A dual role of lysophosphatidic acid type 2 receptor(LPAR2)in nonsteroidal anti-inflammatory drug-induced mouse enteropathy  

作　　者：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 

机构地区：[1]Department of Pharmacology and Pharmacotherapy,Semmelweis University,Budapest,Hungary [2]Pharmacological and Drug Safety Research,Gedeon Richter Plc,Budapest,Hungary [3]Department of Pathology and Experimental Cancer Research,Semmelweis University,Budapest,Hungary [4]HCEMM-SU Cardiometabolic Immunology Research Group,Semmelweis University,Budapest,Hungary [5]MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group,Budapest,Hungary [6]MTA-SE System Pharmacology Research Group,Budapest,Hungary [7]Department of Genetics,Cell and Immunobiology,Semmelweis University,Budapest,Hungary [8]Department of Physiology,College of Medicine,University of Tennessee Health Science Center(UTHSC),Memphis,TN,USA [9]Institute of Translational Medicine,Semmelweis University,Budapest,Hungary [10]HUN-REN–SU Cerebrovascular and Neurocognitive Diseases Research Group,Budapest,Hungary

出　　处：《Acta Pharmacologica Sinica》2024年第2期339-353,共15页中国药理学报（英文版）

基　　金：supported by the National Research,Development and Innovation Office of Hungary(NKFI FK 138842,K 131627,FK 134751,K 125174,K 139230,VEKOP-2.3.3-15-2017-00016,and EFOP-3.6.3-VEKOP-16-2017-00009);by TKP2021-EGA-25,by the European Union’s Horizon 2020 Research and Innovation Program under grant agreement number 739593;by a Momentum Research Grant from the Hungarian Academy of Sciences(LP-2021-14 to ZVV);by the Harriet Van Vleet Endowment(to GT).Project number RRF-2.3.1-21-2022-00003 has been implemented with the support provided by the European Union.

摘　　要：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.

关 键 词：ENTEROPATHY nonsteroidal anti-inflammatory drug lysophosphatidic acid LPAR2 DBIBB AUTOTAXIN 

分 类 号：R574[医药卫生—消化系统]