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Expression and Role of the Hyaluronan Receptor RHAMM in Inflammation after Bleomycin Injury

Division of Neonatology, Department of Pediatrics, Children's Hospital of Philadelphia; Divsion of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and Division of Pediatric Nephrology, University of California San Diego, San Diego, California

Correspondence and requests for reprints should be addressed to Rashmin C. Savani, M.B., Ch.B., Division of Neonatology, Department of Pediatrics, Room 416F, Abramson Research Center, Children's Hospital of Philadelphia, 3516 Civic Center Boulevard, Philadelphia, PA 19104-4318. E-mail: rsavani{at}mail.med.upenn.edu

Lung injury is associated with increased concentrations of hyaluronan (hyaluronic acid, HA). HA modifies cell behavior through interaction with cell-associated receptors such as receptor for HA-mediated motility (RHAMM, CD168). Using a function blocking anti-RHAMM antibody (R36), we investigated the expression and role of RHAMM in the inflammatory response to intratracheal bleomycin in rats. Immunostaining showed increased expression of RHAMM in macrophages 4–7 d after injury. Surface biotin labeling of cells isolated by lavage confirmed increased surface expression of a 70-kD RHAMM after lung injury, and in situ hybridization demonstrated increased RHAMM mRNA in macrophages responding to injury. Time-lapse cinemicrography demonstrated a 5-fold increase in motility of alveolar macrophages from bleomycin-treated animals that was completely blocked by R36 in vitro. Further, HA-stimulated macrophage chemotaxis was also inhibited by R36. Daily administration of R36 to injured animals resulted in a 40% decrease in macrophage accumulation 7 d after injury. Further, H&E staining of tissue sections showed that bleomycin-mediated changes in lung architecture were improved with R36 treatment. Taken together with previous results showing the inhibitory effects of HA-binding peptide on inflammation and fibrosis, we conclude that the interaction of RHAMM with HA is a critical component of the recruitment of inflammatory cells to the lung after injury.

Key Words: lung injury • bleomycin • inflammation • hyaluronan • RHAMM

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