BACKGROUND: Respiratory
viral infections are characterized by the infiltration of leukocytes, including activated neutrophils into the lung that can lead to sustained
lung injury and potentially contribute to chronic
lung disease. Specific mechanisms recruiting neutrophils to the lung during virus-induced
lung inflammation and injury have not been fully elucidated. Since CXCL1 and CXCL2/3, acting through CXCR2, are potent neutrophil
chemoattractants, we investigated their role in dsRNA-induced
lung injury, where dsRNA (Poly IC) is a well-described synthetic agent mimicking acute
viral infection. METHODS: We used 6-8 week old female BALB/c mice to intratracheally inject either single-stranded (ssRNA) or
double-stranded RNA (dsRNA) into the airways. The lungs were then harvested at designated timepoints to characterize the elicited
chemokine response and resultant
lung injury following dsRNA exposure as demonstrated qualititatively by histopathologic analysis, and quantitatively by FACS,
protein, and
mRNA analysis of BAL fluid and tissue samples. We then repeated the experiments by first pretreating mice with an anti-PMN or corresponding control antibody, and then subsequently pretreating a separate cohort of mice with an anti-CXCR2 or corresponding control antibody prior to dsRNA exposure. RESULTS: Intratracheal dsRNA led to significant increases in neutrophil infiltration and
lung injury in BALB/c mice at 72 h following dsRNA, but not in response to ssRNA (
Poly C; control) treatment. Expression of CXCR2
ligands and CXCR2 paralleled neutrophil recruitment to the lung. Neutrophil depletion studies significantly reduced neutrophil infiltration and
lung injury in response to dsRNA when mice were pretreated with an anti-PMN monoclonal Ab. Furthermore, inhibition of CXCR2
ligands/CXCR2 interaction by pretreating dsRNA-exposed mice with an anti-CXCR2 neutralizing Ab also significantly attenuated neutrophil sequestration and
lung injury. CONCLUSION: These findings demonstrate that
CXC chemokine ligand/CXCR2 biological axis is critical during the pathogenesis of dsRNA-induced
lung injury relevant to acute
viral infections.