title: Mast cells are critical for protection against peptic ulcers induced by the NSAID piroxicam.
abstract: Many commonly used non-steroidal anti-inflammatory drugs (NSAIDs) also cause gastrointestinal toxicity, including the development of life-threatening peptic ulcers. We report that mast cell-deficient mice have an extremely high incidence of severe peptic ulceration when exposed to the NSAID piroxicam. This enhanced ulcer susceptibility can be reversed by reconstitution with mast cells. Furthermore, wild type mice treated with diphenhydramine hydrochloride, a commonly used antihistamine that blocks histamine H1 receptors, develop a similarly high incidence of peptic ulcers following piroxicam exposure. The protective effect of mast cells is independent of TNF, blockade of H2 receptors, or acid secretion. These data indicate a critical role for mast cells and the histamine that they produce in prevention and/or repair of piroxicam-induced gastric mucosal injury. Additional studies will be required to determine whether this represents a NSAID class effect that can be exploited to develop novel therapeutic strategies to limit the incidence of NSAID-induced side effects in humans.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Hampton
authors.forename: Laura P
authors.initials: LP
authors.lastname: Hale
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity; D004155:Diphenhydramine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006632:Histamine / Q000378:metabolism; D006801:Humans; D008407:Mast Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010437:Peptic Ulcer / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D010894:Piroxicam / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D010894:Piroxicam; D006632:Histamine; D004155:Diphenhydramine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2