Dexamethasone ameliorates H₂S-induced acute lung injury by alleviating matrix metalloproteinase-2 and -9 expression

Jun Wang; Huazhong Zhang; Chenglei Su; Junjie Chen; Baoli Zhu; Hengdong Zhang; Hang Xiao; Jinsong Zhang

doi:10.1371/journal.pone.0094701

Dexamethasone ameliorates H₂S-induced acute lung injury by alleviating matrix metalloproteinase-2 and -9 expression

PLoS One. 2014 Apr 10;9(4):e94701. doi: 10.1371/journal.pone.0094701. eCollection 2014.

Authors

Jun Wang¹, Huazhong Zhang², Chenglei Su², Junjie Chen², Baoli Zhu³, Hengdong Zhang³, Hang Xiao¹, Jinsong Zhang²

Affiliations

¹ Key Lab of Modern Toxicology, Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
² Department of Emergency Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
³ Department of Occupational Disease Prophylactico-Therapetic Institution, Jiangsu Provincial Center for Disease Prevention and Control, Nanjing, Jiangsu, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Lung Injury / chemically induced
Acute Lung Injury / drug therapy*
Acute Lung Injury / metabolism
Animals
Cell Line
Dexamethasone / pharmacology
Dexamethasone / therapeutic use*
Disease Models, Animal
Glucocorticoids / pharmacology
Glucocorticoids / therapeutic use*
Hydrogen Sulfide
Lung / drug effects
Lung / metabolism
Male
Matrix Metalloproteinase 2 / metabolism*
Matrix Metalloproteinase 9 / metabolism*
Rats
Rats, Sprague-Dawley

Substances

Glucocorticoids
Dexamethasone
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Hydrogen Sulfide

Grants and funding

This work was supported by the Medical Innovation Team Foundation of Jiangsu Province (LJ201122) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.