Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma.
Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma.
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在硬皮病小鼠模型中通过基因缺失或溶血磷脂酸受体 1 的药理学拮抗作用改善真皮纤维化。
DOI：
10.1002/art.30262
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发表时间：
2011-05
影响因子：
--
通讯作者：
Tager, Andrew M.
中科院分区：
文献类型：
--
作者：
Castelino, Flavia V.;Seiders, Jon;Bain, Gretchen;Brooks, Sarah F.;King, Christopher D.;Swaney, James S.;Lorrain, Daniel S.;Chun, Jerold;Luster, Andrew D.;Tager, Andrew M.
硬皮病，或系统性硬化症(SSC)，以进行性多器官纤维化为特征。我们最近发现溶血磷脂酸(LPA)与肺纤维化的发病机制有关。在这里，我们研究了LPA及其两个受体LPA1和LPA2在SSC小鼠模型真皮纤维化中的作用。野生型(WT)和LPA1和LPA2缺陷型(LPA1KO和LPA2KO)小鼠皮下注射博莱霉素或PBS，每日1次，共28次。测定注射博莱霉素和α的皮肤真皮厚度、胶原含量和α-Smad2+或Smad2+细胞数。在单独的实验中，一种新型的选择性LPA1拮抗剂AM095，或单独的赋形剂，通过口服给C57BL/6小鼠灌胃，每天28次注射博莱霉素或PBS。AM095或赋形剂治疗与博莱霉素和PBS注射同时开始，或在开始注射博莱霉素和PBS后7天或14天开始，并持续到实验结束。注射皮肤测定真皮厚度和胶原含量。LPA1 KO小鼠对博莱霉素诱导的真皮厚度和胶原蛋白的增加具有明显的抵抗力，而LPA2 KO小鼠与WTS小鼠一样敏感。博莱霉素诱导的LPA1KO小鼠真皮α、Sma+和Smad2+细胞数量的增加均被抑制。LPA1与AM095的药理拮抗作用显著减轻了博莱霉素引起的皮肤纤维化，无论是预防还是治疗方案。这些结果表明，抑制LPA-LPA1通路有可能成为治疗硬皮病的有效新策略，LPA1是治疗真皮纤维化的可用药靶点。
Scleroderma, or systemic sclerosis (SSc), is characterized by progressive multi-organ fibrosis. We recently implicated lysophosphatidic acid (LPA) in the pathogenesis of pulmonary fibrosis. Here we investigated the roles of LPA and two of its receptors, LPA1 and LPA2, in dermal fibrosis in a mouse model of SSc. Wild type (WT) and LPA1- and LPA2-deficient (LPA1 KO and LPA2 KO) mice were injected subcutaneously with bleomycin or PBS once daily for 28 doses. Dermal thickness, collagen content, and numbers of α-smooth muscle actin (αSMA)+ or phosphoSmad2+ cells were determined in bleomycin- and PBS-injected skin. In separate experiments, a novel selective LPA1 antagonist AM095, or vehicle alone, was administered by oral gavage to C57Bl/6 mice challenged with 28 daily injections of bleomycin or PBS. AM095 or vehicle treatments were initiated concurrently with, or 7 or 14 days after the onset of bleomycin and PBS injections, and continued to the end of the experiments. Dermal thickness and collagen content were determined in injected skin. LPA1 KO mice were markedly resistant to bleomycin-induced increases in dermal thickness and collagen, whereas LPA2 KO mice were as susceptible as WTs. Bleomycin-induced increases in dermal αSMA+ and phosphoSmad2+ cells were abrogated in LPA1 KO mice. Pharmacological antagonism of LPA1 with AM095 significantly attenuated bleomycin-induced dermal fibrosis when administered in either ‘preventive’ or ‘therapeutic’ regimens. These results suggest that LPA-LPA1 pathway inhibition has the potential to be an effective new therapeutic strategy for scleroderma, and that LPA1 is a druggable target for dermal fibrosis.
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影响因子：
6
作者：
Lakos, G;Takagawa, S;Varga, J
通讯作者：
Varga, J
DOI：
10.1083/jcb.130.3.725
发表时间：
1995-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kundra V;Anand-Apte B;Feig LA;Zetter BR
通讯作者：
Zetter BR
DOI：
10.1073/pnas.97.24.13384
发表时间：
2000-11-21
影响因子：
11.1
作者：
Contos, JJA;Fukushima, N;Chun, J
通讯作者：
Chun, J
硬皮病皮肤的基因表达特征中的分子亚群。
影响因子：
3.7
作者：
Milano A;Pendergrass SA;Sargent JL;George LK;McCalmont TH;Connolly MK;Whitfield ML
通讯作者：
Whitfield ML
影响因子：
4.1
作者：
Fang, XJ;Yu, SX;Mills, GB
通讯作者：
Mills, GB