Chapter 1 CELL INJURY CELL DEATH CELL ADAPTATIONS. M.G.Rajanandh, Dept. of Pharmacy Practice, SRM College of Pharmacy, SRM University.

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1 Chapter 1 CELL INJURY CELL DEATH CELL ADAPTATIONS M.G.Rajanandh, Dept. of Pharmacy Practice, SRM College of Pharmacy, SRM University.

2 CONCEPTS IN CELL INJURY The clinical signs and symptoms are several steps removed from the biochemical changes associated with cell injury. Cell injury is common to all pathologic processes. Cell injury results from a disruption of one or more of the cellular components that maintain cell viability.

3 CONCEPTS IN CELL INJURY Injury at one point induces a cascade of effects. Cell injury may be reversible, result in cell adaptation, or lead to cell death. Biochemical alterations occur prior to morphologic changes. The result of cell injury is determined, in part, by the intensity, duration and/or the number of exposures to an etiologic agent. The result of cell injury is determined, in part, by the cell type and its physiologic state.

4 CONCEPTS IN CELL INJURY The clinical signs and symptoms are several steps removed from the biochemical changes associated with cell injury. Cell injury is common to all pathologic processes.

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

6 HYPOXIC INJURY Cerebral infarction Myocardial infarction Renal atrophy

7 CONCEPTS IN CELL INJURY Cell injury results from a disruption of one or more of the cellular components that maintain cell viability. Divergent factors can act at the same point on the cell to induce cell injury.

8 CELL INJURY - THE CELL S PERSPECTIVE

9 CONCEPTS IN CELL INJURY The clinical signs and symptoms are several steps removed from the biochemical changes associated with cell injury. Cell injury results from a disruption of one or more of the cellular components that maintain cell viability. Injury at one point induces a cascade of effects.

10 MECHANISMS OF CELL INJURY Hypoxia / Ischemia Model Generation of Reactive Oxygen Species Increased Cytoplasmic Ca ++

11 HYPOXIA - ISCHEMIA MODEL Blood Clot O 2 Oxidative Phosphorylation ATP Impaired function of the plasma membrane ATP-dependent Na+ pump Glycolysis Detachment of ribosomes

12 HYPOXIA - ISCHEMIA MODEL Glycolysis Detachment of ribosomes ph Chromatin Clumping Glycogen Stores Protein Synthesis Lipid Deposition

13 REACTIVE OXYGEN SPECIES SOD Fe+2 Fe+3 O 2 H 2 O 2 OH + OH 0 2 2GSH Glutathione Glutathione Peroxidase Reductase GSSH CELL INJURY H 2 0

14 Ca++ INDUCED CELL INJURY Ca++ Ca++ Ca++ Cytoplasmic ionic Ca++ ATPase Phospholipase Protease Endonuclease ATP Phospholipids Protein Disruption DNA Damage

15 OTHER CAUSES OF CELL MEMBRANE INJURY Complement - C5-C9 MAC Cytotoxic T Cells - perforin Virus Bacterial Endotoxins and Exotoxins Drugs

16 CONCEPTS IN CELL INJURY Injury at one point induces a cascade of effects. Cell injury may be reversible, result in a cell adaptation, or lead to cell death. Biochemical alterations occur prior to morphologic changes. The result of cell injury is determined, in part, by the intensity, duration and/or the number of exposures to an etiologic agent. The result of cell injury is determined, in part, by the cell type and its physiologic state.

17 OUTCOMES OF CELL INJURY CELL INJURY / CELL STRESS ACUTE CHRONIC REVERSIBLE CELL DEATH CELL ADAPTATIONS NORMAL CELL

18 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.

19 NECROSIS Morphologic types of necrosis Coagulative Liquifactive Caseous Enzymatic (fat) The type of necrosis is dependent upon patterns of enzymatic degradation of cells and extracellular matrix, the type of necrotic debris, and by bacterial products when present.

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

21 APOPTOSIS AND DISEASE Too Much Apoptosis AIDS ischemia neurodegenrative diseases myelodysplasia toxin induced liver injury

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

23 MORPHOLOGY OF APOPTOSIS Chromatin condensation Progressive cell shrinkage Plasma membrane blebbing Apoptotic bodies Phagocytosis - no inflammation

24 MECHANISMS OF APOPTOSIS

25 NECROSIS VS. APOPTOSIS NECROSIS APOPTOSIS Stimuli Pathologic Physiologic Pathologic Morphology Multiple cells Cell swelling Cell lysis Single cell Cell shrinkage Chromatin Condensation Apoptotic bodies Host response Inflammation No inflammation

26 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.

27 METAPLASIA Alteration in cell differentiation with concurrent alteration of tissue/organ function.

28 CELLULAR ADAPTATIONS Alterations in cell size Alterations in cell number Alterations in cell differentiation Abnormal intracellular accumulations

29 METAPLASIA Barrett's Esophagus