Dexamethasone ameliorates H₂S-induced acute lung injury by alleviating matrix metalloproteinase-2 and -9 expression.
Dexamethasone ameliorates H₂S-induced acute lung injury by alleviating matrix metalloproteinase-2 and -9 expression.
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DOI：
10.1371/journal.pone.0094701
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Wang J;Zhang H;Su C;Chen J;Zhu B;Zhang H;Xiao H;Zhang J
急性肺损伤（acute lung injury，ALI）是高浓度硫化氢（H2S）暴露后的致命性后果之一，基质金属蛋白酶（matrix metalloproteinases，MMP-2和MMP-9）通过降解血-气屏障的细胞外基质（extracellular matrix，ECM）参与了ALI的发生发展。然而，MMP-2和MMP-9在H2S诱导的ALI中的作用以及地塞米松（DXM）在临床上治疗ALI的机制仍不清楚。本研究旨在探讨基质金属蛋白酶-2（MMP-2）和基质金属蛋白酶-9（MMP-9）在硫化氢（H2S）致大鼠急性肺损伤（ALI）中的作用及地塞米松（DXM）的保护作用。本研究采用SD大鼠吸入H2S建立急性肺损伤模型，同时用NaHS（H2S供体）孵育A549细胞建立急性肺损伤模型。采用HE染色、光化学、电镜及湿/干比等方法检测H2S诱导的大鼠肺损伤模型，并检测MMP-2、MMP-9在大鼠肺组织及A549细胞中的表达。结果表明，H2S暴露后，大鼠肝组织中MMP-2和MMP-9的mRNA和蛋白水平均明显升高，MMP抑制剂DOX可抑制MMP-2和MMP-9的表达。DXM可通过上调糖皮质激素受体（GR）介导对MMP-2和MMP-9的抑制，显著改善H2S诱导的肺水肿、炎性细胞浸润和BAFL蛋白渗漏等症状。此外，DXM在体内和体外研究中的保护作用可被GR拮抗剂米非司酮（MIF）部分阻断。我们的结果表明，MMP-2和MMP-9参与了H2S诱导的ALI的发展，DXM通过减轻MMP-2和MMP-9的表达而发挥保护作用。因此，MMP-2和MMP-9可能是治疗H2S和其他有害气体诱导的ALI的新的药理学靶点。
Acute lung injury (ALI) is one of the fatal outcomes after exposure to high levels of hydrogen sulfide (H2S), and the matrix metalloproteinases (MMPs) especially MMP-2 and MMP-9 are believed to be involved in the development of ALI by degrading the extracellular matrix (ECM) of blood-air barrier. However, the roles of MMP-2 and MMP-9 in H2S-induced ALI and the mechanisms of dexamethasone (DXM) in treating ALI in clinical practice are still largely unknown. The present work was aimed to investigate the roles of MMP-2 and MMP-9 in H2S-induced ALI and the protective effects of DXM. In our study, SD rats were exposed to H2S to establish the ALI model and in parallel, A549 cells were incubated with NaHS (a H2S donor) to establish cell model. The lung HE staining, immunohistochemisty, electron microscope assay and wet/dry ratio were used to identify the ALI induced by H2S, then the MMP-2 and MMP-9 expression in both rats and A549 cells were detected. Our results revealed that MMP-2 and MMP-9 were obviously increased in both mRNA and protein level after H2S exposure, and they could be inhibited by MMP inhibitor doxycycline (DOX) in rat model. Moreover, DXM significantly ameliorated the symptoms of H2S-induced ALI including alveolar edema, infiltration of inflammatory cells and the protein leakage in BAFL via up-regulating glucocorticoid receptor(GR) to mediate the suppression of MMP-2 and MMP-9. Furthermore, the protective effects of DXM in vivo and vitro study could be partially blocked by co-treated with GR antagonist mifepristone (MIF). Our results, taken together, demonstrated that MMP-2 and MMP-9 were involved in the development of H2S-induced ALI and DXM exerted protective effects by alleviating the expression of MMP-2 and MMP-9. Therefore, MMP-2 and MMP-9 might represent novel pharmacological targets for the treatment of H2S and other hazard gases induced ALI.
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