Project summary The mechanisms by which cigarette smoke (CS) activates the complement cascade to cause distal lung sterile injury and progression to COPD are not completely understood. Considering the critical role of complement in pathogen-induced inflammation, selective inhibition of the lectin complement pathway may result in decreased CS-induced inflammation and emphysema-like airspace enlargement without an indiscriminate inhibition of complement’s response to pathogens. In Aim 1 we propose to investigate a novel mechanism of CS-induced lung injury, focusing on which members of the lectin complement pathway are necessary to induce complement deposition in the lung, type-2 alveolar epithelial (AT2) cell dysfunction, and emphysema during CS exposure. In Aim 2 we will investigate whether decay accelerating factor (CD55), a complement regulator is required to protect against lectin complement deposition on AT2, preventing AT2 cell injury, death, and impaired proliferation. In Aim 3 we propose a translational approach to develop a composite plasma complement activity score encompassing complement proteins and their regulators that could identify smokers at risk and early emphysema individuals. My proposal addresses the clinically relevant question whether harnessing membrane CD55 expression and signaling in AT2 cells can prevent lectin complement deposition and activation, ameliorating AT2 dysfunction and emphysema development in relevant murine models of CS exposure. Our animal studies are accompanied by measurements of complement proteins and regulators levels and activity in plasma from active smokers with and without COPD enrolled in COPDGene using a multiplex platform, SomaScan. Validated SomaScan measurements using standard complement activity tests, total complement hemolytic activity (CH50) and Wieslab lectin pathway activity are used to develop a “complement activity score”. We will test the ability of complement activity score to predict clinical and radiological parameters of distal lung injury progression. Completion of this project will provide compelling experimental evidences that targeting lectin pathway activation and preserving membrane CD55 expression on AT2 cells ameliorates distal lung injury in murine models of emphysema and it can be harnessed as next generation biomarkers in human COPD disease. Our newly complement activity score could identify smokers at risk and early COPD subjects in future research and pharmacological clinical trials. The complementary expertise of our team, the translational aspect of the proposal, and access to well-phenotyped human specimens increase the relevance and chance of successful completion of this project.