Respiratory syncytial virus infection increases chlorine-induced airway hyperresponsiveness

Abstract

-Exposure to chlorine (Cl2) 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 Cl2-induced lung injury. By using a murine respiratory syncytial virus (RSV) infection model, we found that preexisting RSV infection increases Cl2 (187 ppm for 30 min)-induced lung inflammation and airway AHR at 24 h after exposure (5 days after infection). RSV infection and Cl2 exposure synergistically induced oxygen desaturation and neutrophil infiltration and increased MCP-1, MIP-1␤, IL-10, IFN-␥, 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 Cl2 exposure. Cl2 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 Cl2-induced AHR was mitigated by treatment with inter-␣-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 Cl2-induced injury. These data emphasize the necessity for further research on the effects of Cl2 in vulnerable populations and the development of appropriate treatments. flexiVent; methacholine; bronchoalveolar lavage; cytokines; inflammatory cells CHLORINE (Cl 2 ) is an irritant and reactive gas with significant occupational and environmental hazard concerns due to its wide industrial and domestic usage. Spillage of Cl 2 in the environment during accidents or terrorist acts may result in significant morbidity and mortality to animals and humans (2,15,34,38). Exposure of animals to Cl 2 at concentrations comparable to the vicinity of industrial accidents damages airway epithelia and results in sloughing of airway mucosa, increased alveolar permeability, decreased ability of alveolar epithelial cells to clear fluid, damage to the pulmonary surfactant system (2, 5, 18, 33), coagulation abnormalities (42), and extensive systemic injury (1, 28). Animals surviving the initial exposure show significant structural and functional abnormalities, including the presence of foamy alveolar macrophages, patchy areas of ciliated airway cells (25,26), the presence of excess amounts of goblet cells, hyperplasia and airway hyperreactivity (11), and inability to clear inhaled fungi (15). These injuries may result from chemical reactions of Cl 2 and hypochlorous acid (HOCl), as well as various secondary reaction products, like chloramines (1, 33), chlorinated fatty acid, and low-molecular-weight hyaluronan (HA), a proinflammatory fragment generated by the fractionation of HA (19,21).Currently, little is known about the effects of previous existing respiratory infections on the subsequent Cl 2 -induced lung injury. Herein...

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