Lymphatic Dysfunction in the Pathogenesis of COPD

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Project Summary/Abstract Chronic Obstructive Pulmonary Disease (COPD) is a destructive inflammatory lung disease that is the 4th leading cause of death in the U.S., killing more than 150,000 people yearly. Current therapies can improve symptoms and reduce hospitalization, but none modify this disease or stop its relentless progression. COPD is commonly caused by cigarette smoke (CS), but we do not yet fully understand the early events that trigger inflammation and tissue destruction that could be intervened upon to halt the cycle of lung injury. This knowledge gap has led to an absence of disease-modifying therapies and a therapeutic pipeline that has thus far led to only incremental advances on existing drugs. The lymphatic vessels are uniquely positioned to regulate inflammatory responses in most tissues because they drain fluid and traffic immune cells in the form of lymph. We have recently published our findings that impaired lymphatic drainage alone is sufficient to induce lung inflammation that culminates in the hallmarks of human COPD. Furthermore, we have discovered that lymphatic endothelial cell injury and lymphatic vessel thrombosis are early events after CS exposure. Interestingly, we not only identified lung lymphatic thrombosis in human lung tissue from patients with COPD, we also found that the degree of lymphatic thrombosis is linked to COPD severity. This work suggests that lymphatic dysfunction may be central to COPD pathogenesis but the role of the lymphatics in CS-induced lung injury and inflammation is not well understood. Filling this critical knowledge gap promises to result in new classes of lymphatic-targeted agents that have the potential to block or reverse COPD and lead to prolonged survival in these patients. We will investigate the novel concept that lymphatic dysfunction is a defining early event in the pathogenesis of emphysema that can contribute to progressive tissue destruction. Therefore, the objective of this proposal is to define the actionable mechanisms that result in lymphatic endotheliopathy after CS exposure and drive progression of COPD. Our central hypothesis is that lymphatic thrombosis due to CS drives disease progression through activation of thrombin in the lymphatic endothelium. Our approach consists of lymphatic- specific manipulation of the coagulation pathway and thrombin signaling in order to mechanistically address the consequences of lymphatic thrombosis on disease progression in a murine model of COPD (Aim 1), and the mechanism by which CS causes lymphatic dysfunction (Aim 2). Furthermore, we will use these models to test how inhibition of thrombin activity or specific inhibition of the thrombin receptor affects the inflammatory response to CS and disease progression. When completed, these studies will lead to a shift in the current paradigm for the pathogenesis of COPD to include early changes in lung lymphatic function. In doing so, we will both broaden the field and set the stage for further studies with immediate clinical relevance given the use of existing therapies to target lymphatic function.