MicroRNAs in idiopathic pulmonary fibrosis

doi:10.1016/j.trsl.2011.01.012

Translational Research

Volume 157, Issue 4, April 2011, Pages 191-199

https://doi.org/10.1016/j.trsl.2011.01.012 Get rights and content

In this review, we describe the recent advances in the understanding of the role of microRNAs in idiopathic pulmonary fibrosis (IPF), a chronic progressive and lethal fibrotic lung disease. Approximately 10% of the microRNAs are significantly changed in IPF lungs. Among the significantly downregulated microRNAs are members of let-7, mir-29, and mir-30 families as well as miR-17∼92 cluster among the upregulated mir-155 and mir-21. Downregulation of let-7 family members leads to changes consistent with epithelial mesenchymal transition in lung epithelial cells both in vitro and in vivo, whereas inhibition of mir-21 modulates fibrosis in the bleomycin model of lung fibrosis. Perturbations of mir-155 and mir-29 have profibrotic effects in vitro but have not yet been assessed in vivo in the context of lung fibrosis. A recurrent global theme is that many microRNAs studied in IPF are both regulated by transforming growth factor β1 (TGFβ1) and regulate TGFβ1 signaling pathway by their target genes. As a result, their aberrant expression leads to a release of inhibitions on the TGFβ1 pathway and to the creation of feed-forward loops. Coanalysis of published microRNA and gene expression microarray data in IPF reveals enrichment of the TGFβ1, Wnt, sonic hedgehog, p53, and vascular endothelial growth factor pathways and complex regulatory networks. The changes in microRNA expression in the IPF lung and the evidence for their role in the fibrosis suggest that microRNAs should be evaluated as therapeutic targets in IPF.

Section snippets

LET-7 in Lung Fibrosis

When we analyzed the initial microRNA dataset, we were impressed by the extent of the changes and looked for a potential regulatory mechanism.³² Because transforming growth factor β1 (TGFβ1) is a key regulator of lung fibrosis,³³ we scanned the promoters of differentially expressed microRNAs for SMAD binding elements (SBE) and found a SBE upstream of the microRNA let-7d. We confirmed physical binding of SMAD3 to the putative let-7d promoter by chromatin immunoprecipitation using an antibody to

miR-21 in Lung Fibrosis

Liu et al studied the role of miR-21 in IPF.⁴¹ They showed that expression of miR-21 is increased in the lungs of bleomycin-treated mice as well as in the lungs of IPF patients where it localized to myofibroblasts. Inhibition of miR-21 in bleomycin-treated lungs reduced the severity of fibrosis and myofibroblast differentiation. TGFβ1 induced miR-21 expression and miR-21 in turn promoted TGFβ1-induced fibrogenic activation of pulmonary fibroblasts by inhibiting the inhibitory Smad and Smad7 as

miR-155 in Lung Fibrosis

Pottier et al⁵² have shown an increased expression of miR-155 after treatment with TNF-α and IL-1β as well as reduced expression after treatment with TGFβ1 in human lung fibroblasts. Functional studies demonstrated that keratinocyte growth factor (FGF-7) was a direct target of miR-155 and that miR-155 transfection caused fibroblast migration. Upregulation of miR-155 was correlated with the degree of lung fibrosis in C57BL⁄6 and BALB⁄c mice after bleomycin administration. Although the authors

miR-29 in Lung Fibrosis

Cushing et al⁵⁸ demonstrated a reduction in the miR-29 family in the lungs of bleomycin-treated mice as well as a corresponding increase in collagens and extracellular matrix-related genes. Although they did not report on the expression of mir-29 in IPF lungs, we observed a significant decrease in miR-29 in the lungs of IPF patients.³² miR-29 knockdown in human fetal lung fibroblasts caused an increase in fibrosis-associated genes including its direct targets integrin, alpha 11; ADAMTS9;

MicroRNAs and Feedforward Loops

A recurrent theme in changes in microRNA expression in human disease is that a differentially expressed microRNA is both regulated by a disease-promoting pathway and is a regulator of the same pathway. As a result, in many cases, a change in the expression of a microRNA inhibits an inhibitory feedback mechanism and causes a feedforward loop that promotes the activation of the pathway and sustains the diseased phenotype. For example, although let-7d and miR-21 are diametrically expressed in IPF

IPF Lungs are Enriched With Target Genes of Dysregulated MicroRNAs

The gene-expression profile of IPF lungs is enriched with genes involved in developmental pathways, EMT, TGFβ1 signaling, extracellular matrix, and repair and epithelial markers.24, 65, 66, 67 Pathway analysis of the predicted targets of differentially expressed microRNAs demonstrates enrichment of targets belonging to pathways such as TGFβ1, Wnt signaling, sonic hedgehog, p53, and vascular endothelial growth factor (VEGF) pathways. To illustrate joint analysis of both the microRNA and the

MicroRNAs in Fibrosis of Other Organs

MicroRNA dysregulation also has been studied in heart, liver, and kidney fibrosis (Table I).32, 41, 52, 58, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87 MicroRNA involvement in heart development and heart failure and fibrosis has been studied extensively.31, 59, 88, 89, 90, 91 Among the usually upregulated microRNAs mentioned are miR-21, miR-23a, miR-125b, miR-195, miR-199a, and among the downregulated microRNAs mentioned are miR-1, miR-7, miR-29b, miR-30, miR-150, and miR-378.92,

Therapeutic Implications

The evidence presented in this review highly support the design of therapeutic interventions that either are aimed at supplementing downregulated microRNAs or at inhibiting upregulated microRNAs. Considering that the number of differentially expressed microRNAs is probably close to 100 and that some of them overlap in their seed sequences, it should be relatively feasible to test the effects of inhibiting each one of the upregulated microRNAs and replenishing the inhibited ones in animal models

Conclusions

In this review, we summarized the current knowledge on the role of microRNAs in lung fibrosis. The potential roles of let-7, miR-21, miR-155, and miR-29 in IPF sheds significant light on our understanding of the regulatory networks that determine the lung phenotype in IPF. Although not yet fully completed, these initial studies already have provided exciting and novel observations suggesting that detailed analysis of the role of all microRNAs differentially expressed in IPF will have a

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: Supported by NIH Grants HL095397, HL101715, and LM009657 and by the Dorothy P. and Richard P. Simmons Endowed Chair for Pulmonary Research.

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Review ArticleMicroRNAs in idiopathic pulmonary fibrosis

Section snippets

LET-7 in Lung Fibrosis

miR-21 in Lung Fibrosis

miR-155 in Lung Fibrosis

miR-29 in Lung Fibrosis

MicroRNAs and Feedforward Loops

IPF Lungs are Enriched With Target Genes of Dysregulated MicroRNAs

MicroRNAs in Fibrosis of Other Organs

Therapeutic Implications

Conclusions

Int J Biochem Cell Biol

Int J Biochem Cell Biol

Curr Opin Cell Biol

J Thorac Oncol

J Biol Chem

Am J Pathol

Cell

J Biol Chem

J Biol Chem

Gastroenterology

J Biol Chem

Biochem Biophys Res Commun

J Biol Chem

Cancer Cell

Am J Pathol

J Hepatol

FEBS Lett

J Heart Lung Transplant

J Mol Cell Cardiol

J Biol Chem

Incidence and prevalence of idiopathic pulmonary fibrosis

Am J Respir Crit Care Med

Rehabilitation and palliative care in lung fibrosis

Respirology

Disorders of lung matrix remodeling

J Clin Invest

Epithelial-mesenchymal interactions in pulmonary fibrosis

Semin Respir Crit Care Med

Fibroblast phenotypes in pulmonary fibrosis

Am J Respir Cell Mol Biol

Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury

J Clin Invest

Evolving concepts of apoptosis in idiopathic pulmonary fibrosis

Proc Am Thorac Soc

Apoptosis in pulmonary fibrosis: too much or not enough?

Antioxid Redox Signal

NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury

Nat Med

Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix

Proc Natl Acad Sci U S A

TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease

Am J Physiol Lung Cell Mol Physiol

Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis

J Clin Invest

Idiopathic pulmonary fibrosis: aberrant recapitulation of developmental programs?

PLoS Med

WNT5A is a regulator of fibroblast proliferation and resistance to apoptosis

Am J Respir Cell Mol Biol

Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans

Proc Natl Acad Sci U S A

Genomewide RNA expression profiling in lung identifies distinct signatures in idiopathic pulmonary arterial hypertension and secondary pulmonary hypertension

Am J Physiol Heart Circ Physiol

Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis

Am J Respir Crit Care Med

Accelerated variant of idiopathic pulmonary fibrosis: clinical behavior and gene expression pattern

PLoS ONE

MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis

PLoS Med

Gene expression profiles of acute exacerbations of idiopathic pulmonary fibrosis

Am J Respir Crit Care Med

Molecular phenotypes distinguish patients with relatively stable from progressive idiopathic pulmonary fibrosis (IPF)

PLoS ONE

Gene expression profiling of familial and sporadic interstitial pneumonia

Am J Respir Crit Care Med

An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans

Science

MicroRNAs in cell proliferation, cell death, and tumorigenesis

Br J Cancer

Non-coding RNAs: a key to future personalized molecular therapy?

Review Article
MicroRNAs in idiopathic pulmonary fibrosis