Abstract
To investigate the regulatory roles of neutrophil elastase (NE) and matrix metalloproteinase-9 (MMP-9) in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. To construct LPS-induced ALI mouse models, wild-type C57BL/6 mice were administered 5.0 mg/kg of LPS through endotracheal, and/or 1.0 mg/kg of ONO-5046, and/or 20.0 mg/kg of chemically modified tetracycline-3 (CMT-3) by gavage. The levels of MMP-9, tissue inhibitor of metalloprotease-1, interleukin (IL)-6 were detected by real time RT-PCR at 6 h, 24 h and 48 h, and tumor necrosis factor (TNF), lung wet-dry weight ratio, white blood cell (WBC) count and polymorphonuclear (PMN) count in bronchoalveolar lavage fluid (BALF) were tested at 48 h after administration. The 5-day survival analysis of the ALI mice was also performed. Both ONO-5046 and CMT-3, regardless of being used individually or combined, significantly reduced the levels of MMP-9, IL-6, and TNF in lung tissue as well as in BALF, and the WBC and PMN count in BALF. Combined treatment with ONO-5046 and CMT-3 remarkably improved the survival rate of ALI mice. Neutrophil elastase synergizes with matrix metalloproteinase-9 to promote and regulate the release of inflammatory mediators and the infiltration of inflammatory cells, consequently affecting the survival of lipopolysaccharide-induced acute lung injury mice.
Highlights
The pathophysiological characteristics of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) include direct or indirect injury to the alveolar epithelial and capillary endothelial cells, increased permeability of the alveolar-capillary membrane, infiltration of inflammatory cells, and release of inflammatory mediators, which in turn lead to interstitial and alveolar pulmonary edema, oxygenation damage, progressive hypoxemia, and dyspnea
We examined the levels of Matrix metalloproteinases (MMPs)-9, neutrophil elastase (NE), and inflammatory mediators in the lung tissues and bronchoalveolar lavage fluid (BALF) from LPS-induced ALI mice to investigate the role of matrix metalloproteinase-9 (MMP-9) and the involvement of NE in this pathogenic process
Total RNA was extracted from these samples and used for the detection of MMP-9, IL-6, and tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA expression and for the determination of the MMP-9/TIMP-1 ratio in the lung tissues in ALI mice
Summary
The pathophysiological characteristics of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) include direct or indirect injury to the alveolar epithelial and capillary endothelial cells, increased permeability of the alveolar-capillary membrane, infiltration of inflammatory cells, and release of inflammatory mediators, which in turn lead to interstitial and alveolar pulmonary edema, oxygenation damage, progressive hypoxemia, and dyspnea. Owing to the severe clinical manifestations, ALI and ARDS have considerably high mortality rates. ALI and ARDS can be induced by a variety of conditions, including sepsis, pancreatitis, ischemia-reperfusion injury, and inhalation injury. The exact mechanisms underlying the onset of ALI and ARDS remain unclear. MMPs are involved in a variety of cellular activities, including the proteolysis of cell surface receptors, release of apoptosis-inducing ligands, and cytokine activation, as well as cell proliferation, migration, adhesion, differentiation, and apoptosis. MMPs play critical roles in tissue remodeling processes, such as neovascularization, tissue reconstruction, cirrhosis, arthritis, metastasis, and in the formation of aortic aneurysm
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