Early loss of selective membrane permeability, leading ultimately to overt membrane damage, is a consistent feature of most forms of cell injury (except apoptosis). Membrane damage may affect the functions and integrity of all cellular membranes. The following paragraphs discuss the mechanisms and pathologic consequences of membrane damage.

Mechanisms of Membrane Damage. In ischemic cells, membrane defects may be the result of ATP depletion and calcium-mediated activation of phospholipases. The plasma membrane can also be damaged directly by various bacterial toxins, viral proteins, lytic complement components, and a variety of physical and chemical agents. Several biochemical mechanisms may contribute to membrane damage (Fig.1):

• Reactive oxygen species. Oxygen free radicals cause injury to cell membranes by lipid peroxidation, discussed earlier.

• Decreased phospholipid synthesis. The production of phospholipids in cells may be reduced as a consequence of defective mitochondrial function or hypoxia, both of which decrease the production of ATP and thus affect energy-dependent biosynthetic pathways. The decreased phospholipid synthesis may affect all cellular membranes, including the mitochondria themselves.

• Increased phospholipid breakdown. Severe cell injury is associated with increased degradation of membrane phospholipids, probably due to activation of calciumdependent phospholipases by increased levels of cytosolic and mitochondrial Ca2+. Phospholipid breakdown leads to the accumulation of lipid breakdown products, including unesterified free fatty acids, acyl carnitine, and lysophospholipids, which have a detergent effect on membranes. They may also either insert into the lipid bilayer of the membrane or exchange with membrane phospholipids, potentially causing changes in permeability and electrophysiologic alterations.

• Cytoskeletal abnormalities. Cytoskeletal filaments serve as anchors connecting the plasma membrane to the cell interior. Activation of proteases by increased cytosolic calcium may cause damage to elements of the cytoskeleton. In the presence of cell swelling, this damage results, particularly in myocardial cells, in detachment of the cell membrane from the cytoskeleton, rendering it susceptible to stretching and rupture.

Fig1. Mechanisms of membrane damage in cell injury. Decreased O2 and increased cytosolic Ca2+ are typically seen in ischemia but may accompany other forms of cell injury. Reactive oxygen species, which are often produced on reperfusion of ischemic tissues, also cause membrane damage (not shown).

Consequences of Membrane Damage. The most important sites of membrane damage during cell injury are the mitochondrial membrane, the plasma membrane, and membranes of lysosomes.

• Mitochondrial membrane damage. As discussed earlier, damage to mitochondrial membranes results in opening of the mitochondrial permeability transition pore, leading to decreased ATP generation and release of proteins that trigger apoptotic death.

• Plasma membrane damage. Plasma membrane damage results in loss of osmotic balance and influx of fluids and ions, as well as loss of cellular contents. The cells may also leak metabolites that are vital for the reconstitution of ATP, thus further depleting energy stores.

• Injury to lysosomal membranes results in leakage of their enzymes into the cytoplasm and activation of the acid hydrolases in the acidic intracellular pH of the injured cell. Lysosomes contain RNases, DNases, proteases, phosphatases, and glucosidases. Activation of these enzymes leads to enzymatic digestion of proteins, RNA, DNA, and glycogen, and the cells die by necrosis.

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