Cellular responses to stress (Adaptations, injury and death) (2 of 5) Ali Al Khader, M.D. Faculty of Medicine Al-Balqa’ Applied University

Most injurious stimuli are grouped into: Oxygen deprivation Chemical agents Infectious agents Immunologic reactions Genetic factors Nutritional imbalances Physical agents Aging

*Oxygen deprivation *Chemical agents What is the most common cause? Ischemia is different from hypoxia Examples of hypoxia not due to ischemia: -Anemia -CO poisoning *Chemical agents Many agents and many effects (damage to membranes, proteins or changes in gradients) Even oxygen, glucose, salts, or even water

*Immunologic reactions...Mention 2 important general examples *Infectious agents *Immunologic reactions...Mention 2 important general examples *Genetic factors: -Direct phenotypical abnormalities or -Increased susceptibility to injurious factors…2 persons are phenotypically normal (= no disease) but one is susceptible to have disease while the other is not…and this is called: …….

Examples of genetic abnormalities

*Nutritional imbalances nutrients: -Protein-calorie deficiencies…chiefly among under- privileged populations -Vitamin deficiencies or abnormalities such as: -obesity -self-induced starvation, called: …….. -diets rich in animal fat

*Physical agents: *Aging: -Trauma -Radiation -Electric shock -Extremes of temperature -Sudden changes in atmospheric pressure -…etc *Aging: = cellular senescence -problems in replication and repair…more susceptibility to cell damage and death of the cell or the organism

Sequence of events Cell function change: molecular and biochemical changes

Example: Cardiac myocyte: -1-2 minutes after ischemia: Non-contractile -20-30 minutes: cell death -2-3 hours: by EM -6-12 hours: by LM

Morphology of reversible injury 2 main features: -cellular swelling…failure of Na+3/K+ pump the first structural change -fatty change

Morphology of reversible injury, by organelles Plasma membrane changes: -blebbing -distortion of microvilli -loosening of intercellular attachments Mitochondrial changes: -swelling -amorphous densities rich in phospholipids ER: -swelling -detachment of ribosomes -dissociation of polysomes -pinched-off segments…vacuolar (hydropic degeneration) Nucleus: clumping of chromatin Cytoplasm: -Fatty change (lipid vacuoles)…esp. cells participating in fat metabolism (myocardial cells, hepatocytes…etc.) -myelin figures (phospholipid masses from damaged membranes) -eosinophila

2 characteristics of irreversibility Inability to correct mitochondrial function Profound disturbances in membrane function…including lysosomal membrane **If irreversible injury occurs death will follow

Necrosis…general features Swelling Damage of membranes Lysosomal enzymes leakage Digestion of the cell (moth-eaten appearance) and leakage of contents outside Surrounding inflammation

Necrosis… Cytoplasm: - eosinophilia…mention the causes for this - glassy (homogenous) appearance…due to loss of glycogen - myelin figures are more prominent Membranes: more damage than injury …esp. damage of lysosomes Mitochondria: more damage than injury…large amorphous densities Nucleus: -Karyolysis: fading of basophilia due to DNase -pyknosis: shrinkage with increased basophilia -karyorrhexis: fragmentation …1-2 days: disappears

Fates of necrotic cells or digested by enzymes and disappear replaced by myelin figures phagocytosed degraded into fatty acids may bind calcium (calcification)

Some terms used to describe specific patterns of tissue necrosis: Coagulative necrosis Liquefactive necrosis Gangrenous necrosis Caseous necrosis Fat necrosis Fibrinoid necrosis

Coagulative necrosis Architecture is preserved because enzymes of proteolysis are also denatured by the injury Eosinophilic anucleate cells…ghosts of cells Surrounded by inflammation…will be phagocytosed Infarcts of all solid organs except ------- Infarct = ischemic necrosis

Coagulative necrosis

Liquefactive necrosis Infections…inflammatory cells, their enzymes and bacterial products “liquefy” the tissue Ischemic necrosis of brain In acute inflammation: pus…creamy yellow in color

Gangrenous necrosis Clinical term…when we talk about a limb Ischemia coagulative necrosis (dry gangrene) superimposed infection liquifaction (wet gangrene)…pus and smell

Caseous necrosis Most often in tuberculosis (TB) Cheesy appearance On LM: -granular pink material of lysed cells -no cellular outlines -often surrounded by epithelioid histiocytes… = caseating granuloma

Caseating granuloma

Fat necrosis = necrosis of adipose tissue *Typical example: pancreatitis (pancreatic cells die due to inflammation and lipases are released from them…digesting peritoneal fat (TGs FAs) …Fatty acids may bind calcium…chalky white material (saponification) *On LM: shadows of fat cells with basophilic material (calcium) and surrounding inflammation

Fibrinoid necrosis Usually in vasculitis usually autoimmune antigen-antibody complexes in the vessel wall + leaked fibrin from the vessels Detected by LM, not grossly …bright pink material in the vessel wall:

Lab investigations can detect tissue-specific necrosis (increased serum levels of cell products) Heart…creatine kinase (CK-MB) and troponin I Bile ducts…alkaline phosphatase (ALK) Hepatocytes…transaminases (ALT and AST) …etc.