This proposal outlines a five-year training program for Dr. Kadl to establish an academic career in Pulmonary and Critical Care Medicine. With the guidance of the candidate's mentor Dr. Kodi Ravichandran, her supervising committee and the institutional support provided by the Department of Medicine, Dr. Kadl will acquire new knowledge and expertise in research methods and develop the skills needed to evolve into an independent clinician scientist. Acute lung injury and acute respiratory distress syndrome are a common problem in the intensive care unit with a mortality rate of 30-40%. Despite extensive research in the past 45 years, pharmacotherapy has not resulted in significant improvement in mortality of this disease condition. Apoptosis of lung epithelial cells has been described as an early event in the progression of acute lung injury, followed by accumulation of inflammatory cells within the alveolus. Although recruited neutrophils show an extended life span in acute lung injury they eventually undergo apoptosis. Recognition and subsequent clearance of apoptotic cells results in the production of anti-inflammatory cytokines from the engulfing phagocytes. However, mechanisms involved in clearance during ALI are yet not clearly understood. The overall goal of this study is to elucidate how apoptotic cells are removed during acute lung injury and furthermore, investigate whether boosting this process could lead to new treatment option for acute lung injury. In detail, this study will (1) test the hypothesis that activation of phagocytes by apoptotic cells will improve lung injury and resolve tissue inflammation, and (2) test the hypothesis that non-professional phagocytes (such as bronchial epithelial cells) can actively contribute to tissue homeostasis and prevention of ALI/ARDS. Previous studies have suggested that exogenous apoptotic cells can ameliorate lung injury, potentially by creation of an anti-inflammatory environment supporting tissue repair and resolution of inflammation. We will take this a step further and evaluate carefully how exogenously instilled apoptotic cells can contribute to attenuation of lung injury and resolution o inflammation. Using an experimental lung injury model induced by bleomycin, and using genetically modified mice that lack receptors that recognize apoptotic cells, such as BAI1 and TIM4 or downstream signaling molecules, such as Elmo1, Dock180, and Rac1 we will test the hypothesis that activation of the engulfment cascade is required for the beneficial effects seen with apoptotic cells. We will further test whether non-professional phagocytes such as bronchial epithelial cells contribute to this therapeutic effect by paracrine release of anti-inflammatory cytokines, challenging the current concept of ALI. SIGNIFICANCE: This study will lead to a better understanding of the role of apoptosis and engulfment of apoptotic cells in the progression of acute lung injury. The use of genetic mouse models will elucidate pathways involved downstream of the recognition of the apoptotic cell. The results of this study may provide new molecular targets and may result in a new cell based treatment strategy for patients with ALI/ARDS.
Acute respiratory distress syndrome (ARDS) affect about 200,000 patients every year in the United States, with mortality as high as 30-40%. This proposal will investigate how the lungs clear dying cells and debris using an experimental model of acute lung injury and relate this to human condition. We will further explore how manipulation of this cell clearance process can improve disease outcome with significant therapeutic implications for ARDS.