The development of bleomycin-induced lung injury, which is a model of pulmonary fibrosis, results from inflammatory cell infiltration, a process highly regulated by the expression of multiple adhesion molecules. Therefore, bleomycin-induced lung fibrosis was examined in E-selectin-/- mice, P-selectin-/- mice, and E-selectin-/- mice treated with anti-P-selectin monoclonal antibody (mAb) in comparison of wild-type mice. E-selectin-/- mice treated with anti-P-selectin mAb exhibited augmented lung fibrosis histologically, increased lung collagen deposition, and increased mortality compared to wild-type mice. Furthermore, lung interferon-gamma mRNA expression decreased in E-selectin-/- mice treated with anti-P-selectin mAb relative to wild-type mice, while tumor necrosis factor-alpha and interleukin-6 mRNA expression increased in these mice. Similar changes were observed in E-selectin-/- mice, albeit to a lesser extent than those treated with anti-P-selectin mAb. Remarkably, flow cytometric analysis revealed that the frequency of interferon-gamma-producing natural killer T (NKT) cells in the bronchoalveolar lavage was decreased in E-selectin-/- mice and E-selectin-/- mice treated with anti-P-selectin mAb compared with wild-type mice. Moreover, the majority of NKT cells expressed high levels of CXCR3, suggesting that NKT cell infiltration is also dependent on CXCR3 expression. These results suggest that E- and P-selectins synergistically inhibit lung fibrosis by promoting the recruitment of NKT cells.