1. Cell Injury, Adaptation,Free Radicals

2. CONCEPT OF INJURY AND CELLULAR RESPONSE TO INJURY Cells are constantly exposed to a variety of stresses. When too severe, INJURY results. Injury alters the preceding normal steady state of the cell.

3. What hurts cells? • Causes of Cell Injury/Lesions • oxygen deprivation (anoxia) • physical agents • chemical agents • infections agents • immunologic reactions • genetic defects • Nutritional imbalances • Aging

4. Abscess of the brain (bacterial) This is a lesion caused by infectious agent

5. Brain – massive haemorrhagic focus (ischemia) in the cortex This is a lesion caused by oxygen deprivation

6. Hepatic necrosis (patient poisoned by carbon tetrachloride) This is a lesion caused by chemical agent

7. Pulmonary caseous necrosis (coccidioidomycosis) This is a lesion caused by infectious agent

8. Gangrenous necrosis of fingers secondary to freezing This is a lesion caused by physical agent

9. The “boutonnière” (buttonhole) deformity This is a lesion caused by intrinsic factors (auto aggression)

10. Liver: macronudular cirrhosis (HBV) This is a lesion caused by infectious agent (chemical:alcohol, genetic:a1-AT deficiency)

11. Liver: cirrhosis This is a lesion caused by HBV infectious agent (chemical:alcohol, genetic:a1AT deficiency)

12. MECHANISMS OF CELL INJURY General principles: • The cellular response to injurious stimuli depends on 1. type of injury 2. Its duration 3. Severity • The consequences depend on • the type, status, adaptability, and genetic makeup of the injured cell. • The structural and biochemical components of a cell are so integrally connected that multiple secondary effects rapidly occur • Cellular function is lost far before cell death occurs

13. Etiologic agents • EXCESS or DEFICIENCY OF OXYGEN • PHYSICAL AGENTS • CHEMICAL AGENTS • INFECTION • IMUNOLOGICAL REACTIONS • GENETIC DERANGEMENTS • NUTRITIONAL IMBALANCE

14. CONCEPT OF INJURY AND • CELLULAR RESPONSE TO INJURY • one of two things can happen to the cell: • It can survive in a damaged state and adapt to the injury (REVERSIBLEINJURY) or • It can die (IRREVERSIBLE INJURY) or cell death. • Injury of a CHRONICnature: the cell may be able to adapt to it, resulting in a variety of cellular changes known as ADAPTATIONS

15. Principle of signaling

16. Principle of signaling

17. Environment – ECM – other cells Signals/injury No change Adjustment Adaptation No adaptation No adjustment Change 1. Atrophy 2. Metaplasia 3. Hypertrophy 4. Hyperplasia 5. Dysplasia

18. Cellular adaptations include: • Atrophy - shrinkage of cells • Hypertrophy - increase in the size of cells which results in enlargement of the organs • Hyperplasia - increased number of cells in an organ or tissue • Metaplasia - transformation or replacement of one adult cell type with another

19. Atrophy • Hypoplasia: • Developmental failure • Atrophy of organ • Failure in morphogenesis Signals/injury Atrophy Reversible Decrease in size of cell (-s) previously of normal size • Pathologic • Decreased function • Loss of innervation • Pressure (“bed soars”) • Malnutrition/cahexia/cancer-TNF • Loss of endocrine stimulation • Aging • Physiologic • Morphogenetic (apoptosis) • Thymus • Ductus arteriosus • Uterus • Bones Branchial clefts Notochord Mullerian ducts Wolffian ducts Net results: tissue /organ smaller than normal

20. Normal Atrophy - testis

21. Small intestine Normal Atrophy

22. Alzheimer disease – brain atrophy

23. Hypertrophy – cell or organ Signals/injury Reversible Increase in size of cell (-s) in response to increased functional demand (-s) and/or in response to H/GF stimulation • Physiologic • Cardiac muscle • Athletes muscle • Uterine muscle • Prostatic tissue (elderly) • Pathologic • Cardiac muscle • Thyroid • Arterial smooth muscle • Cushing syndrome Net effect: increase in size/volume/weight of tissue / organ

24. Left ventricular hypertrophy

25. Hyperplasia – cell or organ Signals/injury Reversible Increase in number of cell (-s) in response to increased functional demand (-s) and/or in response to H/GF stimulation • Pathologic • Thyroid • Arterial smooth muscle • Breast , fibrocystic disease • Focal nodular hyperplasia (liver) • Physiologic • Lactating breast • Uterine muscle • Prostatic tissue (elderly) Net effect :increase in size/volume/weight of tissue / organ

26. Polypoid hyperplasia of endometrium Polipoid endometrium

27. Cystic endometrial hyperplasia

28. Endometrial carcinoma and endometrial hyperplasia

29. Signals/injury Metaplasia Reversible But not always Substitution of mature (differentiated) cell for another mature cell • Physiologic • (metaplastic tissue/organs) • cervical canal • Pathologic • (metaplastic tissue/organs) • Gastric/duodenal metaplasia • Squamous metaplasia-cervix • Ciliated to squamous • Osseous metaplasia • Barret’s oesophagus • Myeloid metaplasia Net effect: another cell/tissue - protective – changes in function

30. Metaplasia

31. Metaplasia Ciliated Squamous

32. Metaplasia

33. Objectives • Overview of Cell Injury and Cell Death • Reversible cell injury ( nonlethal hit) • Irreversible injury and cell death ( lethal hit) • Mechanisms of Cell Injury • Free radical injury • Necrosis • Apoptosis

34. Objectives • Overview of Cell Injury and Cell Death • Reversible cell injury (nonlethal hit) • Irreversible injury and cell death ( lethal hit) • Mechanisms of Cell Injury • Free radical injury • Necrosis • Apoptosis

35. Cell Injury • Causes of Cell Injury/Lesions • oxygen deprivation (anoxia, hypoxia) • physical agents • chemical agents • infections agents • immunologic reactions • genetic defects • Nutritional imbalances • Aging

37. Cellular Responses to Injury

39. MECHANISMS OF CELL INJURY • The most important targets of injurious stimuli are: (1) aerobic respiration involving mitochondrial oxidative phosphorylation and production of ATP Result: 1- ATP depletoion 2- Mitochondrial damage 3- loss of Calcium homeostasis 4- Generation of reactive oxygen species (2) the integrity of cell membranes, on which the ionic and osmotic homeostasis of the cell and its organelles depends (3) the cytoskeleton (4) the integrity of the genetic apparatus of the cell (5) protein synthesis

41. MECHANISMS OF CELL INJURY • The most important targets of injurious stimuli are: (1) aerobic respiration involving mitochondrial oxidative phosphorylation and production of ATP Result: 1- ATP depletoion 2- Mitochondrial damage 3- loss of Calcium homeostasis 4- Generation of reactive oxygen species (2) the integrity of cell membranes, on which the ionic and osmotic homeostasis of the cell and its organelles depends (3) the cytoskeleton (4) the integrity of the genetic apparatus of the cell (5) protein synthesis

42. MECHANISMS OF CELL INJURY (1) DEPLETION OF ATP • ATP depletion and decreased ATP synthesis are frequently associated with both hypoxic and chemical (toxic) injury • Depletion of ATP to <5% to 10% of normal levels has widespread effects on many critical cellular systems: • Plasma membrane energy-dependent sodium pump is reduced, resulting in cell swelling • increased rate of anaerobic glycolysis, glycogen stores are rapidly depleted. Glycolysis results in the accumulation of lactic acid. This reduces the intracellular pH, resulting in decreased activity of many cellular enzymes. • Failure of the Ca2+ pump leads to influx of Ca2+ • In cells deprived of oxygen or glucose, unfolded protein formed, that may lead to cell injury and even death.

43. MECHANISMS OF CELL INJURY MITOCHONDRIAL DAMAGE • Mitochondria are important targets for virtually all types of injurious stimuli, including hypoxia and toxins. • Cell injury is frequently accompanied by morphologic changes in mitochondria.

44. GENERAL MECHANISMS OF INJURY Result in apoptosis

45. GENERAL MECHANISMS OF INJURY INFLUX OF INTRACELLULAR CALCIUM AND LOSS OF CALCIUM HOMEOSTASIS • Calcium ions are important mediators of cell injury. • Cytosolic free calcium is maintained at extremely low concentrations (<0.1 μmol) compared with extracellular levels of 1.3 mmol, and most intracellular calcium is sequestered in mitochondria and endoplasmic reticulum. • Such gradients are modulated by membrane-associated, energy-dependent Ca2+, Mg2+-ATPases. • Ischemia and certain toxins cause an early increase in cytosolic calcium concentration, owing to the net influx of Ca2+ across the plasma membrane and the release of Ca2+ from mitochondria and endoplasmic reticulum

46. GENERAL MECHANISMS OF INJURY Failure of intracellular calcium homeostasis

47. FREE RADICAL MEDIATION OF CELL INJURY Generation of reactive oxygen species Important mechanism of cell damage. Free radical are chemical species with a single unpaired electron in an outer orbital. This state is unstable and react with organic and inorganic chemical.

48. MECHANISMS OF INJURY BY FREE RADICALS • Cell injury by oxygen radicals  • Superoxide • Hydrogen peroxide • Hydroxy radical 

49. Causes of Cell Injury/LesionsSeveral injurious processes produce injury by free radical.

50. MECHANISMS OF INJURY BY FREE RADICALS • Cell injury by oxygen radicals  • Superoxide • Hydrogen peroxide • Hydroxy radical  • What happen when the cell is injured by free radicals? • Lipid peroxidation • Protein damage • DNA damage