Idiopathic pulmonary fibrosis (IPF) is the most common and devastating of the interstitial lung diseases. Epithelial dysfunction is thought to play a prominent role in disease pathology, and we sought to characterize secreted signals that may contribute to disease pathology. Transcriptional profiling of senescent type II alveolar epithelial cells from mice with epithelial-specific telomere dysfunction identified the transforming growth factor-β family member, growth and differentiation factor 15 (Gdf15), as the most significantly upregulated secreted protein. Gdf15 expression is induced in response to telomere dysfunction and bleomycin challenge in mice. Gdf15 mRNA is expressed by lung epithelial cells, and protein can be detected in peripheral blood and bronchoalveolar lavage following bleomycin challenge in mice. In patients with IPF, GDF15 mRNA expression in lung tissue is significantly increased and correlates with pulmonary function. Single-cell RNA sequencing of human lungs identifies epithelial cells as the primary source of GDF15, and circulating concentrations of GDF15 are markedly elevated and correlate with disease severity and survival in multiple independent cohorts. Our findings suggest that GDF15 is an epithelial-derived secreted protein that may be a useful biomarker of epithelial stress and identifies IPF patients with poor outcomes.

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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.

MicroRNAs (miRNAs) may function as oncogenes or tumor suppressors. Here, we identified that miR-590-5p was up-regulated in human cervical cancer. Over-expression of miR-590-5p promoted cervical cancer cell growth, cell cycle and invasion via Growth curve, Colony formation, FACS and Transwell assays in HeLa and C33A cell lines. Subsequently, CHL1 was identified as a potential miR-590-5p target by bioinformatics analysis. Moreover, we showed that CHL1 was negatively regulated by miR-590-5p at the posttranscriptional level, via a specific target site within the 3'UTR by luciferase reporter assay. Furthermore, the mRNA and protein levels of CHL1 in cervical cancer cells were downregulated by miR-590-5p. And we identified the cell phenotype altered by miR-590-5p can be rescued by over-expression of CHL1. Therefore, our findings suggest that miR-590-5p acts as an oncogene by targeting the CHL1 gene and promotes cervical cancer proliferation. The findings of this study contribute to current understanding of the functions of miR-590-5p in cervical cancer.

Deterin, a new apoptosis inhibitor fromProgrammed cell death is a process that specifies the elimination of superfluous or otherwise unwanted cells and tissues (1-4). Observed as a programmed cell death in insect systems (5), the process has been distinguished from cell death by necrosis (6, 7) and has since been conventionally characterized by cell shrinkage, blebbing of the plasma membrane, convolution of the nuclear membrane, chromatin condensation, and chromosomal DNA fragmentation into a nucleosomal ladder. In some tissues, these apoptotic cells are phagocytosed intact, without an acute inflammatory reaction. These phenomena are in contrast to cell death by necrosis, in which cells swell and lyse to release cellular contents, inducing an inflammatory reaction.The various diverse stimuli that induce apoptosis can be external to the cell (e.g. UV, antibiotics, hormones, and liposomal cytotoxicants) or endogenous (e.g. transcriptional regulators and DNA damage due to free radicals). These apoptotic stimuli feed into apoptotic pathways of the cell by routes not well understood, although many pathways appear to converge into common or at least overlapping biochemical machinery. These pathways include activators that can activate special effector proteolytic enzymes, caspases, that in turn cleave and activate other caspases, which then cleave end target molecules; the molecular death of these target molecules causes the apoptotic death of the cell (8, 9). Because many caspases in the apoptotic pathway are apparently always present in the cell, either as procaspases or perhaps performing otherwise nonapoptotic functions (10), the cell must have a means to prevent "leaky" or inadvertent triggering of the pathway. This protection is accomplished in part by the presence of inhibitors of various steps in the apoptotic machinery. For example, in vertebrates and the invertebrate Caenorhabditis elegans there are inhibitors of the "activators," such as the well known BCl-2 and related BCL-X L (11).There are also other caspase inhibitors, such as certain inhibitors of apoptosis (IAP) 1 proteins, first discovered in baculoviruses (12) and then identified in both vertebrate and invertebrate systems (13)(14)(15)(16)(17). These proteins are typically characterized by BIR type repeats and a RING finger motif (18,19). However, there is much that we do not yet understand about the role and action of the IAPs generally in apoptosis and normal cell physiology. Structurally, the function of the characteristic BIR type repeat in IAPs is also little understood. Roy et al. (20) report that for the vertebrate c-IAP-1 and c-IAP-2, the BIR region alone could bind to caspases and block caspase activation. However, the inhibitory effect was greater when the RING finger was also present. More paradoxically, Hauser et al. (21) report a ubiquitin conjugating complex component that has a single BIR and no RING finger and no activity to inhibit apoptosis. Similarly, both an insect virus (AcIAP, Ref. 22) and an unrelated mammalian virus (23) e...