Pathophysiology of Acute Lung Injury

The acute respiratory distress syndrome (ARDS) affects approximately 150,000-200,000 people each year in the United States, and has an unacceptably high mortality rate of ~30-40%. Injury to the lung epithelium leads disruption of the alveolo-capillary barrier resulting in pulmonary edema, impaired gas exchange, and death if not corrected. This Program Project Grant application is founded on the hypothesis that the alveolar epithelial response to sterile and infectious injury is of crucial importance to the outcome of patients with (ARDS). The Project Investigators,Core directors, who are all leaders in the field of lung biology and metabolism will use both a sterile model of epithelial injury caused by hypoxia and an infectious model of acute lung injury induced by infection with the influenza A virus to study the role of the epithelium and the cells with which it interacts in the pathophysiology of acute lung injury. The investigators propose to study alveolar epithelial cell injury via three interrelated projects and three supportive cores. In Project # 1, Dr. Sznajder presents preliminary data suggesting that the linear ubiquitination assembly complex (LUBAC) and the Na,K-ATPase in the lung epithelium play a central role in the pathophysiology of hypoxia and influenza A-induced lung injury. His data suggest that the activation of LUBAC in response to influenza A infection is a major determinant of the severity of the lung injury and the resulting inflammatory response. In Project # 2, Dr. Ridge provides preliminary data showing that vimentin acts as scaffold for the assembly and activation of the NLRP3 inflammasome and that the NOD2 protein interaction with vimentin is required for the activation of IRF3 signaling in response to influenza A virus. Her studies, which investigate the molecular mechanisms by which vimentin interacts with Nod-like receptor proteins, suggest a completely novel intracellular checkpoint on the activation of this critical pathway in the innate immune response to infection and offer a novel target for therapy. In Project # 3, Dr. Chandel shows that upon infecting the lung epithelium, the influenza A virus upregulates metabolic pathways that supply metabolites required for synthesis of sialic acid, a key metabolite required for its lifecycle, and activates cellular autophagy pathways to provide metabolic building blocks for viral synthesis. He will study how manipulation of metabolic pathways following influenza infection might limit the severity of lung injury and promote tissue repair following infection with influenza A virus. These projects are supported by a Cell Culture and Translational Studies Core and a Murine Genetics and Phenotyping Core, led by experienced lung scientists. Collaborative studies have been conducted for each of the projects and the preliminary results support the feasibility of this proposal. These projects are interactive conceptually and programmatically, where the aggregate of the projects is greater than the sum of its parts. The project investigators and the Core leaders have designed these studies with the goal of providing short or intermediate term deliverables in the form of novel therapies to treat influenza A induced lung injury.