Tan Jiangning, Tedrow John R, Dutta Justin A, Juan-Guardela Brenda, Nouraie Mehdi, Chu Yanxia, Trejo Bittar Humberto, Ramani Kritika, Biswas Partha S, Veraldi Kristen L, Kaminski Naftali, Zhang Yingze, Kass Daniel J
1 Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease.
2 Division of Pulmonary, Allergy, and Critical Care Medicine.
Am J Respir Crit Care Med. 2016 Dec 1;194(11):1392-1402. doi: 10.1164/rccm.201509-1865OC.
Relaxin is a hormone that has been considered as a potential therapy for patients with fibrotic diseases.
To gauge the potential efficacy of relaxin-based therapies in idiopathic pulmonary fibrosis (IPF), we studied gene expression for relaxin/insulin-like family peptide receptor 1 (RXFP1) in IPF lungs and controls.
We analyzed gene expression data obtained from the Lung Tissue Research Consortium and correlated RXFP1 gene expression data with cross-sectional clinical and demographic data. We also employed ex vivo donor and IPF lung fibroblasts to test RXFP1 expression in vitro. We tested CGEN25009, a relaxin-like peptide, in lung fibroblasts and in bleomycin injury.
We found that RXFP1 is significantly decreased in IPF. In patients with IPF, the magnitude of RXFP1 gene expression correlated directly with diffusing capacity of the lung for carbon monoxide (P < 0.0001). Significantly less RXFP1 was detected in vitro in IPF fibroblasts than in donor controls. Transforming growth factor-β decreased RXFP1 in both donor and IPF lung fibroblasts. CGEN25009 was effective at decreasing bleomycin-induced, acid-soluble collagen deposition in vivo. The relaxin-like actions of CGEN25009 were abrogated by RXFP1 silencing in vitro, and, in comparison with donor lung fibroblasts, IPF lung fibroblasts exhibited decreased sensitivity to the relaxin-like effects of CGEN25009.
IPF is characterized by the loss of RXFP1 expression. RXFP1 expression is directly associated with pulmonary function in patients with IPF. The relaxin-like effects of CGEN25009 in vitro are dependent on expression of RXFP1. Our data suggest that patients with IPF with the highest RXFP1 expression would be predicted to be most sensitive to relaxin-based therapies.
松弛素是一种被认为可用于纤维化疾病患者的潜在治疗手段的激素。
为评估基于松弛素的疗法在特发性肺纤维化（IPF）中的潜在疗效，我们研究了IPF肺部组织及对照中松弛素/胰岛素样家族肽受体1（RXFP1）的基因表达情况。
我们分析了从肺组织研究联盟获取的基因表达数据，并将RXFP1基因表达数据与横断面临床和人口统计学数据进行关联分析。我们还使用体外供体和IPF肺成纤维细胞来检测RXFP1的体外表达情况。我们在肺成纤维细胞和博来霉素损伤模型中测试了一种类松弛素肽CGEN25009。
我们发现IPF中RXFP1显著降低。在IPF患者中，RXFP1基因表达水平与肺一氧化碳弥散量直接相关（P < 0.0001）。体外检测发现，IPF成纤维细胞中的RXFP1明显少于供体对照。转化生长因子-β可降低供体和IPF肺成纤维细胞中的RXFP1。CGEN25009在体内可有效减少博来霉素诱导的酸溶性胶原蛋白沉积。体外实验中，RXFP1沉默可消除CGEN25009的类松弛素作用，并且与供体肺成纤维细胞相比，IPF肺成纤维细胞对CGEN25009的类松弛素作用敏感性降低。
IPF的特征是RXFP1表达缺失。RXFP1表达与IPF患者的肺功能直接相关。CGEN25009在体外的类松弛素作用依赖于RXFP1的表达。我们的数据表明，RXFP1表达最高的IPF患者预计对基于松弛素的疗法最敏感。
