Cell Injury and Cell Death

Learning Objectives
Describe the pathogenesis of irreversible cell injury with ischemia Identify morphology of reversible cell injury Differentiate between reversible and irreversible cell injury

Overview
Normal cell Injury Reversibly injured cell
+ Stress - Stress

Adapted Cell

+Stres s Stress

Irreversibly Injured cell

Apoptosi s Necrosi s

Dead cell

Mechanisms of Cell Injury

Depletion of ATP Mitochondrial Damage Influx of Intracellular Calcium and Loss of Calcium Homeostasis Accumulation of Oxygen-Derived free radical (Oxidative stress) Defects in Membrane Permeability

Morphology of Cell Injury and Necrosis

Cell Injury Reversible Irreversible Cell Death Necrosis Apoptosis

Cell Injury and Death

Reversible Injury
o

Cell swelling develops when cells are incapable of fluid an ion homeostasis (ed function of ATP dependant pumps). Fatty change the accumulation of lipid vacuoles in the cytoplasm.
Two basic processes underlie the morphologic changes of necrosis
Denaturation of protein Enzymatic digestion of cell components

Irreversible injury (Necrosis)

o

Ischemic injury

Cell injury and death

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

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

Reversible vs irreversible cell injury

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

Mechanisms of Cell Injury

Ischemic injury

Morphology of Cell Injury

Reversible Injury
Cellular swelling Fatty change

Plasma membrane alteration Mitochondrial Changes Dilation of Endoplasmic reticulum Nuclear Alteration

Fatty liver
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 October 2005 05:51 PM) 2005 Elsevier

 Hydropic change or vacuolar degereration. Appears whenever cells are incapable of maintaining ionic and fluid homeostasis. The first manifestation of almost all forms of sell injury. Reversible injury. Gross Findings Pallor, increased turgor, and increased in weight.

Micro Findings 1. Cell swelling, cytoplasm contains coarse granules. 2. Nucleus not affected in light microscopy.. 3. Pigmented cast, hyaline cast. D. Others: 1. The first manifestation of cell injury and is reversible. 2. Increasing hydration of the cell due to alteration in ion transport at cell membrane. 3. Cause: infection, physico-chemical injury ( toxic ), ischemia