High molecular weight hyaluronan is a novel inhibitor of acute lung injury
Patrick A. Singleton
Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, IL, 60637
Abstract:
Endothelial cell (EC) barrier dysfunction results in increased vascular permeability, a perturbation observed in inflammatory states, tumor angiogenesis, atherosclerosis and both sepsis and acute lung injury. Therefore, agents that enhance EC barrier integrity have important therapeutic implications. We observed binding of high molecular weight hyaluronan (HMW-HA) to its cognate receptor, CD44, within caveolin-enriched microdomains (CEM) enhances human pulmonary EC barrier function. Immunocytochemical analysis indicated that HMW-HA promotes redistribution of a significant population of CEM to areas of cell-cell contact. Quantitative proteomic analysis of CEM isolated from human EC demonstrated HMW-HA-mediated recruitment of cytoskeletal regulatory proteins (annexin A2, protein S100-A10, filamin-A/B). Inhibition of CEM formation (caveolin-1 siRNA, cholesterol depletion) or silencing (siRNA) of CD44, annexin A2, protein S100-A10 or filamin-A/B expression abolished HMW-HA-induced actin cytoskeletal reorganization and EC barrier enhancement. To confirm our in vitro results in an in vivo model of inflammatory lung injury with vascular hyper-permeability, we observed that the protective effects of HMW-HA on LPS-induced pulmonary vascular leakiness were blocked in caveolin-1 knockout mice. Further, targeted inhibition of CD44 expression in the mouse pulmonary vasculature significantly reduced HMW-HA-mediated protection from lipopolysaccharide (LPS)-induced hyper-permeability. These data suggest that HMW-HA, via CD44-mediated CEM signaling events, represents a potentially useful therapeutic agent for syndromes of acute lung injury.
