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Published ahead of print on March 29, 2007, doi:10.1165/rcmb.2006-0413OC

Am. J. Respir. Cell Mol. Biol., Volume 37, Number 2, August 2007, 160-168

A more recent version of this article appeared on August 1, 2007
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Submitted on November 3, 2006
Revised on March 27, 2007

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

Dahis Manzanares1, Maria-Elena Monzon1, Rashmin C Savani2, and Matthias Salathe1*

1 Department of Medicine, Division Pulmonary and Critical Care Medicine, University of Maimi Miller School of Medicine, Miami, FL, USA, 2 Department of Pediatrics, Divisions of Pulmonary and Vascular Biology and Neonatal-Perinatal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

* To whom correspondence should be addressed. 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 re-differentiated 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 RHAMM (the receptor for hyaluronic acid mediated motility) 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 RON (recepteur d'origine nantais), 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 non-specific tyrosine kinase inhibitor, and MSP {beta} chain ({beta}-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 ROS to form low molecular weight fragments that signal via RHAMM and RON to stimulate CBF.




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