CELLULAR CHANGES DURING INJURY
Cellular responses to injury include adaptation (hypertrophy or atrophy, hyperplasiaor metaplasia), reversible injury, and irreversible injury and cell death (necrosis, apoptosis, or necroptosis).
The cellular response to injury depends on several important factors, including the type of injury, duration (including pattern) of injury, severity and intensity of injury, type of cell injured, the cell’s metabolic state, and the cell’s ability to adapt.
The critical intracellular targets that are susceptible to injury are DNA, produc-tion of ATP via aerobic respiration, cell membranes, and protein synthesis.
Important mechanisms of cell injury are as follows:
· Damage to DNA, proteins, lipid membranes, and circulating lipids (LDL) can be caused by oxygen-derived free radicals, including superoxide anion (O2• –), hydroxyl radical (OH•), and hydrogen peroxide (H2O2).
· ATP depletion: Several key biochemical pathways are dependent on ATP. Disruption of Na+/K+ or Ca++ pumps cause imbalances in solute concentra-tions. Additionally, ATP depletion increases anaerobic glycolysis that leads to a decrease in cellular pH. Chronic ATP depletion causes morphological and functional changes to the ER and ribosomes.
· Increased cell membrane permeability: Several defects can lead to movement of fluids into the cell, including formation of the membrane attack complex via complement, breakdown of Na+/K+ gradients (i.e., causing sodium to enter or potassium to leave the cell), etc.
· Influx of calcium can cause problems because calcium is a second messenger, which can activate a wide spectrum of enzymes. These enzymes include pro-teases (protein breakdown), ATPases (contributes to ATP depletion), phospho-lipases (cell membrane injury), and endonucleases (DNA damage).
· Mitochondrial dysfunction causes decreased oxidative phosphorylation and ATP production, formation of mitochondrial permeability transition (MPT) channels, and release of cytochrome c (a trigger for apoptosis).
· Decreased synthesis of ATP by oxidative phosphorylation.
· Decreased function of Na+K+ ATPase membrane pumps, which in turn causesinflux of Na+ and water, efflux of K+, cellular swelling (hydropic swelling), and swelling of the endoplasmic reticulum.
· The switch to anaerobic glycolysis results in depletion of cytoplasmic glyco-gen, increased lactic acid production, and decreased intracellular pH.
· Decreased protein synthesis leads to detachment of ribosomes from the roughendoplasmic reticulum.
· Plasma-membrane blebs and myelin figures may be seen.
· Severe membrane damage plays a critical role in irreversible injury, allowsa massive influx of calcium into the cell, and allows efflux of intracellular enzymes and proteins into the circulation.
· Marked mitochondrial dysfunction produces mitochondrial swelling, largedensities seen within the mitochondrial matrix, irreparable damage of the oxidative phosphorylation pathway, and an inability to produce ATP.
· Rupture of the lysosomes causes release of lysosomal digestive enzymes intothe cytosol and activation of acid hydrolases followed by autolysis.
· Nuclear changes can include pyknosis (degeneration and condensation ofnuclear chromatin), karyorrhexis (nuclear fragmentation), and karyolysis (dissolution of the nucleus).