The epithelial glycocalyx at the blood-gas barrier of the lung

The alveolar epithelial glycocalyx is a hydrogel
consisting of proteoglycans, glycoproteins and glycosaminoglycans that covers the entire 120 m² of alveolar surface area in the human lung. As such, the alveolar epithelial glycocalyx is an essential part of the first line of defense of the blood-gas barrier, an ultrathin structure between the airspaces and the blood vessels
of the lung that allows for gas exchange of O2 and CO2, while contemporaneously restricting leakage of fluids and proteins into the airspace, or entry of inhaled pathogens into the circulation. Despite its relevance in lung barrier function and pathogen defense, the alveolar epithelial glycocalyx is so far virtually unexplored. Importantly, the alveolar epithelial glycocalyx differs from other glycocalices at cell or organ surfaces with respect to its unique physicochemical microenvironment within the alveolar space where it is a) constantly exposed to cyclic biaxial stretch as a result of alveolar inflation and deflation over the respiratory cycle, and b) co-localizes, and presumably interacts, with alveolar surfactant, a surface tension lowering mix of amphiphilic lipids and surfactant proteins secreted by alveolar epithelial type II cells. Based on preliminary data, we propose that the unique alveolar microenvironment serves as a critical regulator of alveolar epithelial glycocalyx structure and function. Specifically, we hypothesize that the effects of epithelial stretch in mechanical ventilation alter glycocalyx structure and function with direct impact on ventilation-associated pathologies, and that surfactant proteins A and D act as scaffold proteins that contribute to alveolar glycocalyx stability and barrier function.
To address these questions, we will combine our complementary expertise in alveolar mechanotransduction, alveolar barrier function, and intravital microscopy of the lung and in surfactant biology and electron microscopy of the alveolus. The PIs microscopic toolbox will be further enriched by metabolic glycol-engineering and
fluorescence lifetime imaging of molecular rotor dyes via collaborations within the CRC.