Published ahead of print on July 21, 2005, doi:10.1165/rcmb.2004-0333OC
Am. J. Respir. Cell Mol. Biol., Volume 33, Number 5, November 2005, 447-454
A more recent version of this article appeared on November 1, 2005
Submitted on October 25, 2004
Revised on July 19, 2005
Expression and Role of the Hyaluronan Receptor RHAMM in Inflammation After Bleomycin Injury
Aisha Zaman1, Zheng Cui1, Joseph P Foley1, Hengjiang Zhao1, Paul C Grimm2, Horace M DeLisser3, and Rashmin C Savani1*
1 Division of Neonatology, Department of Pediatrics, Children's Hospital of Philadelphia; University of Pennsylvania, Philadelphia, PA, USA,
2 Division of Pediatric Nephrology, Department of Pediatrics, University of California San Diego, San Diego, CA, USA,
3 Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
* To whom correspondence should be addressed. 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 RHAMM (Receptor for HA-Mediated Motility). 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 four to seven days after injury. Surface biotin labeling of cells isolated by lavage confirmed increased surface expression of a 70 kDa RHAMM after lung injury, and in situ hybridization demonstrated increased RHAMM mRNA in macrophages responding to injury. Timelapse 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 seven days 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.
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