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Therapeutic efficacies of neutrophil elastase and RIP1 inhibitors in acute lung injury

中性粒细胞弹性蛋白酶和RIP1抑制剂治疗急性肺损伤的疗效

基本信息

批准号：
10311120
负责人：
HASEM HABELHAH
金额：
$ 23.18万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-02 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10311120
关键词：
Ablation Acute Lung Injury Adverse effects Affect Alveolar American Animal Model Apoptosis Attenuated Bacteria Biochemical Breathing CASP8 gene Cell Death Cell Survival Cessation of life Clinical Research Clinical Trials Consensus Development Effectiveness Endothelium Enzymes Event FDA approved Genetic Goals Human Human body Hypoxemia Incidence Inflammation Injury Invaded Japanese Knock-out Knockout Mice Lethal Dose 50 Leukocyte Elastase Leukocytes Lipopolysaccharides Lung Measures Mediating Metalloproteases Modeling Molecular Multicenter Studies Mus Neutrophil Activation Pathway interactions Peptide Hydrolases Perinatal Pharmacology Phase Phase III Clinical Trials Phosphotransferases Play Proteins Pulmonary Edema Pulmonary Inflammation RIPK1 gene RIPK3 gene Reactive Oxygen Species Receptor Inhibition Respiratory Failure Role Stains Study models Syndrome TNF gene Tissues Treatment Efficacy Treatment Protocols Ubiquitination United States Ventilator experimental study improved in vivo inflammatory milieu inhibitor insight interstitial kinase inhibitor lung injury mortality mouse model neutrophil neutrophil elastase inhibitor novel novel therapeutic intervention pathogen prevent public health relevance pulmonary function small molecular inhibitor ventilation

项目摘要

5. Project Summary/Abstract Acute lung injury (ALI) is a syndrome of respiratory failure characterized by protein-rich pulmonary edema that causes severe hypoxemia and labored breathing. In the United States, the annual incidence of ALI is about 200,000 with a mortality rate of 30-40%; yet, there is no FDA-approved pharmacological therapy for ALI. Neutrophils are the most abundant circulating white blood cells in the human body and provide the first line of defense against invading pathogens. In the lung, while neutrophils are essential for pathogen elimination, exuberant accumulation and prolonged survival of neutrophils in the interstitial and alveolar spaces contribute to ALI by releasing a variety of injurious molecules, including neutrophil elastase (NE), metalloproteases, reactive oxygen species (ROS), and other proteolytic enzymes. Although all these injurious molecules contribute to ALI, an increasing body of studies have demonstrated that NE is the most potent hydrolytic enzyme that plays a key role in lung alveolar injury, and that inhibition of NE with small molecular inhibitors [e.g. Sivelestat (Siv)] reduces measures of lung injury and inflammation in animal models of ALI. However, clinical studies have not yet provided a clear consensus. Whereas in Japanese phase III clinical trials, Siv improved pulmonary functions, in North American multicenter studies, Siv rather increased long-term mortality by unknown mechanisms. Thus, identification of molecular events associated with adverse effects of Siv in ALI is an important task for the development of novel and combination treatment regimens. Recently, in unbiased functional protease purification experiments, we discovered that NE cleaves receptor interacting protein 1 (RIP1), and that inhibition of NE with Siv leads to RIP1-dependent necroptosis in mouse and human neutrophils following treatment with lipopolysaccharide (LPS) or TNFα. Such RIP1-induced necroptosis can be inhibited by RIP1 kinase inhibitors (e.g. Nec-1s) or knockout (KO) of RIP3. We found that LPS/Siv-induced necroptosis was significantly inhibited in RIP3 KO neutrophils. Importantly, in a mouse model of ALI induced by 50% lethal dose of LPS, Siv in combination with Nec-1s resulted in 90% survival of the mice (P=0.001), whereas neither Siv nor Nec-1s alone afforded significant protection against the death. Thus, we hypothesize that inhibition of NE with Siv in ALI leads to RIP1-mediated necroptosis in neutrophils, which causes secondary inflammation and lung injury, and that inhibition of RIP1-mediated necroptosis significantly improves the effectiveness of NE inhibitors in ALI. Aim-1. Determine the therapeutic efficacies of RIP1 and NE inhibitors in lung injury and inflammation using mouse models of ALI. Aim-2. Determine how genetic ablation of NE or RIP3 affects lung injury and inflammation in ALI mice.

5. 项目总结/文摘