title: Molecular mechanism of indomethacin-induced gastropathy.
abstract: The probable cross talk among large numbers of inflammatory and angiogenic parameters in indomethacin (IND)-induced gastropathy and the associated signaling mechanism were studied in a mouse model. A single dose of IND (18 mg/kg, po) produced robust gastric ulceration in mice without any mortality, which peaked on the third day, but started healing from the fifth day onward. The ulceration was associated with increased myeloperoxidase activity and expression of proinflammatory (TNF-α, adhesion molecules, COX-2) and antiangiogenic (endostatin) parameters. The levels of proangiogenic factors such as COX-1, prostaglandin E, VEGF, and von Willebrand factor VIII were downregulated by IND. Our results revealed that although the maximal and minimal levels of these parameters were attained sequentially at different time points, TNF-α upregulation was the primary event to initiate and induce gastric ulceration. IND also activated NF-κB and all the MAP kinases, but only the inhibitors of TNF-α, NF-κB, and JNK MAP kinase could abrogate the IND-induced damages. Further TNF-α inhibition also reduced the IND-mediated activation of NF-κB and JNK MAP kinase. All this evidence strongly suggests that mitigation of TNF-α may offer a potential solution to IND-mediated gastropathy.
authors.affiliation: Department of Biochemistry, Dr. B.C. Roy Post Graduate Institute of Basic Medical Sciences & IPGME&R, Kolkata, India.
authors.forename: Sudhir K
authors.initials: SK
authors.lastname: Yadav
authors.forename: Biplab
authors.initials: B
authors.lastname: Adhikary
authors.forename: Saswati
authors.initials: S
authors.lastname: Chand
authors.forename: Biswanath
authors.initials: B
authors.lastname: Maity
authors.forename: Sandip K
authors.initials: SK
authors.lastname: Bandyopadhyay
authors.forename: Subrata
authors.initials: S
authors.lastname: Chattopadhyay
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005753:Gastric Mucosa / Q000187:drug effects*; D007213:Indomethacin / Q000633:toxicity*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D007213:Indomethacin