1. CELL INJURY, CELL DEATH & CELLULAR ADAPTATIONS LECTURE 1 MR. MASRO BIN MOHAMAD (MBM) PHAR2262: GENERAL PATHOLOGY FACULTY OF PHARMACY CUCMS

2. "Live as if your were to die tomorrow. Learn as if you were to live forever." – Mahatma Gandhi

3.  By the end of this lecture students should be able to: 1.Define cell injury 2.List the etiologic agents for cell injury 3.Discuss the mechanism of cell death 4.Compare reversible and irreversible injury 5.Define apoptosis and necrosis 6.Compare apoptosis and necrosis 7.Describe cellular accumulation prior to injury 8.Discuss the cellular adaptations prior to injury 9.Compare atrophy, hypertrophy, hyperplasia and metaplasia LEARNING OBJECTIVES

4. 1.CELL INJURY 1.Definition 2.Etiology of Cell Injury 3.Mechanism of Cell Injury 2.CELL DEATH 1.Cell response to injury 2.Reversible and irreversible injury 3.Cell death – apoptosis and necrosis 3.CELLULAR ADAPTATION 1.Atrophy, hypertrophy, hyperplasia & metaplasia LECTURE’S OUTLINES

5. CELL INJURY 1.Cell injury; defined as a variety of stresses as a result of changes in internal & external environment. 2.Cell injury results from a disruption of one or more of the cellular components that maintain cell viability. 3.Injury at one point induces a cascade of effects. 4.All cells of the body have inbuilt mechanism to deal with changes in environment.

6. CAUSES OF CELL INJURY - THE PATIENT’S VIEW Hypoxia Infectious agents Physical injury Chemicals/drugs Immune response Genetic derangement Nutritional imbalance

7.  Ischemia  Local e.g. embolus  Systemic e.g. cardiac failure  Hypoxemia  Oxygen problems e.g. altitude  Haemoglobin problems e.g. anaemia  Oxidative phosphorylation  E.g. cyanide poisoning HYPOXIC INJURY

8. Cerebral infarction Myocardial infarction Renal atrophy HYPOXIC INJURY

9.  Fungi, Rickettsia, Bacteria and Viruses  E.g. viruses can take over protein translation machinery and subvert it entirely to the production of new virions. INFECTIOUS DISEASE

10. Primary Herpes Candidiasis Tuberculosis Actinomycosis

11. PHYSICAL INJURY Causes of physical agents are as below; I.Mechanical trauma e.g. road accidents II.Thermal trauma e.g. heat or cold III.Electricity e.g. electric shock IV.Radiation e.g. ultraviolet V.Rapid changes in atmospheric pressure

12. PHYSICAL INJURY Thermal Burn Traumatic ulcer

13. CHEMICAL / DRUG INJURY  Causes of chemicals & drugs are as below; I. Chemical poisons II. Strong acids & alkalis III. Environmental pollutants IV. Oxygen at high concentrations V. Hypertonic glucose & salt

14. CHEMICAL / DRUG INJURY Gingival Hyperplasia Asprin Burn

15.  Causes of chemicals & drugs are as below; i. Hypersensitivity reactions ii. Anaphylactic reactions (Allergy) iii. Autoimmune diseases (SLE) IMMUNE RESPONSE

16. Cinnamon Reaction Hemodent Reaction

17. GENETICS DERANGEMENTS  Congenital malformation  Down syndrome  Decreased life of red blood cell  Thalassemia, Sickle cell anemia  Inborn errors of metabolism

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

19. NUTRITIONAL IMBALANCES  Protein-calorie deficiencies  Vitamin deficiencies  Anorexia nervosa  Excesses of lipids  Obesity, Atherosclerosis  Metabolic diseases  Diabetes

20. NUTRITIONAL IMBALANCE Diabetes Scurvy

21. CELL DEATH Cell death occurs when the strength of the insult cannot be compensated for. Necrosis = “cell murder” Apoptosis = “programmed cell death or cell suicide”

22. NORMAL CELL ADAPTATIONSREVERSIBLE CELL INJURY IRREVERSIBLE CELL INJURY ATROPHY, HYPERTROPHY, HYPERPLASIA, METAPLASIA, DYSPLASIA DEGENERATIONS, SUBCELLULAR ALTERATIONS, INTRACELLULAR ACCUMULATIONS Increased functional demand Mild to moderate stress Severe, persistent stress NORMAL CELL RESTORED REPAIR AND HEALING CELL DEATH Stress removed CELLULAR RESPONSES TO CELL INJURY

24. REVERSIBLE CELL INJURY Oftentimes is an acute process. Cell injury of short duration and minimal intensity. Causes include: ischemia, exposure to toxins, infectious agents, and thermal injury. Plasma membrane injury leads to increased intracellular Na+ that leads to an isosmotic gain in water and cell swelling.

25. Reversible hypoxic/ ischemic injury Loss of ATP generation by mitochondria initially results in reversible events: o Na+/K+ ATPase membrane pump leads to a loss of ionic and osmotic gradient ( ↑edCa+2+ Na+, ↓ed K+ and osmotic gain of water) resulting cell swelling & ER dilatation) o ↑ed anaerobic glycolysis results in glycogen depletion and lactate accumulation (↓ed pH). o Reduced protein synthesis due to ribosome detachment from the RER CELL INJURY AND DEATH

26.  Irreversible hypoxic/ ischemic injury These changes are reversible if O2 and flow are reinstated, the transition to irreversible injury depends on the extent of ATP depletion and membrane dysfunction especially of mitochondria. ATP depletion results in MPT with loss of the H+ gradient ATP depletion releases cytochrome c that can induce apoptosis ↑edCa+2 activates o membrane phospholipases with resulting membrane damage o Intracellular proteases leading to cytoskeletal degradation Phospholipid degradation products that accumulate are directly toxic to the cell CELL INJURY AND DEATH

27. Reversible injury  Decreased ATP levels  Ion imbalance  Swelling Decreased pH Fatty change (liver) Irreversible injury  Amorphous densities in mitochondria  Severe membrane damage  Lysosomal rupture  Extensive DNA damage REVERSIBLE VS IRREVERSIBLE CELL INJURY

29. REVERSIBLE CELL INJURY Ischemic injury to the kidney. Pale kidney Hydropic change

30. 12 24 3648 60 72 Hours After Acute MI Myoglobin CK/CK-MB LD/LD1 cTnI cTnT 168 Multiples of URL 5 10 15 20 RELEASE OF CELL PROTEINS FOLLOWING CELL DEATH

31. CONCEPTS - CELL DEATH Necrosis = “cell murder” Apoptosis = “programmed cell death or cell suicide” Cell death occurs when the strength of the insult cannot be compensated for.

32. NECROSIS – MULTIPLE CELL DEATH IN A TISSUE  Definition Death of groups of contiguous cells in tissue or organ  Patterns  Coagulative  Liquefactive  Caseous  Fat necrosis  (gangrene)  (Infarct) Red/haemorrhagic White

33. CONCEPTS - CELL DEATH Necrosis = “cell murder” Apoptosis = “programmed cell death or cell suicide” Cell death occurs when the strength of the insult cannot be compensated for.

34. APOPTOSIS – PROGRAMMED CELL DEATH Is a distinct reaction pattern which represents programmed single-cell suicide. Cells actually expend energy in order to die. Derived from Greek "falling off" (as for autumn leaves) Apoptosis is "the physiological way for a cell to die", seen in a variety of normal situations.

35. APOPTOSIS MAINTAINS HOMEOSTASIS Embryogenesis Normal cell turnover – cells with short half-life – tissue involution due to loss of growth factor stimulation Immune function – Elimination of autoreactive T cells – NK and CTL killing

36. APOPTOSIS IN PHYSIOLOGIC SITUATIONS  Programmed destruction of cell during embryogenesis  Hormone-dependent involution - endometrial cells (menstrual cycle)  Cell deletion in proliferating cell population  Death of host cells - neutrophils  Elimination of self reactive lymphocyte  Cell death induced by cytotoxic T-cells - viral infected or tumor cells

37. APOPTOSIS IN PATHOLOGIC CONDITIONS  Cell death produced by injurious stimuli – radiation, cytotoxic drug  Cell injury in certain viral diseases – viral hepatitis  Pathologic atrophy  Cell death in tumors

38. APOPTOSIS AND DISEASE  Too Much Apoptosis toxin induced liver injury AIDS Ischemia neurodegenerative diseases myelodysplasia

39. APOPTOSIS AND DISEASE  Inhibition of Apoptosis various viral diseases - e.g. Herpes, poxvirus, and adenovirus cancer - e.g. follicular lymphoma, and carcinomas of the breast, prostate and ovaries autoimmune diseases - SLE

40. MORPHOLOGY OF APOPTOSIS 2. Progressive cell shrinkage 1. Chromatin condensation 3. Plasma membrane blebbing 4. Apoptotic bodies 5. Phagocytosis - no inflammation

41. Morphology of Apoptosis Cell shrinkage Chromosome condensation Formation of cytoplasmic blebs and apoptotic bodies Phagocytosis of apoptotic cells or cell bodies

42. NECROSIS versus APOPTOSIS

43. CONCEPTS IN CHRONIC CELL INJURY Cells undergo adaptive changes due to persistent (chronic) stress. Morphologic changes seldom reflect the type of persistent (chronic) stress. Similar responses at the cell level can produce different morphologic changes in different organs.

44. CAUSES OF CHRONIC CELL INJURY Ischemia, hormones, infections, chemicals/drugs, trauma, etc. Strength of the insult may be minimal. Duration of stress is prolonged as compared to acute cell injury.

45. Our lives are filled with joys and strife, And what is death but part of life? Will come the day that we must die, And leave behind those learning why. FINAL THOUGHT…

46. TO BE CONTINUED, CELLULAR ADAPTATION LECTURE ON MONDAY Muscle Hypertrophy