Abnormal expression of IGF-binding proteins, an initiating event in idiopathic pulmonary fibrosis?

Ruan, Wenjie; Ying, Kejing

doi:10.1016/j.prp.2010.03.010

Cited by 17 publications

(14 citation statements)

References 67 publications

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“…[46] demonstrated adenoviral treatment with Igfbp5 to have the same effect, thus directly implicating the IGF-1 pathway in fibrosis development. Ruan and Ying [48] suggest that this change in IGF binding proteins could be an initiating factor in IPF and Veraldi and Feghali-Bostwick [49] propose IGF binding proteins to be central mediators of fibrosis. Our findings, indicting the IGF pathway to be significantly represented in microRNA regulation of bleomycin-induced pulmonary fibrosis, coupled with increased Igf-1 levels in fibrotic lung tissue, support this line of investigation and suggest the involvement of microRNA regulation.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA profiling implicates the insulin-like growth factor pathway in bleomycin-induced pulmonary fibrosis in mice

Honeyman

Bazett

Tomko

et al. 2013

Fibrogenesis Tissue Repair

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BackgroundIdiopathic pulmonary fibrosis is a disease characterized by alveolar epithelial cell injury, inflammatory cell infiltration and deposition of extracellular matrix in lung tissue. As mouse models of bleomycin-induced pulmonary fibrosis display many of the same phenotypes observed in patients with idiopathic pulmonary fibrosis, they have been used to study various aspects of the disease, including altered expression of microRNAs.ResultsIn this work, microRNA expression profiling of the lungs from treated C57BL/6J mice, relative to that of untreated controls, was undertaken to determine which alterations in microRNAs could in part regulate the fibrosis phenotype induced by bleomycin delivered through mini-osmotic pumps. We identified 11 microRNAs, including miR-21 and miR-34a, to be significantly differentially expressed (P < 0.01) in lungs of bleomycin treated mice and confirmed these data with real time PCR measurements. In situ hybridization of both miR-21 and miR-34a indicated that they were expressed in alveolar macrophages. Using a previously reported gene expression profile, we identified 195 genes to be both predicted targets of the 11 microRNAs and of altered expression in bleomycin-induced lung disease of C57BL/6J mice. Pathway analysis with these 195 genes indicated that altered microRNA expression may be associated with hepatocyte growth factor signaling, cholecystokinin/gastrin-mediated signaling, and insulin-like growth factor (IGF-1) signaling, among others, in fibrotic lung disease. The relevance of the IGF-1 pathway in this model was then demonstrated by showing lung tissue of bleomycin treated C57BL/6J mice had increased expression of Igf1 and that increased numbers of Igf-1 positive cells, predominantly in macrophages, were detected in the lungs.ConclusionsWe conclude that altered microRNA expression in macrophages is a feature which putatively influences the insulin-like growth factor signaling component of bleomycin-induced pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

MicroRNA profiling implicates the insulin-like growth factor pathway in bleomycin-induced pulmonary fibrosis in mice

Honeyman

Bazett

Tomko

et al. 2013

Fibrogenesis Tissue Repair

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“…Similarly, there are reports showing that some other IGFBP super families such as IGFBP-3, IGFBP-5 and CTGF (IGFBP-rP2) are expressed in and contribute to pathological fibrosis. (30,(32)(33)(34) In addition, CTGF has been shown to promote transdifferentiation of mesenchymal stem cells to fibroblasts. (35) Therefore, the connective tissue formation may be a common function of IGFBPrelated proteins.…”

Section: Discussionmentioning

confidence: 99%

Elevated expression of angiomodulin (AGM/IGFBP‐rP1) in tumor stroma and its roles in fibroblast activation

et al. 2012

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Angiomodulin (AGM/IGFBP-rP1), a glycoprotein of about 30 kDa, is overexpressed in tumor vasculature as well as some human cancer cell lines, but it has been suggested to be a tumor suppressor. To elucidate roles of angiomodulin (AGM) in tumor progression, we here examined distribution of AGM in three types of human cancer tissues by immunohistochemistry. The results showed that AGM was overexpressed in the stroma as well as the vasculature surrounding tumor cells in the human cancer tissues. AGM and a-smooth muscle actin (a-SMA) as an activated fibroblast marker were often colocalized in cancer-associated fibroblasts (CAFs). In vitro analysis indicated that transforming growth factor (TGF)-b1 might be an important inducer of AGM in normal human fibroblasts. AGM strongly stimulated the expression of fibronectin and weakly that of a-SMA in normal fibroblasts. AGM significantly stimulated the proliferation and migration of fibroblasts. The AGM-induced expression of fibronectin and a-SMA was blocked by a TGF-b signal inhibitor but neither the stimulation of cell growth nor migration. These results imply that AGM activates normal fibroblasts by TGF-bdependent and independent mechanisms. These findings also suggest that AGM and TGF-b1 cooperatively or complementarily contribute to the stromal activation and connective tissue formation in human cancer tissues, contributing to tumor progression. (Cancer Sci 2012; 103: 691-699)

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“…Based on these findings, our results indicate that ID1 is a one of the target gene of TGF-β in fibroblasts that is reduced by cyclosporine. IGFBP2 has been reported to be related to IPF in the lung tissues of patients (Ruan and Ying 2010). The concentration of IGFBP2 in bronchoalveolar lavage (BAL) fluid was significantly increased in IPF patients in comparison with normal controls and was significantly related to poor pulmonary function (Chadelat et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling of Lung Myofibroblasts Reveals the Anti-Fibrotic Effects of Cyclosporine

Hirota

Ito

Miyazaki

et al. 2014

Tohoku J. Exp. Med.

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Cyclosporine, a calcineurin inhibitor, is a potent immunosuppressive agent that acts chiefly through the inactivation of T-lymphocytes. Several clinical studies have demonstrated the effectiveness of cyclosporine for treating fibrotic lung disease, but the underlying mechanism remains elusive. We hypothesized that cyclosporine exerts direct effects against fibrogenesis of lung myofibroblasts, and aimed to elucidate the mechanism of this anti-fibrotic effect through gene-expression profiling using DNA microarray analysis. We found that cyclosporine suppressed the expression of alpha-smooth muscle actin and collagen type I in myofibroblasts that had been differentiated from a fetal human lung fibroblast cell line by induction with transforming growth factor (TGF)-β. Furthermore, microarray analysis revealed that cyclosporine downregulated 57 genes whose expression levels were increased by TGF-β, and up-regulated 73 genes, whose expression was decreased by TGF-β. Classifying these 57 down-regulated and 73 up-regulated genes with the Database for Annotation, Visualization and Integrated Discovery (DAVID) web tool, we have identified the involvement of several functional categories, including innate immunity, cytokine interaction, growth factor, and cancer pathway. Of the identified genes, we selected three fibrosis-related genes, insulin-like growth factor binding protein 2 (IGFBP2), inhibitor of DNA binding 1 (ID1) and peroxisome proliferator-activated receptor gamma (PPARG), and validated their expression patterns by quantitative reverse transcription-polymerase chain reaction. Cyclosporine treatment decreased the expression levels of IGFBP2 and ID1, but increased PPARG expression. These results suggest that cyclosporine is a potent anti-fibrotic agent acting on myofibroblasts. Therefore, cyclosporine shows potential as a novel remedy for fibrotic lung disease.

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Abnormal expression of IGF-binding proteins, an initiating event in idiopathic pulmonary fibrosis?

Cited by 17 publications

References 67 publications

MicroRNA profiling implicates the insulin-like growth factor pathway in bleomycin-induced pulmonary fibrosis in mice

MicroRNA profiling implicates the insulin-like growth factor pathway in bleomycin-induced pulmonary fibrosis in mice

Elevated expression of angiomodulin (AGM/IGFBP‐rP1) in tumor stroma and its roles in fibroblast activation

Gene Expression Profiling of Lung Myofibroblasts Reveals the Anti-Fibrotic Effects of Cyclosporine

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