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.
