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However, it remains controversial whether MMP\u20109 improves or deteriorates acute lung injury of different etiologies. The receptor for advanced glycation end products (RAGE) plays a critical role in the pathogenesis of acute lung injury. MMPs are known to mediate RAGE shedding and release of soluble RAGE (sRAGE), which can act as a decoy receptor by competitively inhibiting the binding of RAGE ligands to RAGE. Therefore, this study is aimed at clarifying whether and how pulmonary knockdown of MMP\u20109 affected sepsis\u2010induced acute lung injury as well as the release of sRAGE in a murine cecal ligation and puncture (CLP) model. The analysis of GEO mouse sepsis datasets GSE15379, GSE52474, and GSE60088 revealed that the mRNA expression of MMP\u20109 was significantly upregulated in septic mouse lung tissues. Elevation of pulmonary MMP\u20109 mRNA and protein expressions was confirmed in CLP\u2010induced mouse sepsis model. Intratracheal injection of MMP\u20109 siRNA resulted in an approximately 60% decrease in pulmonary MMP\u20109 expression. It was found that pulmonary knockdown of MMP\u20109 significantly increased mortality of sepsis and exacerbated sepsis\u2010associated acute lung injury. Pulmonary MMP\u20109 knockdown also decreased sRAGE release and enhanced sepsis\u2010induced activation of the RAGE\/nuclear factor\u2010<jats:italic>\u03ba<\/jats:italic>B (NF\u2010<jats:italic>\u03ba<\/jats:italic>B) signaling pathway, meanwhile aggravating sepsis\u2010induced oxidative stress and inflammation in lung tissues. In addition, administration of recombinant sRAGE protein suppressed the activation of the RAGE\/NF\u2010<jats:italic>\u03ba<\/jats:italic>B signaling pathway and ameliorated pulmonary oxidative stress, inflammation, and lung injury in CLP\u2010induced septic mice. In conclusion, our data indicate that MMP\u20109\u2010mediated RAGE shedding limits the severity of sepsis\u2010associated pulmonary edema, inflammation, oxidative stress, and lung injury by suppressing the RAGE\/NF\u2010<jats:italic>\u03ba<\/jats:italic>B signaling pathway via the decoy receptor activities of sRAGE. MMP\u20109\u2010mediated sRAGE production may serve as a self\u2010limiting mechanism to control and resolve excessive inflammation and oxidative stress in the lung during sepsis.<\/jats:p>","DOI":"10.1155\/2021\/8889313","type":"journal-article","created":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T11:25:00Z","timestamp":1613042700000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Upregulation of Matrix Metalloproteinase\u20109 Protects against Sepsis\u2010Induced Acute Lung Injury via Promoting the Release of Soluble Receptor for Advanced Glycation End 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