Rationale: Relaxin is a hormone that has been considered as a potential therapy for patients with fibrotic diseases.Objectives: 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.Methods: 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. Measurements and Main Results: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-b 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.Conclusions: 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.Keywords: relaxin; pulmonary fibrosis; transforming growth factor-b; RXFP1 At a Glance CommentaryScientific Knowledge on the Subject: Relaxin and relaxinbased therapies have been considered as potential therapies for pulmonary fibrosis.What This Study Adds to the Field: We found that expression of the relaxin receptor, RXFP1, is decreased in idiopathic pulmonary fibrosis and is associated with impaired pulmonary function. Understanding how RXFP1 is regulated is critical to the success of relaxin-based therapies in idiopathic pulmonary fibrosis.

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Idiopathic Pulmonary Fibrosis (IPF) is a disease characterized by the accumulation of apoptosis-resistant fibroblasts in the lung. We have previously shown that high expression of the transcription factor twist1 may explain this pro-survival phenotype in vitro. However, this observation has never been tested in vivo. We found that loss of twist1 in COL1A2+ cells led to increased fibrosis characterized by very significant accumulation of T-cells and bone marrow-derived matrix-producing cells. We found that twist1-null cells expressed high levels of the T-cell chemoattractant CXCL12. In vitro, we found that the loss of twist1 in IPF lung fibroblasts increased expression of CXCL12 downstream of increased expression of the non-canonical NF-κB transcription factor RelB. Finally, blockade of CXCL12 with AMD3100 attenuated the exaggerated fibrosis observed in twist1 null mice. Transcriptomic analysis of 134 IPF patients revealed that low expression of twist1 was characterized by enrichment of T-cell pathways. In conclusion, loss of twist1 in collagen-producing cells led to increased bleomycin-induced pulmonary fibrosis, which is mediated by increased expression of CXCL12. Twist1 expression is associated with dysregulation of T-cells in IPF patients. Twist1 may shape the IPF phenotype and regulate inflammation in fibrotic lung injury.

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