell, present in adipose tissue, where fat is stored as a source of energy), digesting triglycerides with release of fatty acids
Fatty acids combine with Calcium to form soaps (saponification)
Grossly: flecks of chalky white material within adipose tissue
Microscopically: adipocytes show loss of nuclei and bluish discoloration of the cell (calcium often appears blue in tissue slides)
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Term
FAT NECROSIS
PANCREAS, ENZYMATIC
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Definition
-Basophilic Calcium Deposits (Stones). Patient comes in with lots of pain in the lower back and in shock.
-Fat Necrosis with Saponification (a chemical reaction in which an ester is heated with an alkali (especially the alkaline hydrolysis of a fat or oil to make soap)).
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Term
SOME CONSEQUENCES OF CELL INJURY MAY BE USEFUL CLINICALLY, Why?
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Definition
1.You can liberate some enzymes to know what’s going on.
2.Gives some idea to the degree of injury.
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Severely damaged cell membranes allow for leakage of intracytoplasmic contents, including enzymes associated with specific tissues
Allow diagnosis of organ specific necrosis
–1. AST and ALT of hepatocytes
–2. Creatine Kinase (CK) and Troponin from myocardial cells
–3. Lipase and amylase from pancreas
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Term
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Definition
1. Programmed cell death
2. A process for ridding the body of damaged or unneeded cells. It may be physiologic or pathologic.
3. Implicated in certain diseases e.g. neoplasia, SLE
4. Some Viral diseases, e.g. Councilman bodies
-Minimal to no inflammatory response.
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Term
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Definition
FEATURE NECROSIS APOPTOSIS
CELL SIZE enlarged(swollen) decreased
NUCLEUS pyknosisàkarryrrhexis fragment
àkaryolysis
MEMBRANE disrupted intact
CELL CONTENT digested/ leak intact (bodies)
INFLAMMATION yes no
PHYSIOLOGIC/ pathologic either
PATHOLOGIC
-You never have Physiological Necrosis.
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Term
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Definition
–Embryogenesis
–Involution in adult organs
–Death of immune cells
– Cell deletion in proliferating Cell populations and tumors
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Term
APOPTOSIS
Pathologic Processes
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Definition
–Mild Injury
–Some Viral diseases, e.g. Councilman bodies
–Pathologic atrophy in organs after duct obstruction
–Cytotoxic T cells
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Term
APOPTOSIS
Inducers and Withdrawal of Inhibitors
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Definition
Activation of Endogenous
Proteases/Endonucleases
to
Degradation of Cytoskeletal Framework
DNA Fragmentation
Formation of Apoptotic Bodies
Uptake by Phogocytic Cells
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Term
ACUTE HEPATITIS, how to differentiate?
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Definition
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Term
REMOVAL OF DEAD CELL: Cell fragment changes
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Definition
–Flip phospholipids
–Secrete soluble factors = recruiting phagocytes
–Express thrombospondin= recognized by phagocytes
–Coated by natural antibodies & C1q
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Term
Irreversible Cell Injury: CLINICO-PATHOLOGIC CORRELATIONS
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Definition
1. Growth factor deprivation: intrinsic path—e.g. neurones deprived of nerve growth factor
2. DNA damage: radiation or chemotherapy—requires p53—functions in transcriptional activationà pro-apoptotic proteins e.g. Bax
3. Protein misfolding: if normal process won’t workàapoptosis e.g. Alzheimers
4. Induced by TNF receptors: mutations in Fas & FasLàautoimmune diseases
5. CTL: act by direct effect on effector phase of apoptosis or by FasL/ Fas interaction
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Term
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Definition
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Term
| Necrosis versus Apoptosis |
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Definition
Tissue Reaction
Necrosis: Inflammation
Apoptosis: No inflammation, Phagoctyosis of Apoptotic Bodies.
Inflammation can be good (get rid of the junk), but it’s bad that it can’t tell the difference btw good and bad cells.
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