The code of non-coding RNAs in lung fibrosis

Xie, Na; Thannickal, Victor J.; Liu, Gang

doi:10.1007/s00018-015-1939-6

Cited by 12 publications

(10 citation statements)

References 118 publications

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“…We found that miR-34a was neither regulated by TGF-b1 nor did it modulate TGF-b1 profibrotic activity in lung fibroblasts, which contrasts with the features of most miRNAs that have been identified thus far to be involved in the pathogenesis of lung fibrosis (18,21,41). This study and previous investigations suggest that the activities of this special Figure 7.…”

Section: Discussioncontrasting

confidence: 73%

miR-34a Inhibits Lung Fibrosis by Inducing Lung Fibroblast Senescence

Cui

Ge²,

Xie³

et al. 2017

Am J Respir Cell Mol Biol

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Cellular senescence has been implicated in diverse pathologies. However, there is conflicting evidence regarding the role of this process in tissue fibrosis. Although dysregulation of microRNAs is a key mechanism in the pathogenesis of lung fibrosis, it is unclear whether microRNAs function by regulating cellular senescence in the disease. In this study, we found that miR-34a demonstrated greater expression in the lungs of patients with idiopathic pulmonary fibrosis and in mice with experimental pulmonary fibrosis, with its primary localization in lung fibroblasts. More importantly, miR-34a was up-regulated significantly in both human and mouse lung myofibroblasts. We found that mice with miR-34a ablation developed more severe pulmonary fibrosis than did wild-type animals after fibrotic lung injury. Mechanistically, we found that miR-34a induced a senescent phenotype in lung fibroblasts because this microRNA increased senescence-associated β-galactosidase activity, enhanced expression of senescence markers, and decreased cell proliferative capacities. Consistently, we found that primary lung fibroblasts from fibrotic lungs of miR-34a-deficient mice had a diminished senescent phenotype and enhanced resistance to apoptosis as compared with those from wild-type animals. We also identified multiple miR-34a targets that likely mediated its activities in inducing senescence in lung fibroblasts. In conclusion, our data suggest that miR-34a functions through a negative feedback mechanism to restrain fibrotic response in the lungs by promoting senescence of pulmonary fibroblasts.

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Section: Discussioncontrasting

confidence: 73%

miR-34a Inhibits Lung Fibrosis by Inducing Lung Fibroblast Senescence

Cui

Ge²,

Xie³

et al. 2017

Am J Respir Cell Mol Biol

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“…First, lack of cell-specific delivery of miR mimics risks potential off-target effects caused by uptake of the mimics by cells that normally do not express the miRs (47). It is also critical for miR replacement/ reconstitution to restore their physiological levels, because miRs at supraphysiological levels could target gene sets that are quite different from those by miRs at endogenous levels, thus causing undesired side effects (48).…”

Section: Lentiviral Delivery Of Mir-27a-3p Attenuates Bleomycin-inducmentioning

confidence: 99%

MicroRNA-27a-3p Is a Negative Regulator of Lung Fibrosis by Targeting Myofibroblast Differentiation

Cui

Banerjee

Xie

et al. 2016

Am J Respir Cell Mol Biol

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Although microRNAs (miRs) have been well recognized to play an important role in the pathogenesis of organ fibrosis, there is a lack of evidence as to whether miRs directly regulate the differentiation of myofibroblasts, the putative effector cells during pathological fibrogenesis. In this study, we found that levels of miR-27a-3p were up-regulated in transforming growth factor-b1-treated human lung fibroblasts in a Smad2/3-dependent manner and in fibroblasts isolated from lungs of mice with experimental pulmonary fibrosis. However, both basal and transforming growth factor-b1-induced expression of miR-27a-3p were reduced in lung fibroblasts from patients with idiopathic pulmonary fibrosis compared with that from normal control subjects. Overexpression of miR-27a-3p inhibited, whereas knockdown of miR-27a-3p enhanced, the differentiation of lung fibroblasts into myofibroblasts. We found that miR-27a-3p directly targeted the phenotypic marker of myofibroblasts, a-smooth muscle actin, and two key Smad transcription factors, Smad2 and Smad4. More importantly, we found that therapeutic expression of miR-27a-3p in mouse lungs through lentiviral delivery diminished bleomycin-induced lung fibrosis. In conclusion, our data suggest that miR-27a-3p functions via a negative-feedback mechanism in inhibiting lung fibrosis. This study also indicates that targeting miR27a-3p is a novel therapeutic approach to treat fibrotic organ disorders, including lung fibrosis.

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“…For example, the direct inhibition of let-7d expression by TGF-β in AECs is associated with epithelial to mesenchymal transition and collagen deposition 68 . Similarly, several circulating miRNAs appear to be differentially expressed in the serum of IPF patients 67 . Moreover, the expression levels of miR-21, miR-155, and miR-101-3p in serum seem to be correlated with FVC and HRCT features of IPF 69 .…”

Section: Epigenetic and Microrna Regulation Phenotypingmentioning

confidence: 99%

“…Lung tissue miRNA profiling identified significantly increased 64 or decreased 65 levels of several regulatory miRNAs in IPF patients, thereby distinguishing the normal lung from the IPF lung and rapidly progressive from slowly progressive disease 66 . TGF-β seems to play a critical role in the upregulation of profibrotic miRNAs and downregulation of antifibrotic miRNAs 67 . For example, the direct inhibition of let-7d expression by TGF-β in AECs is associated with epithelial to mesenchymal transition and collagen deposition 68 .…”

Section: Epigenetic and Microrna Regulation Phenotypingmentioning

confidence: 99%

Recent advances in understanding idiopathic pulmonary fibrosis

Daccord

Maher

2016

F1000Res

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Despite major research efforts leading to the recent approval of pirfenidone and nintedanib, the dismal prognosis of idiopathic pulmonary fibrosis (IPF) remains unchanged. The elaboration of international diagnostic criteria and disease stratification models based on clinical, physiological, radiological, and histopathological features has improved the accuracy of IPF diagnosis and prediction of mortality risk. Nevertheless, given the marked heterogeneity in clinical phenotype and the considerable overlap of IPF with other fibrotic interstitial lung diseases (ILDs), about 10% of cases of pulmonary fibrosis remain unclassifiable. Moreover, currently available tools fail to detect early IPF, predict the highly variable course of the disease, and assess response to antifibrotic drugs. Recent advances in understanding the multiple interrelated pathogenic pathways underlying IPF have identified various molecular phenotypes resulting from complex interactions among genetic, epigenetic, transcriptional, post-transcriptional, metabolic, and environmental factors. These different disease endotypes appear to confer variable susceptibility to the condition, differing risks of rapid progression, and, possibly, altered responses to therapy. The development and validation of diagnostic and prognostic biomarkers are necessary to enable a more precise and earlier diagnosis of IPF and to improve prediction of future disease behaviour. The availability of approved antifibrotic therapies together with potential new drugs currently under evaluation also highlights the need for biomarkers able to predict and assess treatment responsiveness, thereby allowing individualised treatment based on risk of progression and drug response. This approach of disease stratification and personalised medicine is already used in the routine management of many cancers and provides a potential road map for guiding clinical care in IPF.

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The code of non-coding RNAs in lung fibrosis

Cited by 12 publications

References 118 publications

miR-34a Inhibits Lung Fibrosis by Inducing Lung Fibroblast Senescence

miR-34a Inhibits Lung Fibrosis by Inducing Lung Fibroblast Senescence

MicroRNA-27a-3p Is a Negative Regulator of Lung Fibrosis by Targeting Myofibroblast Differentiation

Recent advances in understanding idiopathic pulmonary fibrosis

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