title: BLT1 Mediates Bleomycin-Induced Lung Fibrosis Independently of Neutrophils and CD4+ T Cells.
abstract: Leukotriene B4(LTB4) and its functional receptor BLT1 are closely involved in tissue inflammation by primarily mediating leukocyte recruitment and activation. Elevated LTB4 was reported in patients with lung fibrosis; however, the role of the LTB4/BLT1 axis in lung fibrosis remains unknown. In this study, we demonstrated that BLT1-/-mice exhibited significantly attenuated bleomycin (BLM)-induced lung fibrosis. Interestingly, BLT1 blockade with its specific antagonist U75302 in the acute injury phase (days 0-10 after BLM treatment) significantly attenuated lung fibrosis, which was accompanied by significant decreases in early infiltrating neutrophils and later infiltrating CD4+T cells and the production of TGF-β, IL-13, and IL-17A. In contrast, BLT1 blockade in the fibrotic phase (days 10-21 after BLM treatment) had no effect on lung fibrosis and TGF-β production, although it significantly decreased CD4+T cell infiltration. Furthermore, depletion of neutrophils or CD4+T cells had no effect on BLM-induced lung fibrosis, suggesting the independence of profibrotic activity of the LTB4/BLT1 axis on BLT1-dependent lung recruitment of these two leukocytes. Finally, although BLT1 blockade had no effect on the recruitment and phenotype of macrophages in BLM-induced lung fibrosis, the LTB4/BLT1 axis could promote TGF-β production by macrophages stimulated with BLM or supernatants from BLM-exposed airway epithelial cells in an autocrine manner, which further induced collagen secretion by lung fibroblasts. Collectively, our study demonstrates that the LTB4/BLT1 axis plays a critical role in acute injury phase to promote BLM-induced lung fibrosis, and it suggests that early interruption of the LTB4/BLT1 axis in some inflammatory diseases could prevent the later development of tissue fibrosis.
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China; and.|Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Jiaoyan
authors.initials: J
authors.lastname: Lv
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China; and.|Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Yingluo
authors.identifier: 0000-0003-3421-2119
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China; and.|Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China; and.|Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China; and.|Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Lina
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China; and ruihe@fudan.edu.cn.|Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China ruihe@fudan.edu.cn.
authors.forename: Rui
authors.identifier: 0000-0001-5288-9786
authors.initials: R
authors.lastname: He
mesh_terms: D000818:Animals; D001761:Bleomycin; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D005233:Fatty Alcohols / Q000008:administration & dosage; D006018:Glycols / Q000008:administration & dosage; D007249:Inflammation; D018793:Interleukin-13 / Q000096:biosynthesis / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology* / Q000502:physiology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control; D018102:Receptors, Leukotriene B4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000276:immunology
chemical_list: D005233:Fatty Alcohols; D006018:Glycols; D018793:Interleukin-13; D020381:Interleukin-17; C503704:Ltb4r1 protein, mouse; D018102:Receptors, Leukotriene B4; D016212:Transforming Growth Factor beta; D001761:Bleomycin; C062137:U 75302