Lecture 1 Cell Injury and Cellular Death I and II

Pathology

Lecture 1 Cell Injury and Cellular Death I and II

1)To become aware of the morphologic and functional changes occurring in cells and tissues with sublethal injury through cell death.

Sublethal injury – Morphologic changes include: chromatin clumping, generalized swelling with the formation of blebs as well as swelling of the endoplasmic reticulum and mitochondria. Functional changes include: reduced oxidative phosphorylation which results in decreased ATP production and thus changes in ion concentrations due to a lack of active transport, which causes the swelling.

Irreversible injury and cell death – Morphologic changes include: swelling of endoplasmic reticulum with loss of ribosomes, lysosome rupture, membrane blebs, myelin figures, swollen mitochondria with amorphous densities, and nuclear condensation (pyknosis) followed by fragmentation (karyorrhexis), which ultimately results in fragmentation of the cell membrane and nucleus (karyolysis). Eosinophilia is increased following death (“red is dead”). Functional changes include: reduced integrity of the cell membrane, the cytoskeleton, and the genetic apparatus along with reduced ATP and protein production.

2)To learn the various mechanisms by which cells undergo injury and death.Cell injury is caused by hypoxia, physical agents, chemical agents, infectious agents, immunologic events, genetic disorders, or nutritional disorders. The mechanisms of cell injury and death are as follows:

Depletion of ATP by ischemic/hypoxic injury – ischemia is more rapid than hypoxia because cells are deprived of blood flow and not just O2. This results in reduced aerobic respiration (ATP production), which shuts down ion pumps (causing swelling), compromises protein production (lipids accumulate), and lowers pH due to anaerobic respiration (chromatin clumps).

Loss of Calcium homeostasis – Ca2+ influx due to injury will activate calcium-dependant degradative enzymes.

Oxidative stress – Reactive oxygen species (ROS), including superoxide anion (O2.-), hydroxyl radical (.OH), and hydrogen peroxide (H2O2), react with cell constituents to produce injury or start autocatalytic reactions producing more free radicals. ROSs can come from electron leakage, enzymes (cytochrome P450s, lipoxygenases, and NADPH oxidase), radiation, and chemical reactions (Fenton chemistry). They target lipids, proteins, and DNA. ROSs are removed by antioxidants, enzymes (superoxide dismutases, catalase and glutathione peroxidases), and control of free iron levels by transferrin.

3)To know the various patterns of necrosis and be able to relate them to particular types of insults and tissue types.

Coagulation necrosis – occurs with hypoxic cell death resulting in protein denaturation although the tissue remains firm and the cells appear eosinophilic with nuclear changes.

Liquifactive necrosis – occurs with focal infection (bacterial or fungal) causing inflammatory cells to accumulate and digest the tissue resulting in an abscess.

Fat necrosis – occurs with acute pancreatitis or trauma leading to the digestion of fat cells, which results in saponification (fatty acids bind calcium to form soaps). Cell outlines are present with basophilic calcium deposits.

Caseous necrosis – occurs in the central areas of certain granulomas, which are focal lesions in certain types of chronic inflammation including tuberculosis and Valley Fever. Grossly they have a cheesy appearance and microscopically they appear as granular eosinophilic debris.

Fibrinoid necrosis – occurs in injured blood vessels and has a bright pink, granular appearance. It’s made up of fibrin, plasma proteins and complement components.

Gangrenous necrosis – occurs in the lower extremities resulting from ischemia. Wet gangrene involves bacteria causing liquifactive necrosis and dry gangrene involves coagulation necrosis if bacteria are less involved.

4)To appreciate conditions in which cell death occurs by apoptosis and the biochemical and morphological aspects of this type of cell death.Apoptosis is programmed cell death which is involved in normal development, maintaining homeostasis, and protection from disease. Physiologically this occurs in embryonic development, hormone signaling, cell turnover (e.g. GI tract), immune cells, and cytotoxic T-cells. Pathologically this occurs due to injury that does not deplete ATP, viral infection (e.g., Councilman bodies in viral hepatitis), atrophy in parenchymal organs, and in tumors. Biochemical features include: chromatin condensation (endonucleases), protein cleavage (caspases), cell shape changes (transglutaminases), gene regulation (oncogenes and tumor suppressor genes), and phosphotidylserine presentation on the outer membrane marking the cell for phagocytosis. Morphological features include: Decreased cell size, chromatin condensation, bleb formation (apoptotic bodies), and phagocytosis by healthy cells. Cells are usually eosinophilic with dense shrunken nuclei.