Chlorine gas (CI2) is a readily available chemical warfare agent that causes a dose-dependent toxicity to pulmonary and other mucosal tissues. The major toxicity of CI2 exposure is oxidative damage of lung tissues that is thought to be due to the direct effects of CI2 reaction products combined with inflammatory mediators released by lung-infiltrating leukocytes. This proposed mechanism has not been clearly demonstrated but raises the possibility that inhibition of pulmonary inflammation following CI2 exposure will reduce subsequent morbidity and mortality. Our laboratory has identified the cells and the cell migration events that lead to immune-mediated lung damage, morbidity, and mortality during viral and bacterial infections. Our preliminary studies demonstrate that a similar pattern of inflammation occurs after chlorine exposure. These findings suggest that chlorine-induced lung injury could be substantially lessened using a specific chemokine receptor antagonist. Importantly, a pharmacologic antagonist for the chemokine receptor we have identified has already been developed and proven to be safe and effective in early clinical trials for other indications. This raises the possibility that a drug already exists that would reduce the morbidity and mortality of chlorine exposure in humans. In a series of murine studies, we will determine the extent to which specific pulmonary inflammatory cell types contribute to chlorine-induced lung injury and the consequent epithelial damage, bronchial reactivity, morbidity, and mortality. We will then examine the ability of the chemokine receptor antagonist to reduce these toxicities. These studies will provide a basis for determining if trials of chemokine receptor antagonists should be considered in humans.
|Tata, Aleksandra; Kobayashi, Yoshihiko; Chow, Ryan D et al. (2018) Myoepithelial Cells of Submucosal Glands Can Function as Reserve Stem Cells to Regenerate Airways after Injury. Cell Stem Cell 22:668-683.e6|
|Tadokoro, Tomomi; Gao, Xia; Hong, Charles C et al. (2016) BMP signaling and cellular dynamics during regeneration of airway epithelium from basal progenitors. Development 143:764-73|
|O'Koren, Emily G; Hogan, Brigid L M; Gunn, Michael Dee (2013) Loss of basal cells precedes bronchiolitis obliterans-like pathological changes in a murine model of chlorine gas inhalation. Am J Respir Cell Mol Biol 49:788-97|