Dexamethasone ameliorates H₂S-induced acute lung injury by alleviating matrix metalloproteinase-2 and -9 expression.
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.
Key Lab of Modern Toxicology, Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
Jun
J
Wang
Department of Emergency Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Huazhong
H
Zhang
Department of Emergency Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Chenglei
C
Su
Department of Emergency Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Junjie
J
Chen
Department of Occupational Disease Prophylactico-Therapetic Institution, Jiangsu Provincial Center for Disease Prevention and Control, Nanjing, Jiangsu, China.
Baoli
B
Zhu
Department of Occupational Disease Prophylactico-Therapetic Institution, Jiangsu Provincial Center for Disease Prevention and Control, Nanjing, Jiangsu, China.
Hengdong
H
Zhang
Key Lab of Modern Toxicology, Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
Hang
H
Xiao
Department of Emergency Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Jinsong
J
Zhang
D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use*; D006862:Hydrogen Sulfide; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D005938:Glucocorticoids; D003907:Dexamethasone; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D006862:Hydrogen Sulfide