Abstract
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.
Highlights
Hydrogen sulfide (H2S), a colorless gas with a characteristic rotten-egg odor, is associated with more than 70 types of industries, including petroleum refineries, paper and pulp manufacture, sewage treatment, and artificial fiber synthesis [1]
In the pathogenesis of Acute lung injury (ALI)/ARDS, disruption of the alveolar epithelial-endothelial capillary barrier( known as the blood-air barrier), which consists of alveolar epithelium, capillary endothelium, extracellular matrix (ECM), alveolar macrophages and other cells is considered as a central event [9,10]
Morphology abnormalities induced by H2S To further confirm H2S-induced lung injury, the morphological changes were investigated after H2S exposure
Summary
Hydrogen sulfide (H2S), a colorless gas with a characteristic rotten-egg odor, is associated with more than 70 types of industries, including petroleum refineries, paper and pulp manufacture, sewage treatment, and artificial fiber synthesis [1]. The toxic effects of H2S depend on its concentration and the duration of exposure It is immediately fatal when concentrations are 500–1,000 ppm, while exposed to lower concentrations(10–500 ppm), various respiratory symptoms that range from rhinitis to acute lung injury(ALI)/acute respiratory distress syndrome(ARDS) may occur, of all, the respiratory failure of ALI/ARDS has been largely attributed to death in H2S poisoning [6,7,8]. The matrix metalloproteinases (MMPs) are believed to be the main physiological mediators of ECM degradation, under normal conditions, MMPs are secreted from cells as inactive forms(pro-MMPs), most of MMPs can be activated and significantly secreted during the systemic inflammation response and tissue damage, such as ALI/ARDS, which was characterized by the disruption of blood-air barrier. MMP-9 (gelatinase B, pro-MMP-9 92 kDa, active-MMP-9 82 kDa) is produced mainly by inflammatory cells like polymorphonuclear neutrophils(PMNs)
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