New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis

Fernandez, Isis E.; Eickelberg, Oliver

doi:10.1016/s0140-6736(12)61144-1

Cited by 391 publications

(327 citation statements)

References 92 publications

Supporting

Mentioning

321

Contrasting

Unclassified

Order By: Relevance

“…Current pathogenic theories suggest an aberrant woundhealing process in response to repetitive injuries to the alveolar epithelium in genetically predisposed individuals (3)(4)(5)(6)(7). The IPF lung is characterized by extensive histological changes that include formation of fibroblast/myofibroblast foci, accumulation of extracellular matrix, and areas of aberrant remodeling interspersed with normal lung parenchyma (8).…”

mentioning

confidence: 99%

SH2 Domain–Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis

Tzouvelekis

Cardenas

et al. 2017

Am J Respir Crit Care Med

View full text Add to dashboard Cite

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease with dismal prognosis and no cure. The potential role of the ubiquitously expressed SH2 domain-containing tyrosine phosphatase-2 (SHP2) as a therapeutic target has not been studied in IPF.Objectives: To determine the expression, mechanistic role, and potential therapeutic usefulness of SHP2 in pulmonary fibrosis.Methods: The effects of SHP2 overexpression and inhibition on fibroblast response to profibrotic stimuli were analyzed in vitro in primary human and mouse lung fibroblasts. In vivo therapeutic effects were assessed in the bleomycin model of lung fibrosis by SHP2-lentiviral administration and transgenic mice carrying a constitutively active SHP2 mutation.Measurements and Main Results: SHP2 was down-regulated in lungs and lung fibroblasts obtained from patients with IPF. Immunolocalization studies revealed that SHP2 was absent within fibroblastic foci. Loss of SHP2 expression or activity was sufficient to induce fibroblast-to-myofibroblast differentiation in primary human lung fibroblasts. Overexpression of constitutively active SHP2 reduced the responsiveness of fibroblasts to profibrotic stimuli, including significant reductions in cell survival and myofibroblast differentiation. SHP2 effects were mediated through deactivation of fibrosis-relevant tyrosine kinase and serine/threonine kinase signaling pathways. Mice carrying the Noonan syndrome-associated gain-of-function SHP2 mutation (SHP2 D61G/1 ) were resistant to bleomycin-induced pulmonary fibrosis. Restoration of SHP2 levels in vivo through lentiviral delivery blunted bleomycin-induced pulmonary fibrosis.Conclusions: Our data suggest that SHP2 is an important regulator of fibroblast differentiation, and its loss as observed in IPF facilitates profibrotic phenotypic changes. Augmentation of SHP2 activity or expression should be investigated as a novel therapeutic strategy for IPF.

show abstract

mentioning

confidence: 99%

SH2 Domain–Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis

Tzouvelekis

Cardenas

et al. 2017

Am J Respir Crit Care Med

View full text Add to dashboard Cite

show abstract

“…A central pathway in the pathogenesis of pulmonary fibrosis is activation of transforming growth factor ␤ (TGF␤) in epithelial cells and activation of the downstream Smad signaling pathway (3). TGF␤ is a pleiotropic cytokine involved in development, inflammation, and wound repair.…”

mentioning

confidence: 99%

“…Aberrant activation of TGF␤ is implicated in the pathogenesis of chronic lung disease such as pulmonary fibrosis (4), asthma (5), and emphysema (6). TGF␤ is secreted noncovalently associated with the latencyassociated peptide (LAP), 3 rendering it as an inactive small latent complex. Association of the small latent complex with the latent TGF␤-binding protein (LTBP1-4) forms the large latent complex, which is tethered to, and sequestered in, the extracellular matrix.…”

mentioning

confidence: 99%

Influenza Promotes Collagen Deposition via αvβ6 Integrin-mediated Transforming Growth Factor β Activation

Jolly

Stavrou

Vanderstoken

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:The mechanism of influenza mediated TGF␤ activation, and its role in pathogenesis is unclear. Results: H1N1 infection induced ␣v␤6-dependent TGF␤ activity in iHBECs and increased epithelial cell death and collagen deposition in vivo. Conclusion: ␣v␤6 integrin-mediated TGF␤ activation is involved in cell death and fibrogenesis following virus-induced epithelial injury. Significance: Viral infection may promote acute exacerbations of fibrotic lung disease.

show abstract

“…Although several genetic, epigenetic, and proteomic studies have been conducted to date, studies investigating miRNA regulatory networks in IPF have only recently gained significant attention [2]. Our previous study revealed that miR-30a can block mitochondrial fission, which is dependent on Drp-1, to regulate the development of IPF.…”

Section: Discussionmentioning

confidence: 99%

“…IPF is characterized by alveolar epithelial cell injury and activation, the formation of myofibroblast foci, and the exaggerated accumulation of extracellular matrix in the lung parenchyma. Despite significant progress, the etiology and molecular mechanisms underlying IPF are largely unknown [2].…”

Section: Introductionmentioning

confidence: 99%

miR-30a as Potential Therapeutic by Targeting TET1 through Regulation of the Hydroxymethlation of Drp-1 Promoter in IPF

Zhang¹,

Liu²,

Liu³

et al. 2017

Preprint

View full text Add to dashboard Cite

(X.S.) † These authors contributed equally to this work.Abstract：Several recent studies have indicated that miR-30a plays critical roles in various biological processes and diseases. However, the mechanism of miR-30a participation in the regulation of idiopathic pulmonary fibrosis (IPF) is ambiguous.Our previous study demonstrated that miR-30a may function as a novel therapeutic target for lung fibrosis by blocking mitochondrial fission, which is dependent on dynamin-related protein-1 (Drp-1). However, the regulatory mechanism between miR-30a and Drp-1 has yet to be investigated. In addition, whether miR-30a can act as a potential therapeutic has not been verified in vivo. In this study, the miR-30a expression in IPF patients was evaluated. Computational analysis and a dual luciferase reporter system assay were used to identify the target gene of miR-30a, and cell transfection was used to confirm this relationship. Ten-eleven translocation 1 (TET1) was validated as a direct target of miR-30a, and the transfection of miR-30a mimic/inhibitor significantly reduced/increased the expression of TET1 protein.Further experiment verified that the interference on TET1(siRNA) could inhibit the hydroxymethlation of the Drp-1 promoter. Finally, miR-30a agomir was designed and applied to identify and validate the therapeutic effect of miR-30a in vivo. Our study demonstrated that miR-30a could inhibit the TET1 expression by base pairing with complementary sites in the 3′ untranslated region to regulate the hydroxymethlation of the Drp-1 promoter. Furthermore, miR-30a could act as a potential therapeutic target for IPF.

show abstract

New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis

Cited by 391 publications

References 92 publications

SH2 Domain–Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis

SH2 Domain–Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis

Influenza Promotes Collagen Deposition via αvβ6 Integrin-mediated Transforming Growth Factor β Activation

miR-30a as Potential Therapeutic by Targeting TET1 through Regulation of the Hydroxymethlation of Drp-1 Promoter in IPF

Contact Info

Product

Resources

About