number Done by Corrected by Doctor Heyam Awad

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1 number 4 Done by Waseem Abu Obeida Corrected by Saad Al-Hayek Doctor Heyam Awad

2 Cell injury

3 -in the previous lectures we talked about the causes (etiology) and the mechanism (pathogenesis) of cell injury. And we will talk about morphology of cell injury in this lecture. Morphology of cell injury The first effect of all injuries is on the biochemical and molecular level. Functional derangement(loss of function) happens next. Ultrastructural changes seen by electron microscopy. Follow. Then light microscopic changes occur. The last visible change is at the gross; macroscopic level. Examples: In heart attack= myocardial infarction, first change is at the molecular level: so cardiac enzymes increase in the blood. Example troponin Then cardiac muscle becomes non contractile (loss of function). This happens within 1-2 minutes of ischemia note that loss of function doesn't mean cell death Cells die within minutes of ischemia

4 It takes 2-3 hours to see any EM changes (the first morphological evidence of cell death is seen by EM) Light microscopic changes need 6-12 hours to be noted Macroscopic changes are the last to be seen; within hours. -morphological changes need time to appear,that s why we should depend on the molecular changes to diagnose before morphological changes starts appearing.

5 -Myocardial infarction: Microscopic changes need time to develop.(lm) -normal myocardial cells on the right, on the left we notice the disappearance of myocardial cells, these cells have died and been eaten by neutrophils (the blue dots). -the first inflammatory cells to appear in the dead tissue are neutrophils then after several hours macrophages start to appear.

6 Macroscopic changes due to cell injury are the last to be recognized. -normal cells appear in brown. 2-this area appears yellowish and it is an indication of myocardial infraction which caused tissue damage in that area. 1-this area appears whitish and it is an indication of an old heart attack but did not lead to death, and the color is due to fibrous tissue (fibrosis) which replaced dead myocardial cells.(scar) -because the myocardial tissue is not a regenerative tissue it will always end by fibrosis at cell injury regardless the severity of the injury, other regenerative tissue will regenerate at mild injury, severe injuries will end by fibrosis.

7 Morphology of reversible cell injury: The main two morphologic changes in reversible cell injury under the light microscope are: 1)Cellular swelling: Results from failure of the sodium potassium pump due to ATP depletion It is the first manifestation of all forms of injury It is reversible The organ affected will have increased weight Microscopy shows small clear vacuoles within the cytoplasm this is called hydropic change or vacular degeneration The organelles within the cells are also swollen Seen in all types of cells. Cells will retain homeostasis as soon as we remove the cause of injury, this will happen when ATP goes back to normal and pumps reactivate. 2) Fatty change: Occurs mainly in hypoxic injury and in toxic and metabolic injury.

8 Occurs due to lack of lipid digestive enzyme in the cell, so fat accumulate in the cells. Microscopy: lipid vacuoles in the cytoplasm Seen mainly in cells that participate in fat metabolism like hepatocytes and myocardial cells It is reversible, if the stress is removed, digestive enzymes will appear and mobilize the fat. Fatty change: the white vacuoles are lipid Electron microscopic changes in reversible injury: -observation of swelling and injury on the level of organelles.

9 Plasma membrane blebbing (indication of cell swelling). Mitochondrial swelling with appearance of amorphous densities.(indication of cell swelling). Dilation of endoplasmic reticulum with detachment of ribosomes and dissociation with polysomes (indication of swelling). Nuclear changes with clumping of chromatin. This happens due to changes in ph and can be reversible, this happens due to decrease in the PH as lactic acid accumulate in the cell, this will affect the coiling of chromatin,which is normally highly organized,retaining of normal PH will solve the problem. Nuclear clumping is the only reversible injury that happens to the DNA. Formation of phospholipid aggregates called myelin figures which are derived from damaged cellular membranes.

10 Necrosis : pathologic death. -Necrosis is the type of cell death that is associated with loss of cell membrane integrity and leakage of cellular contents causing dissolution of cells. -The dissolution occurs due to enzymatic action. -Leakage of cellular content causes inflammation which aims at getting rid of the dead necrotic tissue. It is caused mainly by: 1-Denaturation of intracellular proteins.

11 2-Digestion of cells by lysosomal enzymes of dying cells (autolysis) and leukocytes (heterolysis). -Usually denaturation and enzymatic digestion occur together. -Protein denaturation: a change in protein structure caused by changes in ph, temperature. It can be reversible at the beginning but then it will not be reversible if denaturation is severe. Denaturation:

12 Denaturation may change the protein completely, for example: from liquid to solid, from soluble to insoluble. Morphology of necrosis: There are cytoplasmic and nuclear changes. Denaturation of proteins will be seen in the cytoplasm mainly, they will bind to eosin stain more than normal proteins.(as their surface area increases which results in more eosin binding) -Cytoplasmic changes: increased eosinophilia (pink staining from the eosin dye). -Increased eosinophilia is due to 1. Increased binding of eosin to denatured proteins and 2.the loss of basophilia (decreases hematoxylin binding to RNA), because RNA in the cytoplasm decreases. -Due to these changes cells appear homogenous and glassy.

13 -Myelin figures can be a nidus for calcium deposition and calcifications might occur.

14 Nuclear changes in necrosis: one of three patterns: 1) karyolysis: decreased chromatin basophilia (decreased hematoxylin binding to DNA) secondary to deoxy ribonuclease (DNase) activity. 2) pyknosis: nuclear shrinkage and increased basophilia (DNA condenses into a solid shrunken mass). 3) karyorrhexis, fragmentation then disappearance of nucleus. One of the three patterns could happpen, but usually nuclear necrosis must end by karyorrhexis. EM changes: 1) Discontinuities in plasma and organelle membranes. 2) Marked dilation of mitochondria and large amorphous densities.(small densities is seen in reversible injury) 3) Disruption of lysosomes. 4) Intracytoplasmic myelin figures.

15 Myelin figures: Myelin figures: aggregates of damaged cell membranes (phospholipids), it attracts calcium it is seen as a morphologic change in reversible and irreversible cell injury. Fate of Myelin figures: -phagocytosed by other cells,or further degraded into fatty acids and calcify. Morphologic patterns of necrosis: Denaturation of protein predominates. Coagulative necrosis.

16 Enzymatic digestion predominates liquefactive necrosis. Special circumstances: caseous necrosis and fat necrosis. Coagulative necrosis: -preserved architecture of dead tissue. -Denaturation of structural proteins and enzymes so no cellular proteolysis. -Eosinophilic anucleated cells. -Cells are removed by inflammatory cells. -Ischemia in all solid organs may lead to coagulative necrosis except in the brain it leads to liquefactive.

17 Liquifactive necrosis: digestion of the dead cells resulting into a liquid jellylike mass. In focal bacterial or fungal infections and in hypoxic death in central nervous system.

18 Caseous necrosis White cheese like friable necrosis. Prototype: Tuberculosis (mainly affects lungs) caused by mycobacterium tuberculosis. Typical finding is granuloma: Collection of fragmented or lysed cells with amorphous granular eosinophilic debris surrounded by macrophages. Granuloma is a collection of macrophages the try to phagocytose something that is resistant to phagocytose, that s why macrophages aggregate in large number to collaborate in phagocytosis, under the LM it appears as a circle and inside there as a cheesylike material which is the cells that undergone necrosis.

19 Fat necrosis -used as a clinical terms and not a specific type. -Necrosis of fat. Typical example: pancreatic enzymes (lipases) release in acute pancreatitis, necrosis in breast fat which appears solid. The normal fat appears in yellow, necrotic fat cells appear in white.

20 Fate of necrotic tissue Phagocytosis. Replacement by scar. Regeneration. Calcification.

21 خلقت بلسما فال تشتكي For deep care go to biochemistry sheet 5