Role of Aldehyde Dehydrogenase 2 in Resolution of Fibroproliferative ARDS - PROJECT SUMMARY/ABSTRACT This proposal presents a revised 2-year research plan focused on improving the understanding of pathologic pulmonary fibrogenesis following acute lung injury and ARDS. The candidate is currently an Assistant Professor of Medicine at the University of Colorado in the Division of Pulmonary Sciences and Critical Care Medicine. The outlined proposal builds on data generated during the candidate’s current NIH/NHLBI K08 award to explore new mechanisms in the pathogenesis and resolution of Fibroproliferative ARDS (FP-ARDS). Data generated from the proposed research strategy will position the candidate for submission of an independent R01 proposal. The acute respiratory distress syndrome (ARDS) is a major healthcare problem in the US. Many ARDS survivors experience more severe disease and impaired long-term outcomes due to the development of pathologic pulmonary fibroproliferation. This excessive fibroproliferation, termed Fibroproliferative ARDS, is characterized by early, over-exuberant fibroproliferative responses with accumulation of myofibroblasts and deposition of extracellular matrix components, due in part to increases in TGF-β. This is followed by a late phase typified by persistent fibrotic changes. There remains a critical need to understand the drivers of FP-ARDS, and to develop therapeutics that attenuate, or reverse, the fibrotic sequelae of ARDS. Oxidant injury and the production of toxic, reactive aldehyde compounds, is key to the pathogenesis of lung injury and fibrogenesis. ALDH2 is a mitochondrial NADP-dependent enzyme that is best known for its role in ethanol metabolism, but is also essential for the detoxification of highly reactive lipid aldehydes. This proposal will evaluate the role of ALDH2 in the pathogenesis of FP-ARDS and test the hypothesis that activation of ALDH2 will promote lung repair and reduce fibroproliferative sequelae of lung injury. The candidate will address two research Aims. Specific Aim 1 will focus on the mechanisms by which ALDH2 inhibits fibrogenesis in lung parenchymal cell (fibroblast and epithelial cell) cultures models. Using genetic (siRNA) inhibition of ALDH2, and specific enzyme activators, we will measure levels of oxidant injury, lipid peroxidation products, and enzyme activity. We will evaluate key steps in the pathogenesis of pulmonary fibrosis, including TGF-- dependent signaling and gene expression in fibroblasts, and senescence phenotypes in epithelial cells. Specific Aim 2 will utilize mice with a genetic deletion of Aldh2 (Aldh2-/-) to determine if absence of this enzyme results in enhanced severity or duration of fibroproliferation in a validated pre-clinical model of FP-ARDS (bleomycin). A pharmacologic activator of ALDH2 will be used in a human Precision Cut Lung Slice model to determine if enhanced enzyme activity can attenuate fibroproliferation, or accelerate resolution and repair. The proposed project will define a novel mechanism in the pathogenesis of fibroproliferative ARDS and explore potential therapeutic targets that could lead to improved pharmacologic interventions for patients at risk for developing FP-ARDS.
