Respiratory syncytial virus infection increases chlorine-induced airway hyperresponsiveness

Exposure to chlorine (Cl-2) damages airway and alveolar epithelia resulting in acute lung injury and reactive airway hyperresponsiveness (AHR) to methacholine. However, little is known about the effect of preexisting respiratory disease on Cl-2-induced lung injury. By using a murine respiratory syncytial virus (RSV) infection model, we found that preexisting RSV infection increases Cl-2 (187 ppm for 30 min)-induced lung inflammation and airway AHR at 24 h after exposure (5 days after infection). RSV infection and Cl-2 exposure synergistically induced oxygen desaturation and neutrophil infiltration and increased MCP-1, MIP-1 beta, IL-10, IFN-gamma, and RANTES concentrations in the bronchoalveolar lavage fluid (BALF). In contrast, levels of type 2 cytokines (i.e., IL-4, IL-5, IL-9, and IL-13) were not significantly affected by either RSV infection or Cl-2 exposure. Cl-2 exposure, but not RSV infection, induced AHR to methacholine challenge as measured by flexiVent. Moreover, preexisting RSV infection amplified BALF levels of hyaluronan (HA) and AHR. The Cl-2-induced AHR was mitigated by treatment with inter-alpha-trypsin inhibitor antibody, which inhibits HA signaling, suggesting a mechanism of HA-mediated AHR from exacerbated oxidative injury. Our results show for the first time that preexisting RSV infection predisposes the lung to Cl-2-induced injury. These data emphasize the necessity for further research on the effects of Cl-2 in vulnerable populations and the development of appropriate treatments.