BLT1 Mediates Bleomycin-Induced Lung Fibrosis Independently of Neutrophils and CD4+ T Cells

Leukotriene B (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.