The objective of this Career Development Award is to enhance understanding of acute lung injury (ALI) pathogenesis in order to facilitate development of new effective therapies. ALI is a common and lethal form of respiratory failure, occurring in 200,000 people each year and in as many as 25% of mechanically ventilated patients. There are presently no effective medical therapies for ALI, and mortality remains at nearly 40%. Chronic co-morbid conditions alter the risk for developing ALI, and diabetes mellitus (DM) is the only identified condition shown to decrease the incidence of ALI in patients with septic shock. This unexpected observation serves as the foundation for examining ALI pathogenesis to understand disease-modifying pathways to mitigate the risk for such a morbid acute illness. PPARg activity influences AM host immune functions including phagocytosis, and our preliminary data suggest that PPARg activity, a key regulator of AM activation, is increased in otherwise healthy diabetics;and that AM function is decreased in sepsis, the most common cause of ALI. In this context, one could postulate that the relative PPARg activation in the AM should correlate with the risk of ALI in diabetics as well as in non-diabetics. Therefore, the association between AM function and ALI development is of importance to investigate. In addition, PPARg activation represents an attractive therapeutic target that could decrease the incidence or severity of acute lung injury not only in diabetics, but also in non-diabetics with sepsis or other acute stresses. With this background, we hypothesize that otherwise healthy diabetics will have increased AM PPARg activity when compared to healthy controls and that decreased AM PPARg activity and phagocytic function in severe sepsis are independently associated with increased risk of ALI. Furthermore, we hypothesize that treatment of AMs with a PPARg-ligand in vitro will increase PPARg activity, thereby increasing expression of the alternative activation (M2) anti-inflammatory phenotype and improving phagocytosis. Our hypothesis will be tested in Specific Aims designed to 1) determine the effect of DM on alveolar macrophage (AM) PPARg activity, phenotype and phagocytic function;2) establish the predictive value of AM PPAR3 activity, AM M2 differentiation and phagocytic function for the development of ALI;and 3) determine the effect of PPARg-ligand exposure in vitro on the phenotype and function of AMs isolated from control, diabetic and septic patients. The overall objective is to determine if the association between diabetes and decreased incidence of ALI translates to an association between increase PPARg activity and decreased risk of ALI. To test our hypothesis, we will conduct studies in otherwise healthy diabetics, subjects with severe sepsis and healthy controls. Eligible subjects will undergo bronchoscopy with bronchoalveolar lavage to isolate AMs and perform assays measuring PPARg activity, markers of AM differentiation (M1/M2 markers) and AM phagocytic function. These studies will be repeated, in Aim 3 testing exposure of AMs to PPARg ligand and determining its effect on AM differentiation and phagocytic function. The proposed studies will evaluate the impact of PPARg activity on development of ALI and will determine the role of PPARg in regulating AMs response to pulmonary inflammation. Since PPARg is a key regulatory component of acute inflammatory responses in the lung, and effectively dampens inflammation and injury in animal models of ALI, it is imperative that we investigate the pathogenetic and potential therapeutic role of this receptor in human lung disease. The proposed studies will be carried out under the guidance of an experienced mentor who has expertise in conducting clinical research, and a co-mentor with expertise in conducting basic research;supplemented by a career development committee and collaborations with a multi-disciplinary scientific team. The support provided by the K23 Career Development Award will allow me to build upon the foundation I have created with my previous studies, and continue towards my goal of becoming an independent clinical investigator with the ultimate goal of becoming an expert in ALI pathogenesis. This will be accomplished by receiving didactic training through completion of the MSCR program and courses in immunology, interactions with my mentor and a well-established advisory committee, and the Emory environment, all of which will further refine and develop my investigational and analytical skills. The training opportunity provided by the K23 program will provide a direct path for obtaining future NIH funding, such R01 awards, which will allow me to successfully extend my research focus and broaden our understanding of the pathophysiology of ALI.
Acute lung injury (ALI) is a common, lethal disease that occurs in critically ill patients and that has no effective treatment. Enhancing our understanding of the biological mechanisms that lead to the development of lung injury in specific at-risk populations is imperative for the purpose of developing future therapies. The proposed research seeks to provide vital information about key components of the inflammatory response to infection that lead to ALI, and will evaluate the potential of these components to be modulated.
|Prebil, Sarah E W; Andrews, Joel; Cribbs, Sushma K et al. (2014) Safety of research bronchoscopy in critically ill patients. J Crit Care 29:961-4|