Recessive dystrophic epidermolysis bullosa (RDEB), a genetic skin blistering disease, is a paradigmatic condition of tissue fragility-driven multi-organ fibrosis. Here, longitudinal analyses of the tissue proteome through the course of naturally developing disease in RDEB mice revealed that increased pro-inflammatory immunity associates with fibrosis evolution. Mechanistically, this fibrosis is a consequence of altered extracellular matrix organization rather than that of increased abundance of major structural proteins. In a humanized system of disease progression, we targeted inflammatory cell fibroblast communication with Ang-(1-7)—an anti-inflammatory heptapeptide of the renin-angiotensin system, which reduced the fibrosis-evoking aptitude of RDEB cells. In vivo, systemic administration of Ang-(1-7) efficiently attenuated progression of multi-organ fibrosis and increased survival of RDEB mice. Collectively, our study shows that selective down-modulation of pro-inflammatory immunity may mitigate injury-induced fibrosis. Furthermore, together with published data, our data highlight molecular diversity among fibrotic conditions. Both findings have direct implications for the design of therapies addressing skin fragility and fibrosis.

中文翻译：

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促炎免疫支持大疱性表皮松解症的纤维化进展：Ang-(1-7) 干预

隐性营养不良性大疱性表皮松解症（RDEB）是一种遗传性皮肤起泡疾病，是组织脆性驱动的多器官纤维化的典型病症。在这里，对 RDEB 小鼠自然发展疾病过程中组织蛋白质组的纵向分析表明，促炎免疫的增加与纤维化进化有关。从机制上讲，这种纤维化是细胞外基质组织改变的结果，而不是主要结构蛋白丰度增加的结果。在疾病进展的人源化系统中，我们针对炎症细胞成纤维细胞与 Ang-(1-7)（肾素-血管紧张素系统的一种抗炎七肽）的通讯，降低了 RDEB 细胞纤维化诱发能力。在体内，全身给予 Ang-(1-7) 可有效减弱多器官纤维化的进展并增加 RDEB 小鼠的存活率。总的来说，我们的研究表明，选择性下调促炎免疫可能会减轻损伤引起的纤维化。此外，与已发表的数据一起，我们的数据强调了纤维化病症之间的分子多样性。这两项发现对解决皮肤脆弱和纤维化的疗法的设计具有直接影响。