Selectin-targeted glycocalyx mimetic as a treatment for pulmonary inflammation
Abstracts
Initial Award Abstract |
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Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by obstruction and destruction of lung tissue due to inflammation. COPD is the third leading cause of death in the United States and has been strongly linked with cigarette smoking, accounting for over 95% of cases in the developed world. Dysfunction of endothelial cells (ECs), the cells that line all blood vessels in the human body, is associated with many diseases including COPD. A key feature of EC dysfunction is the loss of the glycocalyx, a thin, protective layer that lines the EC surface. Glycocalyx loss increases exposure of cell adhesion molecules such as selectins, which causes immune cells such as neutrophils to linger, or arrest, on the ECs, leading to inflammation. EC dysfunction is present in lung blood vessels of early COPD patients and has been shown to be associated with severity of disease. We have previously developed a glycocalyx mimetic (termed EC-SEAL) designed to bind overexpressed selectin and discourage excessive neutrophil binding, thereby blunting the inflammatory response and creating a healthier endothelial state. Preliminary data suggests EC-SEAL does indeed bind to selectin on inflamed ECs and results in decreased neutrophil arrest. We therefore hypothesize that EC-SEAL can lessen the degree of fibrosis in affected lung tissue. To test this hypothesis, we will first optimize EC-SEAL such that it binds selectin with high affinity and remains resident on the EC surface during continuous flow, mimicking blood flow. We will employ cell co-culture systems to recapitulate the relationship between airway cells and ECs and expose this system to cigarette smoke to investigate how EC-SEAL impacts the health of the tissue. We will then use our molecule in a mouse model of cigarette smoke-induced acute lung inflammation. We will quantify our findings by measuring degree of tissue damage and levels of inflammatory molecules released by lung cells. Through these means we aim to determine the effectiveness of EC-SEAL as a treatment for inflammatory lung diseases such as COPD. |
