The acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury (All) affects 100- 200K people in the U.S. yearly leading to death in nearly 35% of patients. ARDS is characterized by neutrophilic inflammation, vascular leak, and alveolar filling with proteinaceous fluid. This Program Project Proposal (P01) focuses on elucidating the role of cardiolipin (CL) as a novel damage associated molecular pattern (DAMP-CL) and mediator of tissue damage in acute lung injury. The alveolar epithelium and innate immune system are central to the development of ARDS. The three primary projects detailed within the P01 focus on expounding cardiolipin biology in these key cell types; type II alveolar pneumocytes in Projects 1 and 2 and inflammatory cells including the recently characterized myeloid derived suppressor cell in Project 3. Core C (Animal Models and Human Sample Repository) is designed to optimize the translational exploration of the mechanisms identified in vitro in Projects 1-3 whereby cardiolipin leads to progressive cellular and subsequently tissue damage in All. The Core will serve to standardize the characterization of murine models of acute lung injury across the various projects using bacterial pathogens or hyperoxic insult as indicated. Core personnel will perform physiologic measurements for project investigators including Flexivent lung mechanics and permeability assessments along with tissue and fluid collection for dissemination to project investigators. In addition, a key component of the Core services will be to provide de-identified human tissue and fluid samples (collected via an ongoing IRB approved registry and biospecimen repository and existing Divisional tissue banks) to project investigators for verification of human relevance of novel findings from the bench or from murine models. In providing these services, Core C integrates tightly and interacts closely with all projects comprising the P01 proposal.
ARDS is a devasting disorder and despite several decades of research, few novel pathways have emerged underlying this illness. This Core will greatly facilitate examination of newer pathways studying a rare toxin, cardiolipin, and its production and elaboration from cells that profoundly alters lung stability. This Core will provide invaluable resources for animal studies of lung injury and provide human samples for toxin analysis.
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