In this PPG, all of the Projects and Cores consider the persistence of respiratory failure and the development of multiple organ dysfunction in patients with ARDS as a failure of normal mechanisms of inflammation resolution and lung repair. This hypothesis is clinically supported by a recent analysis of patients enrolled in the ARDSnet where a “hyerinflammatory” endotype of ARDS was associated with poor clinical outcomes including death. The expression of many genes encoding inflammatory cytokines is regulated by the transcription factor NF-B. Hence, understanding how NF-B activity is controlled over the course of lung injury and repair is likely to provide mechanistic insights into the pathobiology of successful or failed lung repair after injury. The Linear Ubiquitin Assembly Complex (LUBAC) is an E3 ubiquitin ligase that performs Met-1 ubiquitination necessary for NF-B activation. In preliminary experiments, we observed that epithelial specific deletion of a modulatory component of LUBAC (HOIL-1L) prevents NF-B signaling and improves outcomes in a murine model of influenza A virus infection. We present additional preliminary data that support our hypothesis that LUBAC promotes persistent NF-B signaling in the alveolar epithelium and monocyte-derived alveolar macrophages to inhibit lung repair after influenza A induced lung injury. Specific Aim 1. To determine whether inhibiting LUBAC-mediated NF-B activation in the lung epithelium during recovery from influenza A infection accelerates lung repair. We will perform timed experiments in which we will genetically inhibit LUBAC mediated NF-B signaling during recovery from influenza A infection and use complementary physiologic and molecular techniques to measure lung repair. Specific Aim 2. To determine whether activation of LUBAC mediated NF-B activation in the lung epithelium directs reparative phenotypes in monocyte-derived macrophages. We will determine whether the inflammatory phenotype of these cells is driven by the changing microenvironment—specifically the lung epithelium, or whether these changes are cell autonomous within the macrophage. Specific Aim 3. To determine whether increased expression of NF-B-dependent inflammatory genes in alveolar macrophages and BAL fluid from patients with severe pneumonia is associated with 30 day mortality. We will take advantage of the infrastructure provided by the Successful Clinical Response in Pneumonia Therapy (SCRIPT) trial to determine whether there is an association between the expression of NF- B target genes in alveolar macrophages and BAL fluid cytokines with clinical outcomes.