title: Importance of cyclooxygenase-1/prostacyclin in modulating gastric mucosal integrity under stress conditions.
abstract: OBJECTIVE
  We investigated the roles of cyclooxygenase (COX) isozymes and prostaglandins (PGs) and their receptors in mucosal defense against cold-restraint stress (CRS)-induced gastric lesions.
  
  
  METHODS
  Male C57BL/6 wild-type (WT) mice and those lacking COX-1 or COX-2 as well as those lacking EP1, EP3, or IP receptors were used after 18 h fasting. Animals were restrained in Bollman cages and kept in a cold room at 10°C for 90 min.
  
  
  RESULTS
  CRS induced multiple hemorrhagic lesions in WT mouse stomachs. The severity of these lesions was significantly worsened by pretreatment with the nonselective COX inhibitors (indomethacin, loxoprofen) or selective COX-1 inhibitor (SC-560), while neither of the selective COX-2 inhibitors (rofecoxib and celecoxib) had any effect. These lesions were also aggravated in animals lacking COX-1, but not COX-2. The expression of COX-2 mRNA was not detected in the stomach after CRS, while COX-1 expression was observed under normal and stressed conditions. The gastric ulcerogenic response to CRS was similar between EP1 or EP3 knockout mice and WT mice, but was markedly worsened in animals lacking IP receptors. Pretreating WT mice with iloprost (the PGI2 analog) significantly prevented CRS-induced gastric lesions in the presence of indomethacin. PGE2 also reduced the severity of these lesions, and the effect was mimicked by the EP4 agonist, AE1-329.
  
  
  CONCLUSIONS
  These results suggest that endogenous PGs derived from COX-1 play a crucial role in gastric mucosal defense during CRS, and this action is mainly mediated by PGI2 /IP receptors and partly by PGE2 /EP4 receptors.
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan.
authors.forename: Kikuko
authors.initials: K
authors.lastname: Amagase
authors.forename: Nahoko
authors.initials: N
authors.lastname: Izumi
authors.forename: Yuka
authors.initials: Y
authors.lastname: Takahira
authors.forename: Tomoko
authors.initials: T
authors.lastname: Wada
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D003080:Cold Temperature / Q000009:adverse effects*; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D015232:Dinoprostone / Q000502:physiology; D011464:Epoprostenol / Q000502:physiology; D005753:Gastric Mucosa / Q000473:pathology*; D006471:Gastrointestinal Hemorrhage / Q000209:etiology* / Q000473:pathology*; D015870:Gene Expression; D007213:Indomethacin / Q000009:adverse effects; D008297:Male; D008810:Mice, Inbred C57BL; D010666:Phenylpropionates / Q000009:adverse effects; D044062:Prostaglandins I / Q000502:physiology*; D011720:Pyrazoles / Q000009:adverse effects; D012333:RNA, Messenger / Q000378:metabolism; D044006:Receptors, Epoprostenol / Q000502:physiology; D018078:Receptors, Prostaglandin E / Q000502:physiology; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D010666:Phenylpropionates; D044062:Prostaglandins I; D011720:Pyrazoles; D012333:RNA, Messenger; D044006:Receptors, Epoprostenol; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; C115461:SC 560; C040656:loxoprofen; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D015232:Dinoprostone; D007213:Indomethacin
keywords: EP and IP receptors; cold-restraint stress; cyclooxygenase isozyme; gastric ulcer; mouse; prostaglandins