CELL ADAPTATION, INJURY AND DEATH By Larry Nichols, MD

1. CELL ADAPTATION, INJURY AND DEATH By Larry Nichols, MD

2. TYPE OF NECROSIS DETERMINES TREATMENT Liquefactive: Drainage Caseous: Anti-fungal and –TB Gangrenous: Amputation

3. HIGH “LIVER FUNCTION TESTS” REFLECT INJURY, NOT FUNCTION Double misnomer: “LFTS” are neither specific for liver nor tests of function

4. ISCHEMIA = REVERSIBLE CELL INJURY Infarction = irreversible cell necrosis due to ischemia not relieved in time

5. METAPLASIA = REPLACEMENT OF A TISSUE TYPE BY ANOTHER ONE, FULLY DIFFERENTIATED BUT NOT NORMAL FOR THE SITE = a breeding ground for cancer

6. PATHOLOGIC APOPTOSIS Important in certain cancers chemotherapy radiation transplant rejection

7. Fundamental Vocabulary Etiology = doctorspeak for “cause” Morphology = pathologistspeak for “visible manifestation” Gross = pathologistspeak for “visible without a microscope”

8. Spectrum of Cellular Responses to Stress and Noxious Stimuli ADAPTATION - INJURY - DEATH Adaptation = physiologic and morphologic changes, modulating cell function, bringing it to a new altered steady state of homeostasis

9. Injury = reversible pathophysiologic and morphologic response to stress or noxious stimulus exceeding cell capacity to adapt, but not enough to kill it

10. Cellular Adaptations Hypertrophy - Atrophy increase in cell size decrease (+/- organ size) in same Hyperplasia increase in cell number All can be physiologic or pathologic

11. Metaplasia = replacement of a tissue type by another one, fully differentiated but not normal for the site, pathologic Examples: replacement of bronchial respiratory epithelium by squamous epithelium due to smoking replacement of esophageal squamous mucosa by intestinal type epithelium due to reflux

12. Metaplasia commonly caused by processes leading to cancer Examples: gastroesophageal reflux leading to intestinal metaplasia “Barrett esophagus” leading to adenocarcinoma of esophagus smoking leading to bronchial squamous metaplasia leading to squamous carcinoma

13. Causes of Cell Injury Hypoxia (deficiency of oxygen) Ischemia (deficiency of blood) Physical agents (trauma, burns, etc.) Chemical agents (alcohol, drugs, etc.) Infectious agents (bacteria, etc.) Immunologic reactions Genetic derangements Nutritional imbalances

14. Mechanisms of Cell Injury Depletion of ATP Impaired cell surface sodium pump (sodium influx, potassium efflux) Cellular swelling Anaerobic glycolysis Impaired calcium pump (calcium influx) Reduction in protein synthesis

15. Mechanisms of Cell Injury Unfolded protein response Mitochondrial permeability transition (loss of cytochrome c) Activation of ATPases, phospholipases, proteases, endonucleases by calcium Accumulation of free radicals (lipid peroxidation of membranes, oxidation of proteins, DNA breaks)

16. Mechanisms of Cell Injury Defects in membrane permeability (mitochondrial dysfunction, cytoskeletal abnormalities, leakage from lysosomes, detergent effect of degraded membrane phospholipids, loss of membrane phospholipids)

17. “LFTs” slang jargon for “liver function tests” usually include bilirubin, alkaline phosphatase (“alk phos”), alanine aminotransferase (“ALT”, “SGPT”) and aspartate amino- transferase (“AST”, “SGOT”) Elevated alk phos, ALT & AST are exceedingly imperfect measures of liver injury, and not at all of function

18. True Liver Function Tests 1. Albumin (sometimes low level due to low liver production) 2. Prothrombin time [INR] (commonly prolonged due to hepatic coagulopathy) 3. Glucose (sometimes low level due to deficient hepatic gluconeogenesis) 4. Ammonia [NH3] (high level correlates with hepatic encephalopathy) 5. Bilirubin (sometimes)

19. Coagulative necrosis = morphological manifestation of irreversible cell injury (cell death) due to ischemia except in brain Liquefactive necrosis = necrosis with conversion of solid tissue to liquid due to severe acute infection, toxicity or (brain only) ischemia

20. Key point: ischemia is reversible (for 3 minutes in brain, for 20 minutes in heart, for 2 hours in liver) Ischemia not relieved in time causes irreversible cell necrosis = INFARCTION

21. Coagulative necrosis: features Preservation of ghost cell outline Cytoplasm: increased pink eosinophilia Nucleus: pyknosis (increased blue basophilia and shrinkage) karyorrhexis (fragmentation) karyolysis (fading away) Acute inflammatory response

22. Caseous necrosis = distinctive form of coagulative necrosis grossly resembling cheese Gangrene = distinctive form of coagu- lative necrosis with blackening and shrinkage, typically of distal extremity Fat necrosis = digested by pancreatic lipase, chalky white saponification

23. Type of necrosis determines treatment: Liquefactive: drainage (surgery) Caseous: anti-TB and anti-fungal Gangrene: amputation (surgery)

24. PATHOLOGIC APOPTOSIS Important in Certain cancers (not too many) Chemotherapy Radiation (and heat) Transplant rejection Hypoxia Certain viral infections

25. APOPTOSIS versus NECROSIS single cells or large groups small clusters of cells cell membrane intact disrupted inflammatory response yes no

26. STEATOSIS (fatty change) Abnormal accumulation of lipid in hepatocytes Due to obesity, alcohol, diabetes mellitus, anoxia, protein malnutrition

27. HEMOSIDEROSIS Accumulation of hemoglobin- derived, refractile, large, granular brown iron pigment Due to recent bleeding, hemolysis or iron overload “secondary hemochromatosis”

28. HEMOCHROMATOSIS Accumulation of hemosiderin in liver, heart, pancreas, joints and endocrine organs Due to a genetic disease causing excess dietary iron absorption “primary hemochromatosis”

29. LIPOFUSCIN Wear-and-tear (aging) pigment, intracellular insoluble small granular brown material composed of lipids & phospholipid polymers complexed with protein

30. CALCIFICATION Dystrophic: abnormal localized deposition of calcium salts in injured, dying or dead tissues Metastatic: abnormal deposition in otherwise normal tissues due to hypercalcemia, usually due to deranged calcium homeostasis

31. INFLAMMATION-1 By Larry Nichols, MD

32. ACUTE INFLAMMATION: 4 CARDINAL SIGNS & SYMPTOMS Redness Swelling Heat Pain

33. NEUTROPHILS: Polymorphonuclear leukocytes (“polys”, “PMNs”) Granulocytes with neutral granules, variably shaped 3- to 5-lobed nuclei First responder phagocytes

34. IMPORTANT MEDIATORS OF INFLAMMATION Histamine, NO, PAF, arachidonic acid, thromboxane, prostacyclin, TNF, IL-1, IL-8, interferon-g, VEGF, selectins, ICAM-1, VCAM-1, integrins, CD31, CD44, complement C3a and C5a, bradykinin, thrombin, XIIa, leukotriene B4, Toll-like receptors, G-protein receptors, serotonin, chemokines, substance P, prostaglandinD2, E2 & F2alpha

35. STEROIDS BLOCK PRODUCTION OF ARACHIDONIC ACID, PROSTA- GLANDINS AND LEUKOTRIENES Non-steroidal anti-inflammatory drugs block only prostaglandin production

36. MANY IMPORTANT MEDIATORS OF INFLAMMATION ARE ALSO IMPORTANT MEDIATORS OF BLOOD CLOTTING Mess with these important mediators of inflammation and you are messing with blood clotting.

37. INFLAMMATION: Complex reaction to injurious agents consisting of (1) vascular responses (2) leukocyte migration and activation (3) systemic effects

38. ACUTE INFLAMMATION: Rapid onset (seconds to minutes) Short duration (minutes to a few days) Exudation of fluid, plasma proteins and leukocytes (primarily neutrophils)

39. ACUTE INFLAMMATION: 4 CARDINAL SIGNS & SYMPTOMS Redness Swelling Heat Pain

40. EXUDATE: Inflammatory extracellular fluid with high protein content, cells and cellular debris TRANSUDATE: Thin serous fluid with low protein content and few (if any) cells

41. PUS: Purulent exudate rich in neutrophils, cellular debris and (commonly) microbes Thick, opaque, variably colored (light green, yellow, tan, crème, off-white)

42. NEUTROPHILS: Polymorphonuclear leukocytes (“polys”, “PMNs”, “segs”) Granulocytes with neutral granules (neither blue or red on smear), and variably shaped nuclei, segmented into 3 to 5 lobes First responder phagocytes

43. NEUTROPHILS: Very short-lived (1-2 days) Normally 40-70% of the leukocytes in the blood Bands: immature (adolescent) neutrophils, with nuclei with 2 lobes normally 0-5% of blood leukocytes

44. ACUTE INFLAMMATION: CAUSES 1) infection 2) tissue necrosis 3) immune reaction 4) trauma 5) foreign bodies 6) physical & chemical agents

45. ACUTE INFLAMMATION: VASCULAR RESPONSES 1) vasodilatation 2) increased permeability LEUKOCYTE MIGRATION 1) margination 2) rolling 3) adhesion 4) diapedesis 5) chemotaxis

46. ACUTE INFLAMMATION RECEPTORS P-selectin Rolling* # ^ E-selectin Rolling, adhesion* # ^ L-selectin Adhesion* # VCAM-1 Adhesion# ^ VLA-4 integrin Adhesion^ ICAM-1 Adhesion, diapedesis* # ^ PECAM Diapedesis *polys #monos ^lymphs

47. LEUKOCYTE ACTIVATION Cytokine (response and secretion) Phagocytosis(recognition, attachment*, engulfment, killing#, degradation) * greatly enhanced by opsonins # hydrogen peroxide, myeloperoxidase

48. CONGENITAL LEUKOCYTE DEFECTs Leukocyte adhesion deficiency-1 and -2 Chronic granulomatous disease Myeloperoxidase deficiency Chediak-Higashi syndrome

49. ACQUIRED LEUKOCYTE DEFECTS Diabetes mellitus Hemodialysis Malnutrition Leukemia

50. IMPORTANT MEDIATORS OF INFLAMMATION Histamine, NO, PAF, arachidonic acid, thromboxane, prostacyclin, TNF, IL-1, IL-8, interferon-g, VEGF, selectins, ICAM-1, VCAM-1, integrins, CD31, CD44, complement C3a and C5a, bradykinin, thrombin, XIIa, leukotriene B4, Toll-like receptors, G-protein receptors, serotonin, chemokines, substance P, prostaglandinD2, E2 & F2alpha