Lec 3. Cell injury- I (Mechanism of Cell Injury).pdf

Cell Injury – I Mechanism of Cell Injury Pathology Unit of BMS (UCM) Learning Objectives By the end of this lecture, the students should be able to:  Cell Path Inj.II.1. List the main causes of cell Injury.  Cell Path Inj.II.2. Discuss the major mechanisms of cell injury.  Cell Path Inj.II.3. Des...

Cell Injury – I Mechanism of Cell Injury Pathology Unit of BMS (UCM) Learning Objectives By the end of this lecture, the students should be able to:  Cell Path Inj.II.1. List the main causes of cell Injury.  Cell Path Inj.II.2. Discuss the major mechanisms of cell injury.  Cell Path Inj.II.3. Describe how reactive oxygen species (ROS) are generated in the cells.  Cell Path Inj.II.4. Name three antioxidant enzymes, 2 storage proteins & 3 vitamins that protect cells from ROS.  Cell Path Inj.II.5. Describe the injurious stimuli that damage mitochondria.  Cell Path Inj.II.6. Explain how mitochondrial dysfunction may lead to apoptosis or necrosis. Cell Injury and Death: Overview Overview  Normal cells are in a steady state: Homeostasis  Excess physiologic or pathologic stress may force the cell to a new steady state: Adaptation  Too much stress exceeds the cell’s adaptive capacity: cell Injury  Cell injury can be reversible or irreversible ending by Cell death  Reversibility depends on the type, severity and duration of injurious stimuli  The consequences of cell injury depend on the type ,the status, and adaptability of the injured cells Principles of cell injury  Different cells show different sensitivities/thresholds  Brain cells, heart cells are susceptible to hypoxia and ischemia  Calf muscle tolerates 2-3 h of ischemia, cardiac muscle dies in 20-30 min  liver cells are susceptible to chemical injury  Nutritional status – glycogen-rich hepatocyte is more resistant to ischemia than depleted one  Cellular function is lost far before cell death occurs  Morphologic changes of cell injury (or death) lag far behind both  Morphologic changes follow functional changes Ultrastructural changes of cell injury  Reversible  Plasma membrane alterations such as blebbing, blunting or distortion of microvilli, and loosening of intercellular attachments  Mitochondrial changes such as swelling and the appearance of phospholipid-rich amorphous densities  Dilation of the ER with detachment of ribosomes and dissociation of polysomes  Nuclear alterations, with clumping of chromatin  Irreversible  Lysosomal swelling →enzymes leak out of lysosomes, enter the cytoplasm, and digest the cell, resulting in necrosis  Two features are characteristic of irreversibility  Irreversible mitochondrial dysfunction  Sever membrane dysfunction Causes of Cell Injury  Oxygen deprivation = HYOPXIA  Most common cause of oxygen deprivation is reduced blood flow = ISCHEMIA  Physical/chemical agents  Infectious agents  Immunologic reactions  Genetic derangements  Nutritional imbalances (deficiency/excess) Mechanisms by which ischemia and hypoxia cause cell injury  Reduced supply of oxygen leads to reduced intracellular generation of ATP which leads to failure of many energy-dependent cellular systems, including Ion pumps  leading to cell swelling, and influx of Ca2+, with its deleterious consequences.  Influx of Na & water , eflux of K  Depletion of glycogen stores with accumulation of lactic acid , thus lowering the intracellular pH  Reduction in protein synthesis Mechanisms of Cell Injury 1 2 3 4 5 Fig. 2-16, PBD 9th, 2015 NOTE: injury may trigger any of these 6 interconnected mechanisms; often several mechanisms involved concurrently 6 Mechanism 1: depletion ATP or chemical toxins 2 ways to generate ATP: 1. Oxidative phosphorylation 2. Glycolytic pathway Effects ATP depletion (