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Chlorine is a chemical threat agent that can be harmful to humans. Acute inhalation of high levels of chlorine results in the death of airway epithelial cells and can lead to persistent adverse effects on respiratory health, including airway remodeling and hyperreactivity. We previously developed a mouse chlorine exposure model in which animals developed inflammation and fibrosis in large airways. In the present study, examination by laser capture microdissection of developing fibroproliferative lesions in FVB/NJ mice exposed to 240ppm-h chlorine revealed upregulation of genes related to macrophage function. Treatment of chlorine-exposed mice with the corticosteroid drug budesonide daily for 7days (30–90μg/mouse i.m.) starting 1h after exposure prevented the influx of M2 macrophages and the development of airway fibrosis and hyperreactivity. In chlorine-exposed, budesonide-treated mice 7days after exposure, large airways lacking fibrosis contained extensive denuded areas indicative of a poorly repaired epithelium. Damaged or poorly repaired epithelium has been considered a trigger for fibrogenesis, but the results of this study suggest that inflammation is the ultimate driver of fibrosis in our model. Examination at later times following 7-day budesonide treatment showed continued absence of fibrosis after cessation of treatment and regrowth of a poorly differentiated airway epithelium by 14days after exposure. Delay in the start of budesonide treatment for up to 2days still resulted in inhibition of airway fibrosis. Our results show the therapeutic potential of budesonide as a countermeasure for inhibiting persistent effects of chlorine inhalation and shed light on mechanisms underlying the initial development of fibrosis following airway injury.Fibrotic lesions in chlorine-exposed mouse lungs had large gene expression changes.Pro-inflammatory gene expression suggested benefits of anti-inflammatory therapy.The corticosteroid budesonide inhibited chlorine-induced airway fibrosis in mice.Budesonide inhibited fibrosis even in the absence of efficient epithelial repair.Inflammation rather than epithelial damage may drive fibrogenesis in this model.