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Expression and role of the hyaluronan receptor RHAMM in inflammation after bleomycin injury.

ABSTRACT: 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.

SUBMITTER: Zaman A

PROVIDER: S-EPMC2715352 | biostudies-literature | 2005 Nov

REPOSITORIES: biostudies-literature

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Expression and role of the hyaluronan receptor RHAMM in inflammation after bleomycin injury.

Zaman Aisha A Cui Zheng Z Foley Joseph P JP Zhao Hengjiang H Grimm Paul C PC Delisser Horace M HM Savani Rashmin C RC

American journal of respiratory cell and molecular biology 20050721 5

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 lab ...[more]

PMID: 16037485

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Project description:Acute lung injury results in early inflammation and respiratory distress, and later fibrosis. The glycosaminoglycan hyaluronan (HA) and the Receptor for Hyaluronan-Mediated Motility (RHAMM, CD168) have been implicated in the response to acute lung injury. We hypothesized that, compared to wild type (WT) mice, RHAMM knockout (KO) mice would be protected from, whereas mice with macrophage-specific transgenic overexpression of RHAMM (TG) would have worse inflammation, respiratory distress and fibrosis after intratracheal (IT) bleomycin. Compared to WT mice, 10?days after IT bleomycin, RHAMM KO mice had less weight loss, less increase in respiratory rate, and fewer CD45+ cells in the lung. At day 28, compared to injured WT animals, injured RHAMM KO mice had lower M1 macrophage content, as well as decreased fibrosis as determined by trichrome staining, Ashcroft scores and lung HPO content. Four lines of transgenic mice with selective overexpression of RHAMM in macrophages were generated using the Scavenger Receptor A promoter driving a myc-tagged full length RHAMM cDNA. Baseline expression of RHAMM and CD44 was the same in WT and TG mice. By flow cytometry, TG bone marrow-derived macrophages (BMDM) had increased cell surface RHAMM and myc, but equal CD44 expression. TG BMDM also had 2-fold increases in both chemotaxis to HA and proliferation in fetal bovine serum. In TG mice, increased inflammation after thioglycollate-induced peritonitis was restricted to macrophages and not neutrophils. For lung injury studies, non-transgenic mice given bleomycin had respiratory distress with increased respiratory rates from day 7 to 21. However, TG mice had higher respiratory rates from 4?days after bleomycin and continued to increase respiratory rates up to day 21. At 21?days after IT bleomycin, TG mice had increased lung macrophage accumulation. Lavage HA concentrations were 6-fold higher in injured WT mice, but 30-fold higher in injured TG mice. At 21?days after IT bleomycin, WT mice had developed fibrosis, but TG mice showed exaggerated fibrosis with increased Ashcroft scores and HPO content. We conclude that RHAMM is a critical component of the inflammatory response, respiratory distress and fibrosis after acute lung injury. We speculate that RHAMM is a potential therapeutic target to limit the consequences of acute lung injury.

Dataset Information

Expression and role of the hyaluronan receptor RHAMM in inflammation after bleomycin injury.

Publications

Expression and role of the hyaluronan receptor RHAMM in inflammation after bleomycin injury.

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