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.
This work was supported by National Natural Science Foundation of China Grant 813220437 (to R.H.), Shuguang Project 13SG03 (to R.H.), and by State Key Basic Research Program (973) Project 2015CB553404 (to R.H.).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- airway epithelial cell
- bronchoalveolar lavage fluid
- bone marrow–derived macrophage
- cysteinyl leukotriene
- idiopathic pulmonary fibrosis
- leukotriene A4 hydrolase
- leukotriene B4
- α smooth muscle actin
- Received March 18, 2016.
- Accepted December 12, 2016.
- Copyright © 2017 by The American Association of Immunologists, Inc.