Dexamethasone Ameliorates H2S-Induced Acute Lung Injury by Alleviating Matrix Metalloproteinase-2 and -9 Expression

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.

Intravenous Superoxide Dismutase Administration Reduces Contralateral Lung Injury Induced by Unilateral Lung Ischemia and Reperfusion in Rats Through Suppression of Activity and Protein Expression of Matrix Metalloproteases

“…Previously, Wang et al [10] showed that reducing MMP-9 and MMP-2 expression protected lungs against H 2 S inhalation-induced acute lung injury and pulmonary edema. Furthermore, Wakisaka et al [11] showed that activation of MMP-9 is strongly associated with vascular dysfunction and vascular leakage in arteries and micro-vessels, and an increase in superoxide levels promotes MMP-9 activation.…”

Assessment of the involvement of the macrophage migration inhibitory factor–glucocorticoid regulatory dyad in the expression of matrix metalloproteinase‐2 during periodontitis

“…For this reason, HC was chosen for our cell‐culture experiments. Other GCs, such as dexamethasone, also feature immunosuppressive properties and were reported to decrease the release of MMP‐2 from host cells . Several GCs were shown to affect MIF production; however, the data are discordant regarding their ability to up‐ or downregulate MIF .…”

Hydrogen sulfide

“…In both in-vitro and in-vivo settings, S-propargyl-cysteine promotes angiogenesis [18 & ] by increasing H 2 S, S-propargylcysteine induced phosphorylation of the transcription factor STAT3, a potential target of angiogenesismediated therapy. Although, studies showing the effect of H 2 S on matrix metalloproteinase-2 and matrix metalloproteinase-9 expression are conflicting [22][23][24]. 1b) [18 & ].…”