RT Journal Article
SR Electronic
T1 Therapeutic efficacy of a novel LPA1 receptor antagonist, UD-009, in a bleomycin-induced pulmonary fibrosis model
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP PA4032
DO 10.1183/13993003.congress-2016.PA4032
VO 48
IS suppl 60
A1 Kenji Nishikawa
A1 Eiji Okanari
A1 Yuuko Shinohara
A1 Hironobu Matsunaga
A1 Hiroshi Nishida
A1 Noriaki Iwase
A1 Shigeru Ushiyama
YR 2016
UL http://erj.ersjournals.com/content/48/suppl_60/PA4032.abstract
AB Background: Lysophosphatidic acid (LPA) is known as a fibrotic lipid mediator. Mice lacking LPA1 receptor or treated with a LPA1 antagonist are protected from bleomycin (BLM)-induced pulmonary fibrosis. However, the therapeutic efficacy has not yet been reported. Therefore we evaluated therapeutic effect of LPA antagonism and a role of LPA in the later fibrotic phase of BLM model using a novel LPA1 antagonist, UD-009.Methods: Potency and selectivity of UD-009 were assessed with recombinant LPA receptors and in normal human lung fibroblasts. In a BLM model, animals were administered with BLM i.v. for 5 days from day 0, and treated with UD-009 (30 mg/kg, p.o., b.i.d.) either from day 0 to 28 for prophylactic assay or from day 14 to 28 for therapeutic assay. The differentiation of fibroblasts was assessed by using primary cultured fibroblasts isolated from the lungs of BLM-injured mice by staining with anti-α-SMA antibody.Results: UD-009 is a potent and selective LPA1 antagonist. Prophylactic treatment of UD-009 significantly reduced collagen accumulation in the BLM model. Interestingly, UD-009 showed inhibition predominantly in the later phase of the model. Primary cultured fibroblasts isolated from the lungs of the BLM-injured mice receiving UD-009 decreased the expression of α-SMA compared to the control. Moreover, therapeutic treatment of UD-009 caused almost same effects as those of the prophylactic treatment.Conclusions: UD-009 is a newly identified LPA1 antagonist and shows clear therapeutic efficacy by restraining the fibrotic phase when the fibroblasts are activated and differentiated. LPA may therefore control progression of fibrotic disorders in IPF.