ischemic cell injury
As the oxygen tension within the cell decreases, there is loss of oxidative phosphorylation and decreased generation of ATP.
The depletion of ATP results in failure of the sodium pump, with loss of potassium, influx of sodium and water, and cell swelling. There is progressive loss of glycogen and decreased protein synthesis. There may be severe functional consequences at this stage.
For instance, heart muscle ceases to contract within 60 seconds of coronary occlusion. Note, however, that loss of contractility does not mean cell death.
If hypoxia continues, worsening ATP depletion causes further morphologic deterioration. The cytoskeleton disperses, resulting in the loss of ultrastructural features such as microvilli and the formation of "blebs" at the cell surface.
"Myelin figures," derived from plasma as well as organellar membranes, may be seen within the cytoplasm or extracellularly. They are thought to result from dissociation of lipoproteins with unmasking of phosphatide groups, promoting the uptake and intercalation of water between the lamellar stacks of membranes.
At this time, the mitochondria are usually swollen, owing to loss of volume control by these organelles; the endoplasmic reticulum remains dilated; and the entire cell is markedly swollen, with increased concentrations of water, sodium, and chloride and a decreased concentration of potassium.
If oxygen is restored, all of these disturbances are reversible. If ischemia persists, irreversible injury and ischemic necrosis ensue.
Irreversible injury is associated morphologically with severe swelling of mitochondria, extensive damage to plasma membranes, and swelling of lysosomes.
Large, flocculent, amorphous densities develop in the mitochondrial matrix. In the myocardium, these are indications of irreversible injury and can be seen as early as 30 to 40 minutes after ischemia.
Massive influx of calcium into the cell then occurs, particularly if the ischemic zone is reperfused. Death is mainly by necrosis, but apoptosis also contributes; the apoptotic pathway is activated probably by release of pro-apoptotic molecules from leaky mitochondria.
After death, cell components are progressively degraded, and there is widespread leakage of cellular enzymes into the extracellular space and, conversely, entry of extracellular macromolecules from the interstitial space into the dying cells.
Finally, the dead cell may become replaced by large masses composed of phospholipids in the form of myelin figures.
These are then either phagocytosed by other cells or degraded further into fatty acids. Calcification of such fatty acid residues may occur with the formation of calcium soaps.
See also
- ischemic necrosis
References
Robbins