前列环素和血栓素A2在机械通气致兔肺通透性增加中的作用机制

Role of prostacyclin and thromboxane A2 in pulmonary hyper-permeability induced by mechanical ventilation in rabbits

目的探讨前列环素(PGI2)和血栓素A2(TXA2)在机械通气(MV)致肺通透性增加中的作用机制。方法48只健康日本大耳白兔随机分为:溶剂治疗组(V组);反苯环丙胺(PGI2合酶抑制剂)治疗组(T组);达唑氧苯(TXA2合酶抑制剂)治疗组(D组);溶剂治疗+MV组(VM组);反苯环丙胺治疗+MV组(TM组)和达唑氧苯治疗+MV组(DM组)。运用ELISA检测实验动物肺组织TXA2和PGI2含量,并测定肺组织和支气管肺泡灌洗液(BALF)中TNF-α含量;以肺湿/干重(W/D)比值、肺通透性指数(PPI)和肌球蛋白轻链激酶(MLCK)蛋白及mRNA表达水平作为反映肺通透性的指标,并通过肺组织学评分对肺损伤的严重程度进行评价。结果单纯药物或溶剂治疗不影响非MV实验动物各检测指标。VM组实验动物肺组织PGI2和TXA2含量明显增加(P<0.05),PGI2/TXA2比值显著上调(P<0.05),伴有BALF和肺组织内TNF-α的大量生成(P<0.05)和明显的肺通透性(肺W/D比值、PPI和MLCK表达水平)增加及肺损伤(P<0.05);运用反苯环丙胺显著抑制MV实验动物肺组织PGI2生成(P<0.05)可下调PGI2/TXA2比值(P<0.05),进一步增加实验动物BALF和肺组织内TNF-α的生成(P<0.05),并加重肺的高通透性和肺损伤(P<0.05);用达唑氧苯显著抑制MV实验动物肺内TXA2生成(P<0.05)会进一步上调PGI2/TXA2比值(P<0.05),降低BALF和肺组织内TNF-α含量(P<0.05),减轻肺高通透性和肺损伤的严重程度(P<0.05)。结论PGI2具有抗MV致肺通透性增加保护作用,其机制与下调TNF-α/MLCK信号通路有关;TXA2可通过上调TNF-α/MLCK信号通路引起MV实验动物肺通透性增加。

Objective To explore the role of prostacyclin(PGI2)and thromboxane A2(TXA2)in lung hyper-permeability induced by mechanical ventilation(MV)in rabbits.Methods Forty-eight healthy Japanese white rabbits were randomly allocated to vehicle treatment group(group V),tranylcypromine(a PGI2 synthase inhibitor)treatment group(group T),dazoxiben(a TXA2 synthase inhibitor)treatment group(group D),vehicle-treated MV group(group VM),tranylcyprominetreated MV group(group TM)and dazoxiben-treated MV group(group DM).The contents of PGI2 and TXA2 in the lung tissues and TNF-αlevel in BALF and lung tissues were measured by ELISA.The lung wet/dry weight(W/D)ratio,lung permeability index and pulmonary expressions of myosin light chain kinase(MLCK)protein and mRNA were detected to evaluate the pulmonary permeability.The severities of lung injury were assessed by lung histological scores.Results The measured parameters did not differ significantly among the rabbits receiving different treatments without MV.In rabbits in group VM,the contents of PGI2 and TXA2 in the lungs,TNF-αin BALF and lung tissues,PGI2/TXA2 ratio,lung W/D ratio,lung permeability index,pulmonary expressions of MLCK protein and mRNA and histological scores of the lungs all increased significantly(P<0.05)as compared with those in group V,group T and group D.In rabbits undergoing MV,inhibition of PGI2 production by tranylcypromine significantly decreased the PGI2/TXA2 ratio(P<0.05),further enhanced the production of TNF-αin the BALF and lung tissue(P<0.05),and worsened lung hyper-permeability and lung injury(P<0.05),while treatment with dazoxiben significantly reduced TXA2 production in the lung tissue(P<0.05),increased the PGI2/TXA2 ratio(P<0.05)and decreased TNF-αproduction in the BALF and lung tissue(P<0.05),thus resulting in alleviated lung hyperpermeability and lung injury(P<0.05).Conclusion PGI2 plays a protective role against MV-induced lung hyper-permeability and lung injury by downregulating TNF-α/MLCK signaling pathway,while TXA2 can exacerbate MV-induced lung hyperpermeability in rabbits by up-regulating TNF-α/MLCK signaling pathway.