Experimental Study Of The Protective Effects Of Extracellular Signal-regulated Kinase Signal Pathway Inhibition PD98059on Acute Pancreatitis (AP) And AP-associated Lung Injury In Mice

Objective To investigate the protective effects and mechanisms of PD98059on acutepancreatitis(AP) and acute pancreatitis-associated lung injury in mice.Methods Seventy-two KM mice were randomized allocated to12groups:control3h，6h，12h group1(C1group,n=6);control3h,6h,12h group2(C2group,n=6);AP3h,6h,12hgroup(n=6) and PD980593h，6h,12h group(T group,n=6).The AP model were induced byinjecting intraperitoneally(ip)100μg/kg cerulein six times with an interval of lh.Controlgroups received physiological saline(PS) in the same manner.PD98059groups wereinjected intraperitoneally(ip)10mg/kg PD98059,0.5h and1h before inducting AP.Mice inthe12groups were killed at hours3,6,12after induction of the model.We measured thelevels of serum amylase(AMY) by using a automatic analytical instrument,the contents ofserum sICAM-1,TNF-,IL-6,IL-18by ELISA,the levels of wet-dry ratios and MPO in thepancreas and MPO in the lung,the expression of ICAM-1mRNA in the pancreas and lungby reverse transcription-polymerase chain reaction(RT-PCR),the histopathological changesand the histologic scores of pancreatic and lung tissue.Results In the pancreas:(1)Compared with C1and C2groups,in AP groups the levels ofSMY,slCAM-1,TNF-,IL-6,IL-18in serum, wet-dry ratios,MPO and the expression ofICAM-1significantly increased(P<0.01).The histologic change and scores of pancreatictissue also significantly increased in AP groups compared with C1,C2groups(P<0.01).(2)Compared with AP groups,in T groups the levels of serum amylase, sICAM-1,TNF-in serum,wet-dry ratios and MPO in the pancreatic tissue,and the expression ofICAM-1mRNA in pancreatic tissue significantly decreased (P<0.05).The contents of serum IL-6in the T groups significantly decreased at6h,12h compared with APgroups(P<0.05);The contents of serum IL-18in the T groups significantly decreased at12hcompared with AP groups(P<0.05);the pancreatic histopathologic change and scoressignificantly decreased in T groups compared with AP groups(P<0.05).In thelung:(1)Compared with C1and C2groups,the levels of MPO,the expression of ICAM-1mRNA in the lung tissue significantly increased in AP groups(P<0.01).The histologicchange and scores of lung tissue also significantly increased in AP groups compared withC1,C2groups(P<0.01).(2)Compared with AP groups, in T groups the levels of theMPO,and the expression of ICAM-1mRNA in lung tissue significantly decreased(P<0.05).The lung histopathologic change and scores significantly decreased in T groups comparedwith AP groups(P<0.05).Conclusions PD98059might have protective effects on AP and AP-associated lunginjury by inhibiting MEK1/2,inhibiting ERK signal transduction pathway,and decreasingthe production of ICAM-1,TNF-,IL-6,IL-18and some other cytokines.These couldprovide us new therapeutic targets in the future.So application of PD98059in the earlystage is good for AP and AP-associated lung tissue injury.