丙烯醛刺激小鼠气道粘液高分泌新的分子机制-p38 MAPK/MMP-9信号通路调控MUCIN5AC表达

A novel molecular mechanism of mucus hypersecretion in acrolein-induced murine model.regulating MUCIN5AC expression via p38 MAPK and MMP-9 signaling pathway

目的探讨p38丝裂原激活蛋白激酶(p38 MAPK)信号通路及其特异性抑制剂SB203580在气道粘液高分泌中的作用,阐明p38 MAPK、基质金属蛋白酶9(MMP-9)在粘蛋白基因转录中的相互作用机制。方法小鼠吸入丙烯醛21d建立模型,对照组采用生理盐水吸入,干预组予SB203580腹腔注射。于第7天、第21天处死动物。结果小鼠吸入丙烯醛21d后出现明显的气道粘液高分泌表现,经SB203580治疗后粘液分泌明显减轻;拮抗p38MAPK后MUCIN5ACTMMP-9蛋白、mRNA表达量下降(P<0.01)。结论丙烯醛吸入可致小鼠气道粘液高分泌,p38 MAPK信号通路可在转录水平调节MMP-9,最终调控MUCIN5AC基因表达,揭示新的引起气道粘液高分泌的分子机制和有效的治疗靶点。

Objective The goals of this study were to illuminate whether p38 MASPK and its specific inhibitor, SB203580, played a significant part in airway mucus hypersecretion, and to clarify the cross-talk mechanism between p38 MAPK and MMP-9 for mucin gene transcription. Methods In order to establish airway mucus hypersecretion, mice were exposed to acrolein for 21 days, meanwhile, SB203580 was intraperitonealy injected into the experimental animals every day, wherase saline inhalation for sham exposure group. On Days 7 and 21, animals were sacifieed so as to investigate airway inflammation and mucus overproduction by means of such approachs as HE, AB-PAS, IHC, RT-PCR analyses. Results In exposed mice treated with acrolein for 21 days, MUCIN5AC, MMP-9 protein and mRNA expression were decreased（ P 〈 0.01 ）by blocking the action of p38 MAPK signaling pathway. Conclusion Our findings indicate that acrolein may give rise to murine airway mucus overproduction ; Regulating the activation of MMP-9 gene and, subsequently, influencing MUCIN5AC mucin transcripation, p38 MAPK signaling pathway contributes a novel molecular mechanism and effectively therapeutic target to mucin hypersecretion.