Despite progress in defining the pathophysiology of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and advances in supportive care, mortality remains high at 30-40%, and no specific pharmacological intervention can be recommended for blocking progression of ALI. Thus, recent attention has focused on identifying pathways that promote resolution of ALI. Our new data show that E-cadherin shedding is associated with pulmonary recruitment of a specialized population of dendritic cells (DC) expressing CD103 (aE?7-integrin), a leukocyte cell-surface receptor for which E- cadherin is the only known ligand. In mice with ALI induced by Pseudomonas aeruginosa infection or bleomycin toxicity, mice lacking CD103 showed delayed resolution of neutrophilic inflammation and had higher mortality than wild type mice. In vitro, soluble E-cadherin altered the LPS-induced cytokine profile of bone marrow derived dendritic cells to an anti-inflammatory phenotype, and mice lacking CD103 had far fewer suppressor regulatory T cells in the bronchoalveolar lavage (BAL) than wild type mice during resolution of P. aeruginosa pneumonia in vivo. These data support our overall hypothesis that E-cadherin-CD103 interactions promote resolution of acute lung injury. Using complementary in vivo and in vitro approaches, we will define the mechanisms by which E-cadherin programs CD103+ DC to resolve pulmonary inflammation.
Specific Aim 1 will assess how E-cadherin-CD103 interactions control dendritic cell function.
Specific aim 2 will determine the anti-inflammatory pathways activated in pulmonary CD103+ DC in the injured lung, and Specific Aim 3 will elucidate the downstream effector mechanisms by which CD103+ DC resolve acute lung inflammation. Significance: Our long-term goal is to understand how lung epithelial injury responses promote repair, and the results of the proposed studies should form the basis for new strategies aimed at enhancing endogenous lung repair in this clinical conditions for which current therapy is quite limited.
Acute lung injury is a common and severe cause of lung disease with no specific pharmacologic treatment. In many patients, acute injury progresses to a chronic lung injury characterized by persistent lung dysfunction and debilitation. Although much has been learned about the biological processes that incite lung injury, little is known about the innate mechanisms that resolve acute lung injury. Consequently, the results of the planned studies should enhance fundamental understanding of how epithelial and immune cells interface to limit progression of lung injury and may identify new therapeutic strategies for this difficult clinical problem.
