| 6 | A dual role of lysophosphatidic acid type 2 receptor(LPAR2)in nonsteroidal anti-inflammatory drug-induced mouse enteropathy显示文摘Lysophosphatidic acid(LPA)is a bioactive phospholipid mediator that has been found to ameliorate nonsteroidal anti-inflammatory drug(NSAID)-induced gastric injury by acting on lysophosphatidic acid type 2 receptor(LPAR2).In this study,we investigated whether LPAR2 signaling was implicated in the development of NSAID-induced small intestinal injury(enteropathy),another major complication of NSAID use.Wild-type(WT)and Lpar2 deficient(Lpar2^(^(^(−/−))))mice were treated with a single,large dose(20 or 30 mg/kg,i.g.)of indomethacin(IND).The mice were euthanized at 6 or 24 h after IND treatment.We showed that IND-induced mucosal enteropathy and neutrophil recruitment occurred much earlier(at 6 h after IND treatment)in Lpar2^(^(^(−/−)))mice compared to WT mice,but the tissue levels of inflammatory mediators(IL-1β,TNF-α,inducible COX-2,CAMP)remained at much lower levels.Administration of a selective LPAR2 agonist DBIBB(1,10 mg/kg,i.g.,twice at 24 h and 30 min before IND treatment)dose-dependently reduced mucosal injury and neutrophil activation in enteropathy,but it also enhanced IND-induced elevation of several proinflammatory chemokines and cytokines.By assessing caspase-3 activation,we found significantly increased intestinal apoptosis in IND-treated Lpar2^(^(^(−/−)))mice,but it was attenuated after DBIBB administration,especially in non-obese diabetic/severe combined immunodeficiency(NOD/SCID)mice.Finally,we showed that IND treatment reduced the plasma activity and expression of autotaxin(ATX),the main LPA-producing enzyme,and also reduced the intestinal expression of Lpar2 mRNA,which preceded the development of mucosal damage.We conclude that LPAR2 has a dual role in NSAID enteropathy,as it contributes to the maintenance of mucosal integrity after NSAID exposure,but also orchestrates the inflammatory responses associated with ulceration.Our study suggests that IND-induced inhibition of the ATX-LPAR2 axis is an early event in the pathogenesis of enteropathy. | Barbara Hutka Anett Várallyay Szilvia B.László András S.Tóth Bálint Scheich Sándor Paku Imre Vörös Zoltán Pós Zoltán V.Varga Derek D.Norman Andrea Balogh Zoltán Benyó Gábor Tigyi Klára Gyires Zoltán S.Zádori | 2024 | Acta Pharmacologica Sinica2024，45，2： | 0 |
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