Apical Oxidative Hyaluronan Degradation Stimulates Airway Ciliary Beating via RHAMM and RON
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 fre...
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Published in | American journal of respiratory cell and molecular biology Vol. 37; no. 2; pp. 160 - 168 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
United States
Am Thoracic Soc
01.08.2007
American Thoracic Society |
Subjects | |
Online Access | Get full text |
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Summary: | 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 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 reactive oxygen species to form low-molecular-weight fragments that signal via RHAMM and RON to stimulate CBF. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. This work was partially supported by NIH grants HL-60644 and HL-67206 (to M.S.) and HL-62472 and HL-73896 (to R.C.S.) and by a James and Esther King Florida Biomedical Research Program Team Science Project Grant from the State of Florida (to M.S.). Originally Published in Press as DOI: 10.1165/rcmb.2006-0413OC on March 29, 2007 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@med.miami.edu |
ISSN: | 1044-1549 1535-4989 |
DOI: | 10.1165/rcmb.2006-0413OC |