TGF-b is a known profibrotic protein and is considered a key player in the pathogenesis of fibrosis. It is synthesized by different cell types, such as monocytes, lymphocytes, or eosinophils, which are recruited to the site of injury or inflammation. It induces the transformation of fibroblasts into myofibroblasts, which are able to secrete TGF-b and stimulate extracellular matrix deposition. CTGF is another important fibrogenic factor. Because CTGF is potently induced by TGF-b, it is considered a downstream mediator of TGF-b1 responses, although some studies suggest that CTGF has a profibrotic effect independent of TGF-b1. Lasky et al. reported an increase in CTGF mRNA expression in both human and murine lung fibroblasts stimulated with TGF-b in vitro, and CTGF mRNA expression was up-regulated in bleomycin-induced lung fibrosis in mice in vivo. Our analysis of BALF showed a reduction in CTGF production without a decrease in TGF-b concentration in S1P3-deficient mice in which lung fibrosis was attenuated. This reduction of fibrosis in S1P3 KO mice may be due to a decrease in the number of total cells followed by a reduction in CTGF concentration in BALF; however, it cannot explain fully the dissociation of CTGF and TGF-b concentrations in BALF. Several in vitro reports suggest that cross-talk occurs between S1P and TGF-b signaling. Xin et al. reported that S1P transactivated the TGF-b receptor and triggered activation of Smads followed by CTGF gene transcription in renal mesangial cells. Cencetti et al. showed that TGF-b1 up-regulated sphingosine kinase-1 in C2C12 myoblasts in a Smad-dependent manner and concomitantly induced high levels of S1P3 expression. They also reported that inhibition of S1P3 strongly attenuated the profibrotic response to TGF-b1. Lowe et al. demonstrated that TGF-b-stimulated collagen production in cardiac fibroblasts involves S1P Solifenacin HCl signaling, whereby intracellular S1P Sulfameter produced by SphK1 is released and acts in an autocrine/paracrine fashion to increase collagen production. Milara et al. reported that transformation of alveolar type II cells to mesenchymal cells was induced via S1P2 and S1P3 activation.