[CXCR2-Airway Inflammation]
CXCR2 Regulates Respiratory Syncytial Virus-Induced Airway Hyperreactivity and Mucus Overproduction1
Allison L. Miller*, Robert M. Strieter, Achim D. Gruber, Samuel B. Ho and Nicholas W. Lukacs2,*
* Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; Department of Pulmonary and Critical Care Medicine, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095; Department of Pathology, School of Veterinary Medicine Hannover, Hannover, Germany; and Department of Medicine, Veterans Affairs Medical Center and University of Minnesota, Minneapolis, MN 55417
Severe inflammation and mucus overproduction are partially responsible for respiratory syncytial virus (RSV)-induced disease in infants. Using a murine model, we characterized the virally induced chemokine receptors responsible for mediating the pathophysiological response to RSV infection, we found that CXCR2 mRNA was induced at 4 days after RSV infection. Immunohistochemical staining demonstrated that CXCR2 protein was expressed on alveolar macrophages. Immunoneutralization of CXCR2 resulted in decreased airway hyperreactivity relative to the RSV-infected controls. In addition, there was decreased mucus in the bronchoalveolar lavage fluid, decreased periodic-acid Schiff staining, and significantly less mucus-associated gob-5 mRNA and protein in anti-CXCR2-treated mice. The effects of anti-CXCR2 treatment were not a result of differences in viral clearance or neutrophil influx, as these parameters were comparable in both groups of animals. To confirm our immunoneutralization studies, we performed experiments in CXCR2-/- mice. Results in CXCR2-/- mice recapitulated results from our immunoneutralization studies. However, CXCR2-/- mice also showed a statistically significant decrease in muc5ac, relative to RSV-infected wild-type animals. Thus, CXCR2 may be a relevant target in the pathogenesis of RSV bronchiolitis, since it contributes to mucus production and airway hyperreactivity in our model of RSV infection. |
