Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India.
Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India.
Free Radic Biol Med. 2013 Dec;65:456-467. doi: 10.1016/j.freeradbiomed.2013.07.027. Epub 2013 Jul 23.
Nonsteroidal anti-inflammatory drug (NSAID)-induced mitochondrial oxidative stress (MOS) is an important prostaglandin (PG)-independent pathway of the induction of gastric mucosal injury. However, the molecular mechanism behind MOS-mediated gastric pathology is still obscure. In various pathological conditions of tissue injury oxidative stress is often linked with inflammation. Here we report that MOS induced by indomethacin (an NSAID) induces gastric mucosal inflammation leading to proinflammatory damage. Indomethacin, time dependently stimulated the expression of proinflammatory molecules such as intercellular adhesion molecule 1(ICAM-1), vascular cell adhesion molecule 1(VCAM-1), interleukin1β (IL-1β), and monocyte chemotactic protein-1 (MCP-1) in gastric mucosa in parallel with the increase of neutrophil infiltration and injury of gastric mucosa in rat. Western immunoblotting and confocal microscopic studies revealed that indomethacin induced nuclear translocation of nuclear factor kappa-B (NF-κB) in gastric mucosal cells, which resulted in proinflammatory signaling. The prevention of MOS by antioxidant tryptamine-gallic acid hybrid (SEGA) inhibited indomethacin-induced expression of ICAM-1, VCAM-1, IL-1β, and MCP-1. SEGA also prevented indomethacin-induced NF-κB activation and neutrophil infiltration as documented by chromatin immunoprecipitation studies and neutrophil migration assay, respectively. Heme oxygenase-1 (HO-1), a cytoprotective enzyme associated with tissue repair mechanisms is stimulated in response to oxidative stress. We have investigated the role of HO-1 against MOS and MOS-mediated inflammation in recovering from gastropathy. Indomethacin stimulated the expression of HO-1 and indomethacin-stimulated HO-1 expression was reduced by SEGA, an antioxidant, which could prevent MOS. Thus, the data suggested that the induction of HO-1 was a protective response against MOS developed by indomethacin. Moreover, the induction of HO-1 by cobalt protoporphyrin inhibited inflammation and chemical silencing of HO-1 by zinc protoporphyrin aggravated the inflammation by indomethacin. Thus, NSAID by promoting MOS-induced proinflammatory response damaged gastric mucosa and HO-1 protected NSAID-induced gastric mucosal damage by preventing NF-κB activation and proinflammatory activity.
非甾体抗炎药（NSAID）诱导的线粒体氧化应激（MOS）是诱导胃黏膜损伤的一种重要的前列腺素（PG）非依赖性途径。然而，MOS 介导的胃病理学背后的分子机制仍然不清楚。在组织损伤的各种病理条件下，氧化应激通常与炎症有关。在这里，我们报告说，吲哚美辛（一种 NSAID）诱导的 MOS 诱导胃黏膜炎症，导致促炎损伤。吲哚美辛时间依赖性地刺激胃黏膜中促炎分子的表达，如细胞间黏附分子 1（ICAM-1）、血管细胞黏附分子 1（VCAM-1）、白细胞介素 1β（IL-1β）和单核细胞趋化蛋白-1（MCP-1），同时伴有中性粒细胞浸润和大鼠胃黏膜损伤的增加。Western 免疫印迹和共聚焦显微镜研究表明，吲哚美辛诱导胃黏膜细胞中核因子 kappa-B（NF-κB）的核转位，从而导致促炎信号。抗氧化剂色胺-没食子酸杂合体（SEGA）通过阻止 MOS 来抑制吲哚美辛诱导的 ICAM-1、VCAM-1、IL-1β 和 MCP-1 的表达。SEGA 还通过染色质免疫沉淀研究和中性粒细胞迁移测定分别预防了吲哚美辛诱导的 NF-κB 激活和中性粒细胞浸润。血红素加氧酶-1（HO-1）是一种与组织修复机制相关的细胞保护酶，它在应对氧化应激时被刺激。我们研究了 HO-1 在从胃病中恢复过来时对 MOS 和 MOS 介导的炎症的作用。吲哚美辛刺激 HO-1 的表达，而抗氧化剂 SEGA 减少了吲哚美辛刺激的 HO-1 表达，从而阻止了 MOS。因此，数据表明 HO-1 的诱导是吲哚美辛引起的 MOS 发展的一种保护反应。此外，钴原卟啉诱导的 HO-1 抑制炎症，锌原卟啉化学沉默 HO-1 加重了吲哚美辛引起的炎症。因此，NSAID 通过促进 MOS 诱导的促炎反应损伤胃黏膜，而 HO-1 通过防止 NF-κB 激活和促炎活性来保护 NSAID 诱导的胃黏膜损伤。
