CXCR2 regulates respiratory syncytial virus-induced airway hyperreactivity and mucus overproduction.
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.
Miller
Allison L
AL
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Strieter
Robert M
RM
Gruber
Achim D
AD
Ho
Samuel B
SB
Lukacs
Nicholas W
NW
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control / Q000821:virology; D001990:Bronchiolitis, Viral / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control / Q000821:virology; D004195:Disease Models, Animal; D005260:Female; D020397:Goblet Cells / Q000276:immunology / Q000473:pathology; D006801:Humans; D007106:Immune Sera / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D008679:Metaplasia; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009093:Mucus / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000276:immunology; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000502:physiology*
D007106:Immune Sera; D023063:Receptors, Interleukin-8B