Cell Injury and Cell Death

Adapted Cell + Stress Injury Normal cell Reversibly injured cell Irreversibly Injured cell Dead cell +Stress Apoptosis Necrosis - Stress Overview

LO Define necrosis Define necrosis Enlist types of necrosis Enlist types of necrosis Identify morphological (gross and microscopic) features of different types of necrosis on image. Identify morphological (gross and microscopic) features of different types of necrosis on image. Enlist three stages in loss of nucleus resulting in cell death Enlist three stages in loss of nucleus resulting in cell death Define apoptosis Define apoptosis

(1) Definition: Localized death of cell or tissue occurring in the living body.

① Ultrastructural changes Margination or progressive loss of nuclear chromatin Margination or progressive loss of nuclear chromatin Focal rupture of the nuclear membrane Focal rupture of the nuclear membrane Breakdown of the plasmalemma. Breakdown of the plasmalemma. Development of flocculent densities in mitochondria. Development of flocculent densities in mitochondria. (2) Cell death is recognized by:

② Changes in the nucleus. Pyknosis: condensation of chromatin of chromatin and shrinkage of the nucleus. Pyknosis: condensation of chromatin of chromatin and shrinkage of the nucleus. Karyorrhexis: fragmentation of the nucleus. Karyorrhexis: fragmentation of the nucleus. Karyolysis: dissolution of the nucleus. Karyolysis: dissolution of the nucleus.

Normal Pyknosis Karyorrhexis Karyolysis Normal Pyknosis Karyorrhexis Karyolysis （参照武忠弼 病理学规划教材第一版 人民卫生出版社 1979 ，修改 )

③ Changes in cytoplasm staining Opacification: denaturation of proteins lead to aggregation with resultant opacification of the cytoplasm. Opacification: denaturation of proteins lead to aggregation with resultant opacification of the cytoplasm. Eosino0.philia: exposure of basic amino groups results in increased affinity for acidic dyes such as eosin. Eosino0.philia: exposure of basic amino groups results in increased affinity for acidic dyes such as eosin.

④ Biochemical changes Release of K + by dead cells. Release of K + by dead cells. Release of enzymes into the blood. e. g. increased plasma levels of creatine kinases, lactic dehydrogenase and aspartate aminotransferase. Release of enzymes into the blood. e. g. increased plasma levels of creatine kinases, lactic dehydrogenase and aspartate aminotransferase. Release of protein or protein breakdown products into the blood. Release of protein or protein breakdown products into the blood.

Morphology of Necrotic Cells Increased Eosinophilia Increased Eosinophilia - loss of RNA (basophilia) - loss of RNA (basophilia) - denatured cytoplasmic protein - denatured cytoplasmic protein Nuclear Changes Nuclear Changes - Pyknosis - Pyknosis - Karyorrhexis - Karyorrhexis - Karyolysis - Karyolysis Myelin figure Myelin figure – large, whorled phospholipid mass (phospholipid precipitate) – large, whorled phospholipid mass (phospholipid precipitate)

HISTOLOGIC FEATURES OF COAGULATIVE NECROSIS Normal cell Reversible cell injury with cytoplasmic & organelle swelling, blebbing & ribosome detachment Irreversible cell injury with rupture of membrane & organelles, & nuclear pyknosis Karyorrhexis Karyolysis

Morphologic pattern of Necrotic Cell mass Coagulative necrosis special types of coagulative necrosis Coagulative necrosis special types of coagulative necrosis Liquefactive necrosis Liquefactive necrosis Caseous necrosis Caseous necrosis Fat necrosis Fat necrosis Fibrinoid necrosis Fibrinoid necrosis

Types: Types: ① Coagulative necrosis: Gross features: The necrosis area is swollen, firm and pale. Gross features: The necrosis area is swollen, firm and pale. LM: cell detail is lost, but architecture preserved. The dead cells retain their outline but only indistinctly. LM: cell detail is lost, but architecture preserved. The dead cells retain their outline but only indistinctly. This type of necrosis is frequently caused by lack of blood supply and is exemplified well in infarcts of solid organs, e. g. heart, spleen, kidney. This type of necrosis is frequently caused by lack of blood supply and is exemplified well in infarcts of solid organs, e. g. heart, spleen, kidney.

This is an example of coagulative necrosis. This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia). Here, there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney.

Coagulative necrosis of the left ventricular wall （ From ROBBINS BASIC PATHOLOGY ， 2003 ）

Ischemic necrosis of the myocardium A, Normal myocardium. B, Myocardium with coagulation necrosis

B. Gangrene Definition: necrosis of big tissue with superadded putrefaction, black, fou- smelling appearance. Definition: necrosis of big tissue with superadded putrefaction, black, fou- smelling appearance. Necrosis of big tissue putrefactive black, green Or organ or limb organisms infection appearance Or organ or limb organisms infection appearance (black or green due to breakdown of haemoglobin) (black or green due to breakdown of haemoglobin) Special types of coagulative necrosis

a. Dry gangrene: Conditions: only occurs on the skin surface following arterial obstruction. It is particularly liable to affect the limbs, especially the toes. Conditions: only occurs on the skin surface following arterial obstruction. It is particularly liable to affect the limbs, especially the toes. Character: mummification Character: mummification Types of : Types of gangrene :

Dry gangrene

b. Wet gangrene: Conditions: Both arterial and venous obstruction; wet in environment; Conditions: Both arterial and venous obstruction; wet in environment; Character: wet swollen, foul- smelling, black or green. Character: wet swollen, foul- smelling, black or green. Commonly in small intestine, appendix, lung, and uterus, also in limbs. Commonly in small intestine, appendix, lung, and uterus, also in limbs. Types of : Types of gangrene :

Moist gangrene

c. Gas gangrene: Conditions: deep contaminated wounds in which there is considerable muscle damaged by gas formation bacteria. Conditions: deep contaminated wounds in which there is considerable muscle damaged by gas formation bacteria. Character: swollen obviously, gas bubbles formation. The infection rapidly spreads and there is associated severe toxaemia. Character: swollen obviously, gas bubbles formation. The infection rapidly spreads and there is associated severe toxaemia. Only occasionally in civilian practice but is a serious complication of war wounds. Only occasionally in civilian practice but is a serious complication of war wounds. Types of : Types of gangrene :

② Liquefactive necrosis: Soft and liquid grossly. Enzymes digest the cell and convert it to a formless proteinaceous mass. Ultimately, discharge of the contents forms a cystic space. i. e. central nervous system after ischemic injury; abscesses. Soft and liquid grossly. Enzymes digest the cell and convert it to a formless proteinaceous mass. Ultimately, discharge of the contents forms a cystic space. i. e. central nervous system after ischemic injury; abscesses.

Caseous necrosis Caseous necrosis :gross appearance :gross appearance :microscopic – granulomatous inflammation :microscopic – granulomatous inflammation Morphologic Pattern of Necrosis

A tuberculous lung with a large area of caseous necrosis

Tuberculous granuloma showing an area of central necrosis, epithelioid cells, multiple Langhans-type giant cells, and lymphocytes.

Special type: Fat necrosis: Fat necrosis: Grossly: Opaque and chalky Grossly: Opaque and chalky LM: outline of necrotic fat cells filled with amorphous basophilic material (calcium soaps). LM: outline of necrotic fat cells filled with amorphous basophilic material (calcium soaps). i. e. Digestion of peritoneal fat by pancreatic enzymes in pancreatic inflammation. i. e. Digestion of peritoneal fat by pancreatic enzymes in pancreatic inflammation.

fat necrosis Foci of fat necrosis with saponification in the mesentery

Definition: This is not a true degeneration but a strongly eosinophilic stain like fibrin. Definition: This is not a true degeneration but a strongly eosinophilic stain like fibrin. Location: interstitial collagen and blood vessels (small artery and arteriole) Location: interstitial collagen and blood vessels (small artery and arteriole) Nature: one kind of necrosis. Nature: one kind of necrosis. e. g. in allergic reactive diseases: active rheumatism, polyarteritis nodose. e. g. in allergic reactive diseases: active rheumatism, polyarteritis nodose. in non-allergic reactive diseases: malignant hypertension. in non-allergic reactive diseases: malignant hypertension. Fibrinoid necrosis:

Fibrinoid change in blood vessel

(4) Consequences of necrosis ① Acute or chronic inflammation ② Immunological reactions to sub cellular components released by dead tissue or self- antigens altered by denaturation.

③ lysis and absorption ④ Isolation and discharge: ulceration and cavity formation ⑤ organization ⑥ encapsulation, calcification.

Apoptosis Programmed cell death Programmed cell death Physiologic Physiologic pathologic pathologic