| NSAIDs, such as aspirin and indomethacin, with their satisfactory analgesic, anti-inflammatory, and antipyretic effects, are widely used in clinical practice. Unfortunately, long-term NSAIDs use has significant gastrointestinal toxicity. Clinical observations show that at least 10 to 20% long-term users complain of dyspepsia, 2 to 30% users develop gastric ulcer and the incidence of duodenal ulcer is about 2 to 19%. NSAIDs use increases the risk of peptic ulcer complications, such as bleeding and perforation, about 4 to 6 fold. Experimental studies also confirm that NSAIDs can induce severe gastric mucosal hemorrhagic lesions. The mechanisms of NSAIDs gastropathy have not been fully elucidated. The reported factors include: inhibition of endogeneous prostaglandin synthesis, reinforcement of gastric mobility, "ion trapping"effect of mucosal epithelial cells, inhibition of the synthesis and secretion of mucus and bicarbonates, increment of mucosal permeability, inhibition of DNA synthesis and cell proliferation, disturbance of mucosal blood flow, impaired mucosa repair process due to the inhibition of angiogenesis, the infiltration and activation of neutrophils resulted from up-regulation of adhesion molecules and the induction of mucosal cell apoptosis. Apoptosis is an active cell death process which can efficiently delete damaged or senescent cells to maintain the integrity of tissue structure and function of multicellular organisms. The initiation and execution of apoptosis have a number of elaborate regulating mechanisms. Many different signals that may originate either from within or outside a cell have been shown to regulate the process of apoptosis. Not supprisingly, the impaired apoptosis will certainly cause pathological cell overgrowth, but the inappropriate activation of it may result in severe tissue damage. Several signaling pathways are involved in inducing apoptosis depending on the initiating stimulus. Proteins of the Bcl-2 family, mitochondria, cytochrome c, and caspases have been identified as essential components of the intracellular apoptotic signaling pathways. Caspases, belonging to ICE family, are a group of cysteine proteases characterized by almost absolute specificity for aspartic acid residue. They are homologous to the product of ced-3, an apoptotic gene in nematode C.elegans. Up to now, fourteen caspases have been identified, in which caspase-2, -3, -6, -7, -8, -9 and -10 are involved in apoptotic signal transduction. Experimental studies have shown that NSAIDs can induce gastric mucosal cell apoptosis both in vivo and in vitro, accompanied by the increased caspase-1, -3, -8 and -9 activities and caspases inhibitors may reverse the pro-apoptotic effects of NSAIDs. But the influence of NSAIDs on caspases gene and protein expressions has not been well studied. Recent studies indicate that NO has a dual-regulating effect on cell apoptosis, that is, physiologically low levels of NO suppress cell apoptotic pathways at multiple levels and by several mechanisms and pathologically higher content of NO overwhelm cellular protective mechanisms resulting in apoptosis of some kinds of cells. Several authors reported that NSAIDs could decrease mucosal cNOS activity and increase iNOS activity, which was relevant to the changes of caspases activities and mucosal cell apoptosis. In addition, NO-NSAIDs or exogenous NO donorscould inhibit caspase 1 and 3 activities and cell apoptosis. But the relationships between NOS gene expression, NOS activities and NO content and mucosal cell apoptosis during NSAIDs-induced gastric mucosal lesions have not been reported. The release of cytochrome c from mitochondria is a key event during apoptotic signal transduction. It has now been recognized that the proteins of Bcl-2 family, with their ability to control cytochrome c release from mitochondria, are main regulating factors of cellular apoptotic signal. For instance, Bax can promote the release of cytochrome c and lead to cell apoptosis, but Bcl-2 inhibits cytochr...
|
PDF Full Text Request