Knockout of endothelial cell-derived endothelin-1 attenuates skin fibrosis but accelerates cutaneous wound healing.
Knockout of endothelial cell-derived endothelin-1 attenuates skin fibrosis but accelerates cutaneous wound healing.
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DOI：
10.1371/journal.pone.0097972
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ihn H
中科院分区：
文献类型：
--
作者：
Makino K;Jinnin M;Aoi J;Kajihara I;Makino T;Fukushima S;Sakai K;Nakayama K;Emoto N;Yanagisawa M;Ihn H
内皮素(ET)-1是已知的最有效的血管收缩多肽，主要由内皮细胞释放。已有多项研究报道ET-1信号参与伤口愈合或纤维化以及血管扩张过程。然而，人们对ET-1在这些过程中的作用知之甚少。为了阐明其机制，我们比较了血管内皮细胞特异性ET-1基因敲除小鼠和它们的野生型小鼠的皮肤纤维化形成和伤口修复。与野生型小鼠相比，注射博莱霉素基因敲除小鼠的纤维化皮肤显示出显著的皮肤厚度和胶原含量降低，这表明博莱霉素诱导的皮肤纤维化在基因敲除小鼠中得到缓解。ET-1基因敲除小鼠皮肤经博莱霉素处理后，转化生长因子-β基因表达水平降低。另一方面，ET-1基因敲除小鼠的皮肤伤口愈合速度加快，这表明这些小鼠的肉芽组织减少和重新上皮化。ET-1基因敲除小鼠创面组织中转化生长因子-β、肿瘤坏死因子-α和结缔组织生长因子基因表达水平降低。在内皮细胞ET-1基因敲除小鼠中，肿瘤坏死因子-α、结缔组织生长因子和转化生长因子-β的表达下调。波生坦是一种双重ET受体拮抗剂，具有减轻系统性硬化症皮肤纤维化和促进创面愈合的作用，这种相互矛盾的作用可能是由上述分子介导的。内皮细胞来源的ET-1是纤维化或创伤愈合的有效治疗靶点，研究ET-1对这些病理状态的整体调控机制可能会导致一种新的治疗方法。
Endothelin (ET)-1 is known for the most potent vasoconstrictive peptide that is released mainly from endothelial cells. Several studies have reported ET-1 signaling is involved in the process of wound healing or fibrosis as well as vasodilation. However, little is known about the role of ET-1 in these processes. To clarify its mechanism, we compared skin fibrogenesis and wound repair between vascular endothelial cell-specific ET-1 knockout mice and their wild-type littermates. Bleomycin-injected fibrotic skin of the knockout mice showed significantly decreased skin thickness and collagen content compared to that of wild-type mice, indicating that bleomycin-induced skin fibrosis is attenuated in the knockout mice. The mRNA levels of transforming growth factor (TGF)-β were decreased in the bleomycin-treated skin of ET-1 knockout mice. On the other hand, skin wound healing was accelerated in ET-1 knockout mice, which was indicated by earlier granulation tissue reduction and re-epithelialization in these mice. The mRNA levels of TGF-β, tumor necrosis factor (TNF)-α and connective tissue growth factor (CTGF) were reduced in the wound of ET-1 knockout mice. In endothelial ET-1 knockout mouse, the expression of TNF-α, CTGF and TGF-β was down-regulated. Bosentan, an antagonist of dual ET receptors, is known to attenuate skin fibrosis and accelerate wound healing in systemic sclerosis, and such contradictory effect may be mediated by above molecules. The endothelial cell-derived ET-1 is the potent therapeutic target in fibrosis or wound healing, and investigations of the overall regulatory mechanisms of these pathological conditions by ET-1 may lead to a new therapeutic approach.
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影响因子：
6
作者：
Han, Gangwen;Li, Fulun;Wang, Xiao-Jing
通讯作者：
Wang, Xiao-Jing
影响因子：
6
作者：
Avraham, Tomer;Daluvoy, Sanjay;Mehrara, Babak J.
通讯作者：
Mehrara, Babak J.
DOI：
10.1016/j.bbrc.2010.11.075
发表时间：
2011-01-07
影响因子：
3.1
作者：
Rho, Seung-Sik;Choi, Hyun-Jung;Kwon, Young-Guen
通讯作者：
Kwon, Young-Guen
影响因子：
2.6
作者：
Bullard, KM;Longaker, MT;Lorenz, HP
通讯作者：
Lorenz, HP
影响因子：
3.2
作者：
LOPEZDELEON, A;ROJKIND, M
通讯作者：
ROJKIND, M