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

Abstract

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.

Mechanisms of the alternative activation of macrophages and non-coding RNAs in the development of radiation-induced lung fibrosis

“…Furthermore, let-7i targets TGFBR1, inhibiting TGF-β signaling, while miR-21 degrades the TGF-β inhibitor SMAD7. Moreover, miR-21 has been shown to be upregulated in several models of fibrosis[45,46], and to be activated by pro-fibrotic TGF-β. The authors postulate that the temporal regulation of let-7i and miR-21 is a mechanism for regulating TGF-β signaling.…”

The code of non-coding RNAs in lung fibrosis

“…There have been a number of studies that tried to identify differentially expressed miRNAs in fibrotic human lungs, in lungs of animals with experimental pulmonary fibrosis, and in in vitro models using relevant cells [50–55]. Many of the miRNAs with altered expression discovered by these efforts have been further studied.…”

Integrative analyses of miRNA and proteomics identify potential biological pathways associated with onset of pulmonary fibrosis in the bleomycin rat model

“…Several "omics" studies, using approaches such as genomics (Katsuma et al, 2001;Zuo et al, 2002;Kaminski, 2003) and proteomics (Kypreou et al, 2008;Kim et al, 2010), have been performed so far using BLM animal models. Furthermore, some studies that comprehensively analyzed micro RNA (miRNA) regulatory networks in pulmonary fibrosis have recently gained much attention (Liu et al, 2010;Xie et al, 2011;Xiao et al, 2012;Honeyman et al, 2013;Makino et al, 2013).…”