The acute respiratory distress syndrome (ARDS) associated with severe sepsis is a neutrophilic inflammatory lung disease (NLI) with excessive morbidity and mortality. In spite of improvements in supportive care that have resulted in better survival rates, there are no effective specific treatments of ARDS that are based on the molecular pathogenesis. We propose to investigate the pre-transcriptional events in pulmonary macrophages that lead to cytokine- and chemokine-mediated inflammation in the lung. In previous years of funding, we have focused on the early effects of NADPH oxidase that result in attenuation of the NF-:B activation pathway. We now propose to investigate the role of NADPH oxidase in the resolution of neutrophilic lung inflammation in pulmonary macrophages. We will consider the effects of NADPH oxidase on gene regulation of cyclooxygenase-2 (COX-2) and lipocalin-prostaglandin D synthase (L-PgDS) gene expression which results in relative increase in prostaglandin D2 (PgD2) and on activation of nuclear factor E2 p45-related factor 2 (Nrf2). Degradation products of PgD2, called cyclopentanones, have potent anti-inflammatory properties and Nrf2 has a role in gene regulation of anti-oxidant and detoxifying proteins that are protective. Our laboratory has identified a novel pathway by which a redox sensitive kinase, NF-:B inducing kinase (NIK), regulates gene expression L-PgDS and production of PgD2 through phosphorylation of PU.1, a macrophage specific transcription factor. In this proposal, we hypothesize that NADPH oxidase generated ROS in pulmonary macrophages has a dual role in mediating neutrophiilc lung inflammation. In early neutrophilc lung inflammation, ROS contributes to activation of NF-:B and generation of cytokine, chemokine, and cyclooxygenase-2 (COX-2) gene expression. However, at later time points, which will be the focus of this proposal, NADPH oxidase- generated ROS mediates resolution of neutrophilc lung inflammation through effects on the production of anti-inflammatory prostanoids and anti-oxidants and detoxifying proteins regulated by Nrf2. We propose two specific aim: 1: To determine the necessity of macrophage NADPH oxidase generated ROS on resolution of neutrophil lung inflammation in response to treatment with endotoxin and 2: To determine the requirement of macrophage NADPH oxidase generated ROS in redox regulation of NIK and Nrf2 activation and to determine the consequences of NIK and Nrf2 activation on the resolution of NLI. By examining the physiological role of NADPH oxidase on the resolution of neutrophilc lung inflammation, we expect to identify novel mechanisms that could provide evidence for effective therapeutic approaches to limit lung injury and restore health in patients suffering from ARDS and other inflammation lung diseases.
Project Narrative: The acute respiratory distress syndrome (ARDS) is a severe and life threatening condition that requires a mechanical breathing machine and other supportive care in an intensive care unit. We have shown that macrophages in the lung have an essential role in initiating the severe lung inflammation that causes ARDS. The purpose of this research is to define the basic molecular mechanisms that regulate macrophage involvement in ARDS in order to design new and effective treatments.
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