Regulatory T Cells Promote Alveolar Epithelial Repair

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Project Summary The global objective of this K08 Mentored Clinical Scientist Career Award Application is to facilitate development of essential skills that will allow the candidate to become an academic physician-scientist. The proposal provides not only new techniques but even more importantly an understanding of the biological significance of the observations and ideas about their translation toward applicability in the care of patients. The candidate, his mentor and his advisory committee have designed a training plan that includes a rigorous research component along with didactic instruction to establish the thought processes and principles necessary for successful career development. Through coursework and practical experience the candidate will develop a deeper understanding of the complex immune mechanisms that underlie the development and resolution of lung injury. His clinical work in the medical intensive care unit caring for patients with severe lung disease will inform his basic research practices as well as guide the translation of that work to patient care. Acute Respiratory Distress Syndrome (ARDS) is characterized by hypoxemia, capillary leakage, edema, and epithelial cell damage and causes high morbidity and mortality in the U.S. each year. There is a paucity of information about the resolution phase of acute lung injury (ALI); however, published work has demonstrated a role for Foxp3+ regulatory T cells (Tregs) in the resolution of experimental ALI. Furthermore, Tregs increase in bronchoalveolar fluid of patients with ARDS, suggesting that they are important in the human immunological response to lung injury. In acute or chronic injury the failure to regenerate the lung epithelium plays a role in such processes as ALI, pneumonia, pulmonary fibrosis, cancer, COPD, and aging. Recently there has been considerable interest in the cell types involved in repair and the regulation of this process. The candidate’s data demonstrate that the presence of Tregs enhances alveolar epithelial repair, a novel finding that has not been previously described. This proposal examines Treg effects on the alveolar epithelium during ALI resolution with the hope of identifying novel mechanisms that may lead to potential treatment options in patients with ARDS. The specific aims utilize both in vivo and in vitro techniques to study the interactions between Tregs and alveolar epithelium. Aim 1 investigates the role of CD103 expression on Treg in ALI resolution and tests the hypothesis that CD103 promotes epithelial repair by retaining Tregs at epithelial sites of inflammation and enhancing their tissue reparative effects. Aim 2 determines the impact of Treg-expressed KGF in ALI resolution, hypothesizing that this KGF promotes epithelial kinetics, surfactant expression, and barrier integrity. Aim 3 determinates the contribution of Treg-derived microparticles to ALI resolution, hypothesizing that Treg-derived microparticles communicate with the alveolar epithelium to amplify resolution of lung inflammation. These studies will explore new observations concerning Treg modulation of the alveolar epithelium during ARDS resolution with the ultimate goal of improving patient outcomes in this often times fatal disease.