Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma

Abstract

Objective. Scleroderma (systemic sclerosis [SSc]), is characterized by progressive multiorgan fibrosis. We recently implicated lysophosphatidic acid (LPA) in the pathogenesis of pulmonary fibrosis. The purpose of the present study was to investigate the roles of LPA and two of its receptors, LPA 1 and LPA 2 , in dermal fibrosis in a mouse model of SSc.Methods. Wild type (WT), and LPA 1 -knockout (KO) and LPA 2 -KO mice were injected subcutaneously with bleomycin or phosphate buffered saline (PBS) once daily for 28 days. Dermal thickness, collagen content, and numbers of cells positive for ␣-smooth muscle actin (␣-SMA) or phospho-Smad2 were determined in bleomycin-injected and PBS-injected skin. In separate experiments, a novel selective LPA 1 antagonist AM095 or vehicle alone was administered by oral gavage to C57BL/6 mice that were challenged with 28 daily injections of bleomycin or PBS. AM095 or vehicle treatments were initiated concurrently with, or 7 or 14 days after, the initiation of bleomycin and PBS injections and continued to the end of the experiments. Dermal thickness and collagen content were determined in injected skin.Results. The LPA 1 -KO mice were markedly resistant to bleomycin-induced increases in dermal thickness and collagen content, whereas the LPA 2 -KO mice were as susceptible as the WT mice. Bleomycin-induced increases in dermal ␣-SMA؉ and phospho-Smad2؉ cells were abrogated in LPA 1 -KO mice. Pharmacologic antagonism of LPA 1 with AM095 significantly attenuated bleomycin-induced dermal fibrosis when administered according to either a preventive regimen or two therapeutic regimens.Conclusion. These results suggest that LPA/LPA 1 pathway inhibition has the potential to be an effective new therapeutic strategy for SSc, and that LPA 1 is an attractive pharmacologic target in dermal fibrosis.

BET Bromodomain Proteins Mediate Downstream Signaling Events following Growth Factor Stimulation in Human Lung Fibroblasts and Are Involved in Bleomycin-Induced Pulmonary Fibrosis

“…Targeting the epigenetic machinery of the LF to effect chromatin remodeling may provide significantly improved efficacy over more targeted pathway-based approaches. Indeed, we have also demonstrated, in addition to the TGF-b and PDGF-BB signaling pathways, that the lysophosphatidic acid pathway, which has recently generated substantial academic and research attention as an important pathway mediating organ fibrosis (Swaney et al, 2010;Castelino et al, 2011;Swaney et al, 2011), induces proliferation of LFs that can be inhibited by pretreating cells with Brd inhibitors (Supplemental Fig. 2).…”

Lysophosphatidic Acid Signaling through the Lysophosphatidic Acid-1 Receptor Is Required for Alveolarization

“…We have previously implicated LPA-LPA 1 signaling in the development of fibrosis in multiple organs, including the lung (6,42), the skin (43), and the peritoneum (44), whereas others have implicated this pathway in renal and hepatic fibrosis (45,46). In the development of organ fibrosis, we have found that LPA-LPA 1 signaling promotes fibroblast recruitment, proliferation, activation, and persistence (5,6,44).…”

LPA receptor signaling: pharmacology, physiology, and pathophysiology

“…Reduced Smad2 prevented the activation of pro-fi brotic factors TGF-␤, CTGF, and PDGF-␤. Another model simulated dermal fi brosis in the mouse by measuring changes in collagen content and dermal thickness (254). This study showed that the fi brosis was prevented in Lpar1 Ϫ/Ϫ mice and its severity reduced by administration of the LPA 1 antagonist AM095.…”