PATHOLOGY vs Physiology

1. PATHOLOGYvsPhysiology

3. Normal cell • MEMBRANE • Selective pemeability – ions • Surface antigens & receptors • NUCLEUS – DNA – control • CYTOSKELETON

4. Organelles • Mitochondria • Ribosomes • Endoplasmic reticulum • Golgi apparatus • Lysosomes

5. CELL INJURY

6. Homeostasis, steady state, can be altered. • Limited ways to respond to injury.

7. STRESS?

8. Cells can and must adapt to stimulus or stress In response to stress, cells may: – Adapt – Be reversibly injured – Die (irreversibly injured)

9. Other responses to stress Intracellular accumulations Pathologic calcification Cellular aging

11. CELL INJURY • Sequence of events that occur in a cell if the limits of adaptive response to a stimulus are exceeded

12. Causes of Cell Injury • Hypoxia and ischemia •“Chemical” agents •“Physical” agents •Infections •Immunological reactions •Genetic defects •Nutritional defects •Aging

13. Oxygen deficiency common and important – Hypoxia reduces aerobic oxidative respiration – Results from l) cardio respiratory failure, 2) loss of blood supply, 3) reduced transport of O2 in blood (i.e. anemia, or CO toxicity), 4) blockage of cell enzymes (cyanide) Compare with ischemia: loss of blood supply.

14. Myocardial infarction Cerebral infarction Renal atrophy HYPOXIC INJURY

15. Chemicals and drugs • Chemical poisons - cyanide, arsenic, mercury • Strong acids, alkalis • Environmental pollutants • Oxygen at high concentrations • Hypertonic glucose, salt • Alcohol, narcotic drugs

16. Chemicals, drugs, toxins multitude of mechanisms - block or stimulate cell membrane receptors, - alter specific enzyme systems, - produce toxic free radicals, - alter cell permeability, - damage chromosomes, - modify metabolic pathways, - damage structural components of cells.

17. Physical agents • Trauma, • extremes of heat and cold, • radiation, • electrical energy • Pressure changes

18. Infectious agentsMICROBIOLOGY – Viruses – Bacteria – Fungi – parasites

19. Immune dysfunction – Immunodeficiency - failure to respond due to congenital or acquired defects – Autoimmunity -- Immune response directed against host antigens – Hypersensitivity -- inappropriate or exaggerated response

20. Nutritional deficiency and imbalances – Protein-calorie deficiencies – Protein-calorie excess (obesity) – Vitamin & mineral imbalances

21. Workload imbalance – Overworked or under worked cells

22. Cancer Ehlers-Danlos GENETIC DERANGEMENTS Down's Syndrome

23. Free radicals • Free radicals are chemical species with a single unpaired electron in an outer orbital • Free radicals are chemically unstable and therefore readily react with other molecules, resulting in chemical damage • Free radicals initiate autocatalytic reactions; molecules that react with free radicals are in turn converted to free radicals

24. Reactive oxygen species: • Superoxide anion • Hydroxyl radical • Hydrogen peroxide

25. Free radicals initiated by: EXOGENOUS SOURCES: • Radiant energy: UV, X ray

26. Free radicals initiated by: • ENDOGENOUS SOURCES: • Inflammation: e.g. neutrophil killing • Chemicals/drugs &their metabolism • Redox reactions of normal metabolism • Transition metals: especially iron & copper, which donate or accept free electrons • Nitric oxide (just say NO!)

27. CELL INJURY BY FREE RADICALS • Lipid peroxidation of membranes • Oxidative modification of proteins • DNA Lesions

28. Protection from ROS Antioxidants block or scavenge • Vits. A,E,C • Binding of catalyzing iron & copper to transport proteins (e.g. transferrin, ceruloplasmin, lactoferrin, ferritin) • Enzymes: •Catalase (in peroxisomes) decomposes hydrogen peroxide •Superoxide dismutase converts superoxide to water and oxygen •Glutathione peroxidase catalyzes free radical breakdown

29. DISEASES CONGENITAL – genetic, non genetic ACQUIRED – • Infective • Inflammatory – injury & disordered repair • Immune • Metabolic • Hemodynamic • Cell growth

30. Others • Iatrogenic • Opportunistic • Hospital acquired infections

31. PATHOGENESIS

32. The cellular response depends on: • Type of lesion • Duration and severity • Type of cell • Physiologic state of the cell • Capacity of the cell for adaptation

33. Type, duration & severity of the injurious agent small dose of chemical toxin or short duration of ischemia cause reversible cell injury, while large dose of the same chemical agent or persistent ischemia causes cell death.

34. Type, status & adaptability of the target cell • nutritional and metabolic status, & adaptation of cell to a hostile environment determine the extent of cell injury skeletal muscles can withstand hypoxic injury for a longer time while cardiac muscles often suffer irreversible cell injury after 30-60 min of persistent ischemia.

35. Important susceptible cell components • Generation of ATP by aerobic respiration. • Integrity of the cell membrane (ionic & osmotic homeostasis) • Protein synthesis • Cytoskeleton • Genetic integrity

36. Cellular and biochemical sites of damage in cell injury • ATP decrease • Mitochondrial damage • Loss of calcium homeostasis • Oxidative stress

37. cell injury ATP is essential for Membrane transport, Protein synthesis, Lipid synthesis Phospholipid metabolism

38. Consequences of ↓ intracellular ATP •Plasma membrane sodium pump failure •Calcium influx •Altered energy metabolism •Reduction in protein synthesis •Unfolded protein response

39. Blood Clot  Oxidative Phosphorylation HYPOXIA - ISCHEMIA MODEL Impaired function of the plasma membrane ATP-dependent Na+ pump  O2 ATP  Glycolysis Detachment of ribosomes

40. SEQUENTIAL CHANGES Failure of aerobic &switch to anaerobic respiration Rapid depletion of glycogen accumulation of lactic acid lowers the intracellular pH Intracellular acidosis-clumping of nuclear chromatin

41. Normally in the ATP dependent Na+-K+ pump there is transport of Na+ out of the cell and diffusion of K+ into the cell lowered ATP Na+ is retained within the cell K+ is diffused out of the cell This results in increased intracellular water accumulation to maintain the iso-osmatic condition (hydropic swelling)

42. As a result of continued hypoxia Ribosomes are detached from the granular endoplasmic reticulum Polysomes are reduced to monosomes Thus reduced protein synthesis

43. Ca++ Ca++ Ca++ Ca++ INDUCED CELL INJURY Cytoplasmic ionic Ca++ ATPase Phospholipase Protease Endonuclease ATP Phospholipids Protein DNA Disruption Damage

44. Mitochondrial Damage by: •Cytosolic Calcium influx •Oxidative stress •Phospholipase - breakdown of phospholipids - and sphingomyelin pathways

45. Mitochondrial damage results in •Mitochondrial permeability transition of inner mitochondrial membrane •Reversible but can become permanent and be death blow •Leakage of cytochrome c and initiation of apoptosis

46. Membrane permeability defectsresult in •Mitochondrial dysfunction •Loss of membrane phospholipids •Cytoskeletal abnormalities •ROS (reactive oxygen species) •Lipid breakdown products

47. Lysosomal membrane injury: Enzyme leakage and activation in cytoplasm →cell digestion, loss of glycogen, loss of RNA & DNA and eventually necrosis

48. Cell Injury and Cell Death • Point of no return: not precise • Two consistent characteristics of irreversibility 1. Inability to restore mitochondrial function 2. Severe cell membrane damage • Leak of lysosomal contents leading to cytoplasmic & nuclear degradation • Massive leak of intracellular substances and influx of calcium

49. CELLDEATH • NECROSIS • APOPTOSIS