Abstract
Dysregulation of matrix metalloproteinase- (MMP-) 9 is implicated in the pathogenesis of acute lung injury (ALI). However, it remains controversial whether MMP-9 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-9 affected sepsis-induced 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-9 was significantly upregulated in septic mouse lung tissues. Elevation of pulmonary MMP-9 mRNA and protein expressions was confirmed in CLP-induced mouse sepsis model. Intratracheal injection of MMP-9 siRNA resulted in an approximately 60% decrease in pulmonary MMP-9 expression. It was found that pulmonary knockdown of MMP-9 significantly increased mortality of sepsis and exacerbated sepsis-associated acute lung injury. Pulmonary MMP-9 knockdown also decreased sRAGE release and enhanced sepsis-induced activation of the RAGE/nuclear factor-κB (NF-κB) signaling pathway, meanwhile aggravating sepsis-induced oxidative stress and inflammation in lung tissues. In addition, administration of recombinant sRAGE protein suppressed the activation of the RAGE/NF-κB signaling pathway and ameliorated pulmonary oxidative stress, inflammation, and lung injury in CLP-induced septic mice. In conclusion, our data indicate that MMP-9-mediated RAGE shedding limits the severity of sepsis-associated pulmonary edema, inflammation, oxidative stress, and lung injury by suppressing the RAGE/NF-κB signaling pathway via the decoy receptor activities of sRAGE. MMP-9-mediated sRAGE production may serve as a self-limiting mechanism to control and resolve excessive inflammation and oxidative stress in the lung during sepsis.
Highlights
Sepsis, which is defined as a syndrome of systemic inflammation in response to infection, often leads to life-threatening multiorgan dysfunction [1]
Pulmonary matrix metalloproteinase- (MMP-)9 expression was determined by RT-Polymerase Chain Reaction (PCR) and western blotting in the cecal ligation and puncture (CLP)-induced mouse sepsis model
We found that administration of recombinant soluble RAGE (sRAGE) protein significantly attenuated oxidative stress and inflammatory responses induced by intrapulmonary knockdown of Matrix metalloproteinases (MMPs)-9, as evidenced by the reduction in MDA level (Figure 6(a)), 8-OHdG-positive cells (Figures 6(b) and 6(c)), MCP-1 level (Figure 6(d)), and macrophage infiltration (Figures 6(e) and 6(f)) in lung tissues
Summary
Sepsis, which is defined as a syndrome of systemic inflammation in response to infection, often leads to life-threatening multiorgan dysfunction [1]. Among MMPs, MMP-9 is of particular interest, because it is elevated in patients with ALI and ARDS and correlates positively with lung injury severity [7,8,9,10]. It remains controversial whether MMP-9 improves or deteriorates acute lung injury of different etiologies. Inhibition of MMP-9 attenuates neutrophilic inflammation and pulmonary injury in ventilator-induced lung injury model [11] and improves survival in rodent models of cecal ligation and puncture- (CLP-) induced sepsis [12]. Further investigations are warranted to explore whether and how MMP-9 is involved in the pathophysiology of sepsisinduced ALI/ARDS
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