miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis

By Gang Liu, A. Friggeri, Yanping Yang, J. Milošević, Q. Ding, V. Thannickal, Naftali Kaminski, E. Abraham. Journal of Experimental Medicine, 2010

950 citations recorded by the source corpus.

Uncontrolled extracellular matrix production by fibroblasts in response to tissue injury contributes to fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), a progressive and ultimately fatal process that currently has no cure. Although dysregulation of miRNAs is known to be involved in a variety of pathophysiologic processes, the role of miRNAs in fibrotic lung diseases is unclear. In this study, we found up-regulation of miR-21 in the lungs of mice with bleomycin-induced fibrosis and also in the lungs of patients with IPF. Increased miR-21 expression was primarily localized to myofibroblasts. Administration of miR-21 antisense probes diminished the severity of experimental lung fibrosis in mice, even when treatment was started 5–7 d after initiation of pulmonary injury. TGF-β1, a central pathological mediator of fibrotic diseases, enhanced miR-21 expression in primary pulmonary fibroblasts. Increasing miR-21 levels promoted, whereas knocking down miR-21 attenuated, the pro-fibrogenic activity of TGF-β1 in fibroblasts. A potential mechanism for the role of miR-21 in fibrosis is through regulating the expression of an inhibitory Smad, Smad7. These experiments demonstrate an important role for miR-21 in fibrotic lung diseases and also suggest a novel approach using miRNA therapeutics in treating clinically refractory fibrotic diseases, such as IPF.

Subfields: Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/90e9a983677d2aa8141963412a64ac165e9873b8

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. B. Hinz
2. TA Wynn
3. O. De Wever
4. M. Mareel
5. Maria-Teresa Piccoli
6. J. Beermann
7. T. Ramalingam
8. J. Viereck

In Pulmonary and Respiratory Medicine

1. TA Wynn
2. B. Hinz
3. T. Ramalingam
4. V. Thannickal
5. Nikolaos G. Frangogiannis

Citations in the corpus

• Mechanisms of fibrosis: therapeutic translation for fibrotic disease (2012, positive): “For example, miR-21 is expressed in the lungs of individuals with IPF, and mice treated with miR-21 antisense probes were protected from bleomycin-induced pulmonary fibrosis 138 and cardiac fibrosis induced by pressure overload 139 .”
• Integrating mechanisms of pulmonary fibrosis (2011, background): “Recently, miR-21 was identified in the lungs of patients with IPF and in mice with bleomycin-induced pulmonary fibrosis (Liu et al., 2010).”
• Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. (2012, background): “Among these, Let7 and miR-21 affect lung myofibroblast differentiation via effects on HMGA2 and Smad7, respectively, although additional effects on other target genes have not been excluded.(18,39) Future miRNA profiling studies, such as the one recently started for bleomycin-induced lung fibrosis,(”
• Non-coding RNAs in Development and Disease: Background, Mechanisms, and Therapeutic Approaches. (2016, background): “Furthermore, miR-21 and miR-29 have also been described in lung fibrosis. miR-21 upregulation is induced by TGFin mice with bleomycin-induced lung fibrosis and promotes the activation of fibroblasts by targeting SMAD7 (169).”