Lansoprazole protects and heals gastric mucosa from non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy by inhibiting mitochondrial as well as Fas-mediated death pathways with concurrent induction of mucosal cell renewal (Retracted article. See vol. 294, pg. 20260, 2019)
Lansoprazole protects and heals gastric mucosa from non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy by inhibiting mitochondrial as well as Fas-mediated death pathways with concurrent induction of mucosal cell renewal (Retracted article. See vol. 294, pg. 20260, 2019)
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DOI：
10.1074/jbc.m800414200
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发表时间：
2008-05-23
影响因子：
4.8
通讯作者：
Bandyopadhyay, Uday
中科院分区：
文献类型：
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作者：
Maity, Pallab;Bindu, Samik;Bandyopadhyay, Uday
我们研究了兰索拉唑（一种质子泵抑制剂）的抗凋亡和细胞更新作用的机制，以保护和愈合由吲哚美辛（一种非甾体抗炎药（NSAID））诱导的胃粘膜损伤。兰索拉唑通过阻断线粒体和Fas凋亡途径的激活预防吲哚美辛诱导的胃损伤。兰索拉唑可阻止吲哚美辛诱导的促凋亡Bax和巴克的上调以及抗凋亡Bcl-2和Bcl（xL）的下调，以维持正常的促凋亡/抗凋亡比率，从而阻止吲哚美辛诱导的Bax线粒体易位和线粒体膜电位崩溃，随后细胞色素c释放和caspase-9激活。兰索拉唑还通过下调Fas或FasL表达和抑制caspase-8活化，抑制吲哚美辛诱导的Fas介导的粘膜细胞死亡。兰索拉唑通过刺激促生存增殖细胞核抗原、生存素、表皮生长因子和碱性成纤维细胞生长因子的基因表达，同时促进粘膜细胞更新。Flt-1的上调进一步表明兰索拉唑激活血管表皮生长因子介导的受控血管生成，以修复胃粘膜。兰索拉唑还可促进吲哚美辛诱导的已形成溃疡的愈合。愈合的时间过程研究表明，它完全关闭线粒体死亡途径，但不是Fas途径。然而，兰索拉唑在克服了持续存在的Fas途径后几乎完全治愈了粘膜病变，这可能是通过促进促生存基因表达实现的。因此，本研究提供了兰索拉唑对吲哚美辛诱导的胃病提供胃保护的抗凋亡和促生存作用的详细机制。
We have investigated the mechanism of antiapoptotic and cell renewal effects of lansoprazole, a proton pump inhibitor, to protect and heal gastric mucosal injury in vivo induced by indomethacin, a non-steroidal anti-inflammatory drug (NSAID). Lansoprazole prevents indomethacin-induced gastric damage by blocking activation of mitochondrial and Fas pathways of apoptosis. Lansoprazole prevents indomethacin-induced up-regulation of proapoptotic Bax and Bak and down-regulation of antiapoptotic Bcl-2 and Bcl(xL) to maintain the normal proapoptotic/antiapoptotic ratio and thereby arrests indomethacin-induced mitochondrial translocation of Bax and collapse of mitochondrial membrane potential followed by cytochrome c release and caspase-9 activation. Lansoprazole also inhibits indomethacin-induced Fas-mediated mucosal cell death by down-regulating Fas or FasL expression and inhibiting caspase-8 activation. Lansoprazole favors mucosal cell renewal simultaneously by stimulating gene expression of prosurvival proliferating cell nuclear antigen, survivin, epidermal growth factor, and basic fibroblast growth factor. The up-regulation of Flt-1 further indicates that lansoprazole activates vascular epidermal growth factor-mediated controlled angiogenesis to repair gastric mucosa. Lansoprazole also stimulates the healing of already formed ulcers induced by indomethacin. Time course study of healing indicates that it switches off the mitochondrial death pathway completely but not the Fas pathway. However, lansoprazole heals mucosal lesions almost completely after overcoming the persisting Fas pathway, probably by favoring the prosurvival genes expression. This study thus provides the detailed mechanism of antiapoptotic and prosurvival effects of lansoprazole for offering gastroprotection against indomethacin-induced gastropathy.