Cellular Injury & Ageing

1. Cellular Injury & Ageing Disease • Dis + Ease = Disease. • “Discomfort due to Structural or functional abnormality” • Disease is caused by an agent. • Causes (etiology) can be • External / Environmental. E.g.. Heat, Bacteria. • Internal E.g. stress, genes, ageing.

2. Cellular Injury & Adaptation: • Normal cell is in a steady state “Homeostasis” • Change in Homeostasis due to stimuli - Injury • Injury - Reversible / Irreversible • Adaptation / cell death

3. Response to Injury: • Adaptations (reversible) • Hydropic degeneration • Hypertrophy • Hyperplasia • Atrophy • Accumulations - hyaline, fat, etc. • Necrosis (irreversible) – cell death.

4. Terminology: • Necrosis: Morphologic changes seen in dead cells within living tissue. • Autolysis: Dissolution of dead cells by the cells own digestive enzymes. (not seen) • Apoptosis: Programmed cell death. Physiological, for cell regulation.

5. Types of Necrosis: • Coagulative – Eg. Infarction • Liquifactive - Brain, abscess • Caseous - Bacterial / Tuberculosis • Gangrene - With infection

6. Sequels of Necrosis: • Cell Death • Necrosis • Autolysis • Phagocytosis • Organization & fibrous repair.

7. Ageing: “Progressive time related loss of structural and functional capacity of cells leading to death” • Senescence, Senility, Senile changes. • Ageing of a person is intimately related to cellular ageing.

8. Factors affecting Ageing: • Genetic – Clock genes, (fibroblasts) • Diet – malnutrition, obesity etc. • Social conditions - • Diseases – Atherosclerosis, diabetes etc. • Werner’s syndrome.

9. Cellular mechanisms of ageing • Cross linking proteins & DNA. • Accumulation of toxic by-products. • Ageing genes. • Loss of repair mechanism. • Free radicle injury • Telomerase shortening.

10. Telomerase in ageing: Germ Cells Somatic Cells

11. Ageing –changes: • Gradual atrophy of tissues and organs. • Dementia • Loss of skin elasticity • Greying and Loss of hair • BV damage – atherosclerosis/bruising. • Loss of Lens elasticity  opacity  vision • Lipofuscin pigment deposition – Brown atrophy in vital organs.

12. Pathology of elderly

13. Stress Infections Diseases Malnutrition Accidents Diminished stress response. Diminished immune response. Good health. Factors affecting ageing:

14. Conclusions: • Cellular Injury - Various causes • Reversible Injury  Adaptations • Hypertrophy, Hyperplasia, Atrophy • Accumulations - Hydropic, hyaline, fat.. • Irreversible Injury - Necrosis • Coagulative, Liquifactive, Caseous • Ageing - Causes, Changes, Factors

15. Inflammation • “Inflame” – to set fire. • Inflammation is “dynamic response of vascularised tissue to injury.” • Is a protective response. • Serves to bring defense & healing mechanisms to the site of injury.

16. Lewis Triple Response: • Flush: capillary dilatation. • Flare: arteriolar dilatation. • Weal: exudation, edema.

17. Red, Warm & Swollen (Flare, Flush & Weal – Lewis) Triple response

18. Cardinal Signs of Inflammation • Rubor : Redness – Hyperaemia. • Calor : Warm – Hyperaemia. • Dolor : Pain – Nerve, Chemical med. • Tumor: Swelling – Exudation • LossofFunction:

19. Inflammation - Mechanism • Vaso dilatation • Exudation - Edema • Emigration of cells • Chemotaxis

20. Mechanism of Inflammation:

22. Chemical Mediators: • Chemical substances synthesised or released which mediate the changes in inflammation. • Histamine by mast cells - vasodilatation. • Prostaglandins – Cause pain & fever. • Bradykinin - Causes pain.

23. Morphologic types • Acute: • Exudative Inflammation: excess fluid. TB lung. • Suppuration/Purulent – Bacterial - neutrophils • Fibrinous – pneumonia – fibrin • Serous – excess clear fluid – Heart, lung • Haemorrhagic – b.v.damage - anthrax. • Chronic inflammation: with healing. • Grannulomatous – clusters of epitheloid* cells eg. TB, Fungus, Foreign body.

24. Fibrosis/Scar Resolution Injury Acute Inflammation Chronic Inflammation Abscess Ulcer Fistula Sinus Inflammation Outcome Fungus Virus Cancers T.B. etc.

25. Flush, Flare & Weal Acute inflammatory cells - Neutrophils Vascular damage More exudation Little or no fibrosis Little signs - Fibrosis, Chronic inflammatory cells – Lymphocytes Neo-vascularisation No/less exudation Prominent fibrosis Acute Vs Chronic

26. Stages of Healing: • Hemorrhage • Inflammation • Granulation tissue (soft callus) • Scar – Fibrosis (hard callus) • Remodeling & Wound strength

27. Repair • Regeneration of injured tissue by parenchymal cells of the same type • Replacement by connective tissue • In other words • Regeneration • Scar

28. Proliferative Potential • Labile cells - continuously dividing • Epidermis, mucosal epithelium, GI tract epithelium etc • Stable cells - low level of replication • Hepatocytes, renal tubular epithelium, pancreatic acini • Permanent cells - never divide • Nerve cells, cardiac myocytes, skeletal mm

29. Polypeptide growth factors • Most Important Mediators affecting Cell Growth • Present in serum or produced locally • Exert pleiotropic effects; proliferation, cell migration, differentiation, tissue remodeling • Regulate growth of cells by controlling expression of genes that regulate cell proliferation

30. Repair by connective tissue • Occurs when repair by parenchymal regeneration alone cannot be accomplished • Involves production of Granulation Tissue • replacement of parenchymal cells with proliferating fibroblasts and vascular endothelial cells

31. Components of the processof fibrosis Angiogenesis - New vessels budding from old Fibrosis, consisting of emigration and proliferation of fibroblasts and deposition of ECM Scar remodeling, tightly regulated by proteases and protease inhibitors

32. Wound healing • Induction of acute inflammatory response by an initial injury • Parenchymal cell regeneration • Migration and proliferation of parenchymal and connective tissue cells

33. Wound healing (cont’d) • Synthesis of ECM proteins • Remodeling of parenchymal elements to restore tissue function • Remodeling of connective tissue to achieve wound strength

34. Healing byFirst IntentionFocal Disruption of Basement Membrane and loss of only a few epithelial cellse.g. Surgical Incision

35. Healing by Second IntentionLarger injury, abscess, infarctionProcess is similar butResults in much larger Scar and then CONTRACTION

36. Wound Strength • After sutures are removed at one week, wound strength is only 10% of unwounded skin (Walker’ Law) • By 3-4 months, wound strength is about 80% of unwounded skin (Walker’s Law)

37. Systemic Age Nutrition Vitamin def. Immune status Other diseases Local Infection Size or extent. apposition Blood supply Mobility Foreign body Factors affecting Healing:

38. Summary: • Healing – Proliferation & Differentiation. • Labile, Stabe & Permanent cells • Stages of Healing: 1-2-3-4…. • Healing by First or Second intention. • Skin wound healing - bone healing. • Factors affecting healing – Local / Systemic

39. Circulatory disorders: • BV - Narrowing, rupture, aneurism. • Thrombosis • Embolism • Venous congestion • Edema • Shock

40. Thrombosis: • Intravascular coagulation • Vessel damage - atheroma, toxins • Blood changes - stasis, *coagulation factors • Types: White, Red & Mixed. • Sites: • Arterial: Brain, Heart, limbs, eys. • Venous: Leg • Capillary: DIC in septicemia

41. Embolism: • Abnormal solid mass carried in blood. • Source – destination • Types. • Thromboembolism - atherosclerosis • Fat - Fractures • Tumor - cancers • Gas – ‘Caisson disease’ • Liquid – Amniotic fluid in new born. • Rapid onset of infarction –vs. Thrombosis

42. Sequels of Block • Collateral circulation: • Ischemia, • Infarction,Gangrene • Haemorrhage

43. Common Sites of B.V block:

44. Edema & Shock….!

45. Normal Microcirculation Capillary Arterial Venous Hydrostatic Pressure + 36 + 16 Oncotic Pressure - 26 - 26 Net filtration Pressure + 10 mmHg - 9 mm Hg (leak-out) (Reabsorb)

46. Edema: • Increased interstitial fluid volume • Two major types • Local - inflammation • Generalised - anasarca - Systemic causes.

47. Edema mechanism: • Leaky vessels – inflammation. • Increased capillary hydrostatic pressure • Venous obstructions • Cardiac failure • Decreased Osmotic pressure • Hypoproteinemia – liver disease, anemia. • Lymphatic obstruction • Elephantiasis

48. Shock: • “Depressed vital functions due to decreased circulating blood volume” • Types: • Hypovolaemic - true/vasovagal • Cardiogenic – Heart failure, MI. • Obstructive – Pulm embolism. • Anaphylactic – vasodilation due to allergy. • Septic – capillary damage by infection.

49. Shock Featurs: • Hypotension • Tachycardia • Cold clammy skin • Rapid shallow respiration. • Drowsiness, confusion, irritability • Multi organ failure.

50. Shock Mechanisms: • Compensatory mechanisms: • Adrenaline cold, clammy skin • Complications: Ischemic damage.