Membrane cell injury

The first is cell injury (cytotoxicity), which can be severe enough to result in cell death. There are many mechanisms by which xenobiotics injure cells. The one considered here is covalent binding to cell macromol-ecules of reactive species of xenobiotics produced by metabolism. These macromolecular targets include DNA, RNA, and protein. If the macromolecule to which the reactive xenobiotic binds is essential for short-term cell survival, eg, a protein or enzyme involved in some critical cellular function such as oxidative phosphorylation or regulation of the permeability of the plasma membrane, then severe effects on cellular function could become evident quite rapidly. 

Recent studies by Crompton et al. have shown that oxidant stress may open a Ca-sensitive, non-selective pore in the inner mitochondrial membrane that is blocked by cyclosporin A (Crompton, 1990 Crompton and Costi, 1990). This pore opening results in massive mitochondrial swelling, dissipation of the transmembrane proton gradient and disruption of mitochondrial energy production (Crompton et al., 1992). Since mitochondria may play a role as a slow, high-capacity cytosolic calcium buffer (Isenberg et al., 1993), disruption of mitochondrial function may also contribute to calcium overload and cell injury. 

In many eukaryotic plasma membranes, PS resides in the inner leaflet (Schroit and Zwaal, 1991 Zachowski, 1993). This transbilayer distribution of membrane hpids is not a static situation but a result of balance between the inward and outward translocation of phospholipids across the membranes. Recent studies showed that the transbilayer lipid asymmetry is regulated by several lipid transporter proteins, such as aminophospholipid translocase (Daleke and Lyles, 2000), ATP-binding cassette transporter family (van Helvoort et al, 1996 Klein et al, 1999), and phospholipid scramblase (Zhou et al, 1997 Zhao et al, 1998). An increment of intracellular due to cell activation, cell injury, and apoptosis affects the activities of these transporters, resulting in exposure of PS (Koopman et al, 1994 Verhoven et al, 1995) and PE (Emoto et al, 1997) on the cell surface. 

Figure 22.6 How various factors increase the risk of atherosclerosis, thrombosis and myocardial infarction. The diagram provides suggestions as to how various factors increase the risk of development of the trio of cardiovascular problems. The factors include an excessive intake of total fat, which increases activity of clotting factors, especially factor VIII an excessive intake of saturated or trans fatty acids that change the structure of the plasma membrane of cells, such as endothelial cells, which increases the risk of platelet aggregation or susceptibility of the membrane to injury excessive intake of salt - which increases blood pressure, as does smoking and low physical activity a high intake of fat or cholesterol or a low intake of antioxidants, vitamin 6 2 and folic acid, which can lead either to direct chemical damage (e.g. oxidation) to the structure of LDL or an increase in the serum level of LDL, which also increases the risk of chemical damage to LDL. A low intake of folate and vitamin B12 also decreases metabolism of homocysteine, so that the plasma concentration increases, which can damage the endothelial membrane due to formation of thiolactone.

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

Cell injury can be initiated by a number of mechanisms, such as inhibition of enzymes, depletion of cofactors or metabolites, depletion of energy (ATP) stores, interaction with receptors, and alteration of cell membranes. In recent years attention has focused on the role of biotransformation of chemicals to highly reactive metabolites that initiate cellular toxicity. Many compounds, including clinically useful drugs, can cause cellular damage through metabolic activation of the chemical to highly reactive compounds, such as free radicals, carbenes, and nitrenes (Chapters 7 and 8). 

C11. Cybulsky, A. V., Rennke, H. G., Feintzeig, I. D., and Salant, D. J., Complement-induced glomerular epithelial cell injury The role of the membrane attack complex in rat membranous nephropathy. J. Clin. Invest. 11, 1096-1107 (1986). 

The stress or growth pathways modulated by vanadium involve specialized effectors and often can be activated by excess ROS. Cytokines, small proteins that effect communication between cells or cell behavior, can be involved in the cellular stress response. Tumor necrosis factor a (TNFa) is a cytokine stress signal that binds to a membrane receptor (tumor necrosis factor receptor, or TNFR). This interaction stimulates kinase activity that leads to cell injury and inflammation and also to the activation of caspases, a family of cysteine-dependent aspartate-directed proteases that are involved in apoptosis. The mitogen-activated protein (MAP) kinase cascade regulates both mitosis and apoptosis signaling pathways. 

N. Uesugi, N. Sakata, S. Horiuchi, J. Meng, and S. Takebayashi, Glycoxidation induces vascular smooth muscle cell injury in diabetes through mediation of membrane attack complement, in G, 2002, 439-440. 

Typically, the integrity of the cell membrane is evaluated by identifying the percentage of cells taking up a vital dye termed trypan blue. Cells that take up trypan blue have defective cell membranes and therefore external loading or contact with materials that cause cells to have faulty membranes are likely to cause cell injury and death. Cell cytotoxicity is evaluated by contacting a surface of a material or the extract of a material or implant with cells in culture. If more than five percent of the cell population stains with dye after contact with the material or an extract then it is considered cytotoxic. 

Diphtheria toxin, inorganic lead, and tellurium are considered toxicants that cause demyelination through injury to the myelinating cell. The mechanism of action of diphtheria toxin was discussed in Section 30.1. The mechanism by which inorganic lead causes Schwann cell injury and demyelination is not well understood, but may be related to uncoupling or inhibition of oxidative phosphorylation secondary to interference of lead with some aspect of ion transport across the mitochondrial membrane. 

It has been shown that the renal bioactivation of xenobiotics such as the herbicides paraquat and diquat [10, 111, 112], and of p-lactams such as cephaloridine and cefsulodin [10, 40, 41] or the antitumor agent adriamycin [113, 114] can induce the generation of reactive oxygen species (oxidative stress) which can be involved in alterations of the structure and functions of cell membranes, cytoskeletal injury, mutagenicity, carcinogenicity, and cell necrosis [115-117]. 

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