Cellular Membrane lesions

The major bioactive products of fatty acid metabolism relevant to atherosclerosis are those that result from enzymatic or non-enzymatic oxidation of polyunsaturated long-chain fatty acids. In most cases, these fatty acids are derived from phospholipase A2-mediated hydrolysis of phospholipids (Chapter 11) in cellular membranes or lipoproteins, or from lysosomal hydrolysis of lipoproteins after internalization by lesional cells. In particular, arachidonic acid is released from cellular membrane phospholipids by arachidonic acid-selective cytosolic phospholipase Aj. In addition, there is evidence that group II secretory phospholipase Aj (Chapter 11) hydrolyzes extracellular lesional lipoproteins, and lysosomal phospholipases and cholesterol esterase release fatty acids from the phospholipids and CE of internalized lipoproteins. Indeed, Goldstein and Brown surmised that at least one aspect of the atherogenicity of LDL may lie in its ability to deliver unsaturated fatty acids, in the form of phospholipids and CE, to lesions (J.L. Goldstein and M.S. Brown, 2001). 

Phosphatidylcholine is the major phospholipid of lesional cells and, as mentioned above, serves both structural and signaling functions (Chapter 8). In terms of cellular membrane structure, the cholesteroLphospholipid ratio in lesional cells must be kept within a certain limit in order for the proper functioning of membrane proteins [14]. Cholesterol-rich foam cells isolated from atherosclerotic lesions have intracellular phospholipid whorl-like structures, and phosphatidylcholine biosynthesis is increased in lesional areas of the arterial wall (Fig. 8). Cell-culture studies have revealed that cholesterol loading of macrophages directly leads to the activation of CTPrphospho-choline cytidylyltransferase and an increase in phosphatidylcholine biosynthesis and mass. Proof that this is an adaptive response to FC excess came from a study in which the cytidylyltransferase-a gene was disrupted in macrophages, which resulted in... 

Incomplete nerve lesions provoke changes in the membrane excitability of afferents spared by the injury. These effects are the consequence of an altered cellular and signaling environment at the lesion site and in the DRG. Wallerian degeneration of axotomized nerve fibers involves degeneration and proliferation of Schwann cells, and an invasion of macrophages (discussed in Chs 30 and 36). Nerve injury is accompanied by a release of trophic... 

Sell DA, Reynolds ES Liver parenchymal cell injury. VUE. Lesions of membranous cellular components following iodoform. 7 Cell Biol M-. 736-752, 1969... 

In addition to the effect of increased VLCFA on membrane and possibly cellular function, the rapid cerebral form of X-ALD is characterized by an inflammatory response that is believed to contribute to the demyelination that characterizes this phenotype and which is similar to that seen in multiple sclerosis. These cerebral lesions are characterized by breakdown in myelin with sparing of the axons accompanied by the accumulation of cholesterol ester in the neurons. A perivascular inflammatory response with infiltration of T cells, B cells, and macrophages also is present. Therefore, it is believed that the rapid cerebral disease has an im-munologically-mediated component. It has been suggested that the inflammatory response occurs in response to the elevated levels of VLCFA in lipids, which elicits an inflammatory cascade that may be mediated in part by cytokines. Once this cascade begins, it may be more difficult to intervene in the disease process, and in general therapeutic interventions studied to date have been most effective when initiated early. Therefore, prevention of the initiation of the immune response is important for improving outcome. 

The most direct mechanism of hepatotoxicity is through specific interaction of a chemical with a key cellular component and consequential modulation of its function. More common mechanisms, however, involve secondary effects of toxicant interaction. These include depletion of cellular molecules, such as ATP and GSH free radical and oxidant damage, in particular to membrane lipids covalent binding of reactive metabolites to critical cellular molecules and collapse of regulatory ion gradients. The following discussion will highlight how these cellular and molecular mechanisms contribute to specific types of chemically induced hepatic lesions. 

These processes can be complemented and enhanced by the liberation of biologically active cellular mediators from intracellular compartments or from the cell membrane. Thus, it is understandable that PFTs provoke inflammatory lesions and acute organ dysfunction in vitro and in vivo, and are lethal in experimental animals. When perfused through an isolated lung, PFTs provoke profound pathophysiological alterations in the pulmonary microvasculature and cause irreversible pulmonary edema. The underlying mechanisms are complex, but include a direct toxic action on endothelial cells, and the pro-... 

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