Neutrophil elastase ameliorates matrix metalloproteinase-9 to promote lipopolysaccharide-induced acute lung injury in mice 1

Abstract

PURPOSE: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. METHODS: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. RESULTS: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. CONCLUSION: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.

Role of inflammatory cells in airway remodeling in COPD

“… 22 Moreover, NE can cooperate with MMPs and amplify the effect of ECM degradation. 23 In addition to matrix degradation, NE can also promote peri-bronchial fibrosis by enhancing fibroblast proliferation. 24 Moreover, NE is a potent stimulant of mucus secretion from submucosal glands and goblet cells, which are involved in airway obstruction.…”

Neutrophil Elastase Inhibitors Suppress Oxidative Stress in Lung during Liver Transplantation

“…In our study, we found that BALF NE significantly increased following OALT, which was closely related to the filtration of neutrophils, suggesting that NE may act as a mediator during neutrophil infiltration-related lung injury during LT. Similarly, a recent study also found that NE promoted ALI induced by lipopolysaccharide stimulation, which may be related to a mechanism of matrix metalloproteinase-9 reduction [28]. Furthermore, our results showed that neutrophil infiltration and NE release contributed to pulmonary barrier dysfunction via aggravating lung oxidative stress, similar to the findings of Aoshiba et al, which showed that the treatment of bronchial epithelial or lung fibroblast cells with the serine protease NE increased mitochondrial and cytoplasm ROS levels [29].…”

Expression of a specific extracellular matrix signature is a favorable prognostic factor in acute myeloid leukemia

“…Intriguingly, we also observe significant up-regulation of ELANE , the neutrophils’ elastase, in these patients. ELANE has not only been reported to directly interact with MMP9 [18] , but also to be linked to a higher risk of neutropenic patients to develop AML when its content is lower than normal [19] . Notably, COL24A1 has also been recently found to have a prognostic value in cancer [20] , though this is the first time it is associated to AML.…”