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Apical Oxidative Hyaluronan Degradation Stimulates Airway Ciliary Beating via RHAMM and RON

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida; and Divisions of Pulmonary and Vascular Biology and Neonatal-Perinatal Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas

Correspondence and requests for reprints should be addressed to Matthias Salathe, Division of Pulmonary and Critical Care Medicine, University of Miami School of Medicine, 1600 NW 10th Ave., RMSB 7063A (R-47), Miami, FL 33136. E-mail: msalathe{at}med.miami.edu

Hyaluronan (HA) is synthesized in high-molecular-weight form at the apical pole of airway epithelial cells, covering the luminal surface. When human airway epithelial cells grown and redifferentiated at the air–liquid interface (ALI) were exposed to xanthine/xanthine oxidase (X/XO), ciliary beat frequency (CBF) increased. This effect was blocked by superoxide dismutase (SOD) and catalase. Inhibition of hyaluronan synthesis inhibited the CBF response to X/XO, while addition of exogenous HA amplified it. A functionally blocking antibody to the receptor for hyaluronic acid–mediated motility (RHAMM) reduced the CBF response to X/XO. Since RHAMM has no transmembrane domain and thus cannot signal on its own, the association of RHAMM with recepteur d'origine nantais (RON), a member of the hepatocyte growth factor receptor family, was explored. Immunohistochemistry of human airway epithelium showed co-localization of RHAMM and RON at the apex of ciliated cells. Physical association of RHAMM and RON was confirmed with co-immunoprecipitations. Macrophage-stimulating protein (MSP), an agonist of RON, stimulated CBF. Genistein, a nonspecific tyrosine kinase inhibitor, and MSP chain (-MSP), a specific RON inhibitor, blocked the X/XO-induced CBF increase. HA present in the apical secretions of human airway epithelial cells was shown to degrade upon exposure to X/XO, a process inhibited by SOD. Low-molecular-weight HA fragments stimulated CBF, an effect blocked by anti-RHAMM antibody and genistein. These data suggest that high molecular form HA is broken down by reactive oxygen species to form low-molecular-weight fragments that signal via RHAMM and RON to stimulate CBF.

Key Words: ciliary beat frequency • hyaluronan • receptor for hyaluronan mediated motility • recepteur d'origine nantais • reactive oxygen species

CLINICAL RELEVANCE This study provides new information on reactive oxygen species modulation of ciliary beat frequency via hyaluronan degradation and signaling by receptor for hyaluronic acid–mediated motility and recepteur d'origine nantais. Thus this research may provide information about mucociliary changes during airway inflammation.

 

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