IL-33 modulates chronic airway resistance changes induced by multi-walled carbon nanotubes

Objective: Instillation of multi-walled carbon nanotubes (MWCNTs) in C57BL/6 mice results in decrements of pulmonary function specifically characterized by increases in airway resistance. In this study, we examined possible mechanisms responsible for these alterations following MWCNT exposure, including the roles of IL-33 and chronic inflammation. Materials and methods: To elucidate the role of IL-33, we assessed lung histology and pulmonary function in C57BL/6 and IL-33(-/-) mice 30 days following MWCNT instillation. In addition, the impact of MWCNT instillation on airway hyperresponsiveness (AHR) was assessed by methacholine challenges of C57BL/6 and IL-33(-/-) mice. To further understand the mechanisms by which MWCNTs may increase airway constriction, C57BL/6 mice were treated with aerosolized albuterol or injected with multiple doses of methylprednisolone via intraperitoneal injections prior to the assessment of MWCNT-induced changes in pulmonary function. Results: Total cell count, macrophages, and neutrophils were increased in the lavage fluid of C57BL/6 mice, but not in IL-33(-/-) mice, following MWCNT exposure. C57BL/6 mice displayed increased inflammation and fibrosis located proximal to the airways which was absent in IL-33(-/-) mice. Aerosolized methacholine increased parameters of airway resistance (R and Rn) in a dose-dependent manner in all groups, with MWCNT-instilled C57BL/6 mice responding more robustly compared to the controls, while no differences were found in IL-33(-/-) mice due to MWCNT exposure. Treatment with methylprednisolone reduced both the MWCNT-induced histopathological changes and increases in R and Rn in C57BL/6 mice. Conclusion: These findings suggest that IL-33 and chronic inflammation in general are critical in the pulmonary toxicity induced by MWCNT resulting in modified pulmonary function.