Cysteinyl leukotriene 1 receptor controls the severity of chronic pulmonary inflammation and fibrosis

The cysteinyl leukotrienes (cys-LTs), leukotriene (LT) C-4, LTD4, and LTE4, are smooth muscle constrictors that signal via the CysLT(1) receptor. Here we report that the cys-LTs play an important role in chronic pulmonary inflammation with fibrosis induced by bleomycin in mice. Targeted disruption of LTC4 synthase, the pivotal enzyme for cys-LT biosynthesis, protected significantly against alveolar septal thickening by macrophages and fibroblasts and collagen deposition. In contrast, targeted disruption of the CysLT(1) receptor significantly increased both the concentration of cys-LTs in the bronchoalveolar lavage fluid and the magnitude of septal thickening as defined by morphology, digital image analysis, and deposition of reticular fibers. These findings change our understanding of the pathobiology mediated by the cys-LTs by revealing their role in chronic inflammation with fibrosis, likely via the CysLT(2) receptor, and by uncovering a dual role for the CysLT(1) receptor, namely proinflammatory acute constriction of smooth muscle and antiinflammatory counteraction of chronic injury.