title: Nonsteroidal anti-inflammatory drug induces proinflammatory damage in gastric mucosa through NF-κB activation and neutrophil infiltration: anti-inflammatory role of heme oxygenase-1 against nonsteroidal anti-inflammatory drug.
abstract: 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.
authors.affiliation: Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India.
authors.forename: Samik
authors.initials: S
authors.lastname: Bindu
authors.affiliation: Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India.
authors.forename: Somnath
authors.initials: S
authors.lastname: Mazumder
authors.affiliation: Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India.
authors.forename: Sumanta
authors.initials: S
authors.lastname: Dey
authors.affiliation: Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India.
authors.forename: Chinmay
authors.initials: C
authors.lastname: Pal
authors.affiliation: Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India.
authors.forename: Manish
authors.initials: M
authors.lastname: Goyal
authors.affiliation: Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India.
authors.forename: Athar
authors.initials: A
authors.lastname: Alam
authors.affiliation: Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India.
authors.forename: Mohd Shameel
authors.initials: MS
authors.lastname: Iqbal
authors.affiliation: Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India.
authors.forename: Souvik
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India.
authors.forename: Asim
authors.initials: A
authors.lastname: Azhar Siddiqui
authors.affiliation: Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India.
authors.forename: Chinmoy
authors.initials: C
authors.lastname: Banerjee
authors.affiliation: Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India. Electronic address: ubandyo_1964@yahoo.com.
authors.forename: Uday
authors.initials: U
authors.lastname: Bandyopadhyay
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D005753:Gastric Mucosa / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007213:Indomethacin / Q000009:adverse effects; D007249:Inflammation / Q000139:chemically induced; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000187:drug effects; D018384:Oxidative Stress; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D051547:Heme Oxygenase-1; D007213:Indomethacin
keywords: Antioxidants; Gastropathy; HO-1; Heme oxygenase-1 (HO-1); ICAM-1; Inflammation; MCP-1; MOS; Mitochondrial oxidative stress; NF-κB; NSAID; heme oxygenase-1; intracellular adhesion molecule 1, VCAM-1, vascular cell adhesion molecule 1, IL-1β, interleukin 1β; mitochondrial oxidative stress; monocyte chemotactic protein-1; nuclear factor-κB