Grant: CIHR Fellowship

Acute respiratory distress syndrome (ARDS) is a life-threatening condition in which the lung is injured to a point such that the normal function is lost. Nearly 40 % of the 18,000 Canadians die each year because of the lack of effective treatment. Thus, understanding ways to reduce the mortality and morbidity of ARDS is critical. In ARDS, immune cells called neutrophils play paradoxical, yet key roles in causing lung injury. At present, we are not certain how exactly these cells hurt the lung. Recent research shows that neutrophils cast web-like structures called neutrophil extracellular traps (NETs). While NETs are an effective defense against pathogens, a growing body of evidence now suggests that an overproduction of NETs injure, rather than protect, infected and inflamed tissues. Thus, the proposed project will determine the roles for NETs as a cause of lung injury in ARDS, and whether counter regulatory measures aimed at reducing NETs release in the lung is a potential novel therapeutic strategy for ARDS. Specialized pro-resolving mediators (SPMs) are an emerging class of bioactive lipid molecules that are naturally produced from essential polyunsaturated fatty acids. Our lab has shown previously that the SPMs enhance host defense against pathogens, while limiting inflammatory response and encouraging tissue healing. Therefore, SPMs should be able to reduce the release of harmful NETs in ARDS and promote tissue healing. I will test this idea in a cell culture reporter assay to determine if select SPMs directly stop NET production. I will also test whether NETs cause lung injury in a mouse model of ARDS that we have developed. Using the candidate SPMs identified, I will test their ability to reduce the production of NETs and lung injury in this mouse model of ARDS. If true, this study will demonstrate that NETs are therapeutic targets in ARDS, and also show the therapeutic potential of SPMs and its molecular pathway for the devastating condition of ARDS.