The cysteinyl leukotrienes (cys-LTs) mediate both acute and chronic inflammatory responses in mice, as demonstrated by the attenuation of the IgE/antigen-mediated increase in microvascular permeability and of bleomycin-induced pulmonary fibrosis, respectively, in a strain with targeted disruption of leukotriene C 4 synthase to prevent cys-LT synthesis. Our earlier finding that the acute, but not the chronic, injury was attenuated in a strain with targeted disruption of the cysteinyl leukotriene 1 (CysLT 1 ) receptor suggested that the chronic injury might be mediated through the CysLT 2 receptor. Thus, we generated CysLT 2 receptor-deficient mice by targeted gene disruption. These mice developed normally and were fertile. The increased vascular permeability associated with IgE-dependent passive cutaneous anaphylaxis was significantly reduced in CysLT 2 receptor-null mice as compared with wild-type mice, whereas plasma protein extravasation in response to zymosan A-induced peritoneal inflammation was not altered. Alveolar septal thickening after intratracheal injection of bleomycin, characterized by interstitial infiltration with macrophages and fibroblasts and the accumulation of collagen fibers, was significantly reduced in CysLT 2 receptor-null mice as compared with the wild-type mice. The amounts of cys-LTs in bronchoalveolar lavage fluid after bleomycin injection were similar in the CysLT 2 receptor-null mice and the wildtype mice. Thus, in response to a particular pathobiologic event the CysLT 2 receptor can mediate an increase in vascular permeability in some tissues or promote chronic pulmonary inflammation with fibrosis.The cysteinyl leukotrienes (cys-LTs), 1 leukotriene (LT) C 4 , LTD 4 , and LTE 4 , are lipid mediators (1, 2) that have been implicated in the pathobiology of allergic and asthmatic inflammatory responses on the basis of the efficacy of specific intervention with a biosynthetic inhibitor (3) or antagonists to a receptor subsequently shown to be the cysteinyl leukotriene 1 (CysLT 1 ) receptor (4). Two types of human receptors for cys-LTs, designated CysLT 1 receptor and CysLT 2 receptor, belonging to the seventransmembrane, G protein-coupled receptor family, were cloned and shown to be 38% homologous in their amino acid sequences (5-9). The rank order of affinities of the cys-LTs for the CysLT 1 and CysLT 2 receptors is LTD 4 Ͼ LTC 4 Ͼ LTE 4 Ͼ Ͼ LTB 4 and LTC 4 ϭ LTD 4 Ͼ Ͼ LTE 4 Ͼ Ͼ LTB 4 , respectively. The CysLT 1 receptor is expressed on airway smooth muscle, monocytes/ macrophages, eosinophils (5, 10, 11), a subset of neutrophils (11), mast cells (12, 13), and endothelial cells (14). The CysLT 2 receptor is expressed on monocyte/macrophages, airway smooth muscle, cardiac Purkinje cells, adrenal medulla cells, peripheral blood leukocytes, brain cells (7), eosinophils (11, 15), mast cells (16), and endothelial cells (17,18). We and others have reported that the mouse CysLT 1 receptor can function as a receptor for LTD 4 in transfected cells with a ligand preference similar to that of the...

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...