浅论外源性一氧化碳释放分子抑制脓毒症炎症反应的实验研究

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1、浅论外源性一氧化碳释放分子抑制脓毒症炎症反应的实验研究作者：孙炳伟,陈曦,KazuhiroKatada,RichardFPotter,GediminasCepinskas【摘要】目的：探讨外源性一氧化碳释放分子对脓毒症炎症反应的抑制作用及可能的机制。方法：应用盲肠结扎及穿孔脓毒症小鼠模型，使用外源性一氧化碳释放分子（CORM2,8mg/kg体质量，尾静脉注射）进行干预。检测肝、肺脏髓过氧化物酶(MPO)活性。应用内毒素(LPS，10g/ml)刺激的人脐静脉内皮细胞炎症模型，使用外源性一氧化碳释放分子（CORM2,10～100mol/L）进行干预。检测核因子κB（N

2、FκB）活性,内皮细胞黏附分子的表达，氧化产物、NO产物以及多形核白细胞对内皮细胞的黏附作用。结果：盲肠结扎及穿孔脓毒症小鼠模型使用外源性一氧化碳释放分子干预后肝、肺组织MPO活性明显下降。CORM2抑制了LPS刺激导致的NFκB活性上调。同时，NO产物下降，内皮细胞ICAM1的表达抑制，白细胞对内皮细胞的黏附作用明显抑制。结论：外源性一氧化碳释放分子通过抑制NFκB活性，抑制ICAM1蛋白和NO的表达，抑制白细胞对内皮细胞的黏附作用，进而有效抑制脓毒症炎症反应。【关键词】一氧化碳；盲肠结扎及穿孔；炎症反应；核因子κBCLP(cecalligationan

3、dpuncture)mayinducetheactivationofaninflammatorycascade,causedamagetomultipleorgansdistantfromtheoriginalburnwoundandmayleadtosepsisandmultipleorganfailure［1］.Therehavebeenseveralreportsindicatingthattheinflammatoryresponsesyndrome,whichcontributestooxidativecell/tissuedamage,mightfrequ

4、entlybeacpaniedbyleukocytesequestrationinmanyimportantorgansystemsinthebody［2］.Theincreaseofproductionofproinflammatorymediatorssuchasinterleukin(IL)1βandtumornecrosisfactor(TNF)αiscloselyassociatedwithactivationofleukocytesandmacrophageswhichweresequestratedinthetissue［3,4］.Leukocyte

5、ssequestrationandtheirsubsequentinfiltrationinorgantissuecancauseleukocyteactivationandcontributetovasculardamageandthedevelopmentofsystemicinflammatoryreaction.Astheprerequisite,activationofleukocytesandendothelialcellsresultsinaggregationofleukocytes,plateletsanderythrocytesinvivo.Thi

6、smayfavordisseminatedintravasalcoagulationandfurthermultipleorganfailure.Carbonmonoxide(CO)haslongbeenknowninbiologyandmedicineasatoxicpound,duetoitsabilitytobindhemoglobinwithamuchhigheraffinitythanoxygen［5］.Evidenceaccumulatedtodatesuggeststhatendogenouscarbonmonoxide(CO),abiproducto

7、finduciblehemeoxygenase(HO1)canmodulateinflammation,inhibitslipopolysaccharide(LPS)inducedproductionofcytokinesbothinvivoandinvitro,andconsequentlyexhibitsimportantcytoprotectivefunctionandantiinflammatorypropertiesthatarebeneficialfortheresolutionofacuteinflammation［6-8］.In