特發性肺纖維化（Idiopathic pulmonary fibrosis, IPF）是一種慢性肺疾病，其特徵在於成纖維細胞增殖和細胞外基質的堆積。目前尚無藥物可以治癒特發性肺纖維化，只有極少數藥物可以有效地減慢輕度至中度患者肺功能下降的病程。唯一能真正治愈特發性肺纖維化的方法是雙肺移植，但在實行上有許多困難與限制。因此發展抗纖維化治療的方向會是組織纖維化治療方式的一道曙光。
在實驗動物模型中，肽激素鬆弛素(relaxin)已被確定具有抗纖維化作用。它可以通過降低膠原蛋白束的密度和鬆弛膠原蛋白纖維來重塑韌帶。有研究曾將嘗試應用鬆弛素在治療硬皮病患者，卻未觀察到有益作用。2016年，匹茲堡大學Daniel J. Kass and張英澤教授的團隊提出了進一步的研究進展：與對照組肺相比，特發性肺纖維化肺組織中的鬆弛素-胰島素樣家族肽受體1（relaxin-insulin like family peptide receptor 1, RXFP1）顯著減少。他們還檢測到肺成纖維細胞中鬆弛素-胰島素樣家族肽受體1的信使核糖核酸（messenger RNA, mRNA）亦有減少的現象。這樣的現象解釋了硬皮病患者使用鬆弛素治療失敗的原因，可能是受鬆弛素-胰島素樣家族肽受體1的不正常向下調控所導致。因此，即使濃度增加，鬆弛素也不能通過其受體活化其抗纖維化作用。
在本研究中，我們推定鬆弛素-胰島素樣家族肽受體1中啟動子和增強子區域調控區的基因組結構，確定了兩個不同長度的主要鬆弛素-胰島素樣家族肽受體1轉錄版本。使用初級肺成纖維細胞在pGL3報告載體系統中測試了這些區域。當將其克隆到pGL3啟動子載體系統中時，我們觀察到了遠端啟動子區域的顯著增強子活性。在從供體肺分離的肺成纖維細胞中，並觀察到增強子的活性在特發性肺纖維化肺成纖維細胞中顯著下降。因此，我們假設異常的轉錄調控可能導致特發性肺纖維化中的鬆弛素-胰島素樣家族肽受體表達下降。本研究鑑定了RXFP1基因調控相關的分子機制和表徵。這項研究的結果可以用作將來開發特發性肺纖維化新療法的策略的相關依據。

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease, characterized by fibroblast proliferation and extracellular matrix accumulation. Few drugs could effectively slow down the disease progression of IPF patients. The only way to cure IPF is a double lung transplant. No treatment is effective for stopping progression of the disease. The idea of anti-fibrotic recombinant treatments may offer hopes for tissue fibrosis patients.
Peptide hormone, relaxin, has been identified to have anti-fibrotic effects in animal model experiments. It can remodel ligaments by reducing the collagen bundle’s density and relaxing collagen fibers. The therapeutic effect of relaxin was studied in scleroderma patients; no beneficial effects were observed, however. In 2016, Professor Daniel Kass and Professor Yingze Zhang’s team at the University of Pittsburgh reported that RXFP1 (relaxin-insulin like family peptide receptor 1) was significantly decreased in IPF lung tissues. They also detected reduced RXFP1 mRNA and protein in lung fibroblasts. This finding may explain the failure of relaxin treatment in scleroderma patients. The down-regulation of RXFP1 receptor makes the therapeutic relaxin not be able to mediate anti-fibrotic effects.
In this study, two putative promoter and enhancer regions of the RXFP1 gene were characterized. The regions were tested in pGL3 reporter vector systems using primary lung fibroblasts. A dramatic enhancer activity observed is in the distal regulatory region. This enhancer activity is much more profound in lung fibroblasts isolated from control donor lungs than IPF. Fine mapping of cis-acting enhancer elements and transcription factors are analyzed and confirmed. Thus, aberrant transcriptional regulation could lead to RXFP1 down-regulation in IPF.
This study results in the identification and characterization of the molecular mechanisms associated with RXFP1 gene regulation. The results are useful for further studies towards developing relaxin-based anti-fibrotic therapy.

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