The cysteinyl leukotrienes (cys-LTs), leukotriene (LT) C4, LTD4, and LTE 4 , 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 LTC 4 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 CysLT1 receptor, namely proinflammatory acute constriction of smooth muscle and antiinflammatory counteraction of chronic injury.T he cysteinyl leukotrienes (cys-LTs), originally termed slow reacting substance (SRS) because of the gradual progression of their contractile response in smooth muscle relative to the brisk action elicited by histamine (1-3), were viewed only as smooth muscle agonists after their structural definition (4) and chemical synthesis (5). When inhaled, cys-LTs constrict human normal or asthmatic airways with a thousand times the potency of histamine (6-8). They also are more active in eliciting an intradermal wheal and flare response (9). Their role in the pathobiology of bronchial asthma was established by the therapeutic efficacy of agents that block their biosynthesis or their action at a receptor defined by transmission of a smooth muscle response (10, 11).The cys-LTs are generated after arachidonic acid is released from the outer nuclear membrane of cells by cytosolic phospholipase A 2 and converted to the epoxide leukotriene (LT) A 4 by 5-lipoxygenase (5-LO) in the presence of the 5-LO activating protein (12). An integral perinuclear membrane protein, LTC 4 synthase (LTC 4 S), conjugates reduced glutathione to LTA 4 to form LTC 4 (13, 14). After carrier-mediated export (15), LTC 4 is converted to additional receptor-active metabolites, LTD 4 and LTE 4 , by the sequential cleavage from the tripeptide adduct of glutamate (16, 17) and glycine. Alternatively, LTA 4 can be converted by LTA 4 hydrolase to a dihydroxy LT, LTB 4 . Two receptors for the cys-LTs, CysLT 1 receptor and CysLT 2 receptor, have been cloned for the human (18-22) and the mouse (23-25).The therapeutic agents developed for the management of bronchial asthma at the receptor level block the agonist activity of the cys-LTs at the CysLT 1 receptor and not at the CysLT 2 receptor. Targeted disruption of either LTC 4 S or the CysLT 1 receptor elicits marked and comparable attenuation of IgEdependent, mast cell-mediated passive cutaneous anaphylaxis and of zymosan-elicited i...