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Loss of Family with Sequence Similarity 13, Member A Exacerbates Pulmonary Fibrosis Potentially by Promoting Epithelial to Mesenchymal Transition.

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a devastating disease with poor prognosis due to limited clinical treatment options. IPF is characterized by the augmented deposition of extracellular matrix driven by myofibroblasts, and the epithelial-mesenchymal transition (EMT) has been known to play an essential role in the mechanism of pulmonary fibrosis. Previous genome-wide association study identified Fam13a as one of genes that showed genetic link with IPF and chronic obstructive pulmonary disease. Here, we analyzed the role of Fam13a in the pathogenesis of pulmonary fibrosis using Fam13a-deficient mice. We found that Fam13a was down-regulated in mouse lungs of bleomycin-induced pulmonary fibrosis model. Of note, genetic deletion of Fam13a exacerbated the lung fibrosis induced by bleomycin in association with enhanced EMT in mice. Moreover, silencing of Fam13a accelerated EMT induced by TGF-? and TNF-? in alveolar epithelial cells, accompanied by increased active ?-catenin and its nuclear accumulation. Our data revealed a crucial role of Fam13a in the development of pulmonary fibrosis potentially through inhibiting EMT, and thus Fam13a has a therapeutic potential in the treatment of IPF.

SUBMITTER: Rahardini EP

PROVIDER: S-EPMC7012324 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Loss of Family with Sequence Similarity 13, Member A Exacerbates Pulmonary Fibrosis Potentially by Promoting Epithelial to Mesenchymal Transition.

Rahardini Elda Putri EP Ikeda Koji K Nugroho Dhite Bayu DB Hirata Ken-Ichi KI Emoto Noriaki N

The Kobe journal of medical sciences 20200120 3

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with poor prognosis due to limited clinical treatment options. IPF is characterized by the augmented deposition of extracellular matrix driven by myofibroblasts, and the epithelial-mesenchymal transition (EMT) has been known to play an essential role in the mechanism of pulmonary fibrosis. Previous genome-wide association study identified Fam13a as one of genes that showed genetic link with IPF and chronic obstructive pulmonary disease ...[more]

PMID: 32029695

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Project description:Intraflagellar transport protein 88 (Ift88) is required for ciliogenesis and shear stress-induced dissolution of cilia in embryonic endothelial cells coincides with endothelial-to-mesenchymal transition (EndMT) in the developing heart. EndMT is also suggested to underlie heart and lung fibrosis, however, the mechanism linking endothelial Ift88, its effect on EndMT and organ fibrosis remains mainly unexplored. We silenced Ift88 in endothelial cells (ECs) in vitro and generated endothelial cell-specific Ift88-knockout mice (Ift88endo) in vivo to evaluate EndMT and its contribution towards organ fibrosis, respectively. Ift88-silencing in ECs led to mesenchymal cells-like changes in endothelial cells. The expression level of the endothelial markers (CD31, Tie-2 and VE-cadherin) were significantly reduced with a concomitant increase in the expression level of mesenchymal markers (αSMA, N-Cadherin and FSP-1) in Ift88-silenced ECs. Increased EndMT was associated with increased expression of profibrotic Collagen I expression and increased proliferation in Ift88-silenced ECs. Loss of Ift88 in ECs was further associated with increased expression of Sonic Hedgehog signaling effectors. In vivo, endothelial cells isolated from the heart and lung of Ift88endo mice demonstrated loss of Ift88 expression in the endothelium. The Ift88endo mice were born in expected Mendelian ratios without any adverse cardiac phenotypes at baseline. Cardiac and pulmonary endothelial cells isolated from the Ift88endo mice demonstrated signs of EndMT and bleomycin treatment exacerbated pulmonary fibrosis in Ift88endo mice. Pressure overload stress in the form of aortic banding did not reveal a significant difference in cardiac fibrosis between Ift88endo mice and control mice. Our findings demonstrate a novel association between endothelial cilia with EndMT and cell proliferation and also show that loss of endothelial cilia-associated increase in EndMT contributes specifically towards pulmonary fibrosis.

Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with no effective treatment. The epithelial-mesenchymal transition (EMT) is a critical stage during the development of fibrosis. To assess the effect of sulforaphane (SFN) on the EMT and fibrosis using an in vitro transforming growth factor (TGF)-β1-induced model and an in vivo bleomycin (BLM)-induced model.MethodsIn vitro studies, cell viability, and cytotoxicity were measured using a Cell Counting Kit-8. The functional TGF-β1-induced EMT and fibrosis were assessed using western blotting and a quantitative real-time polymerase chain reaction. The lungs were analyzed histopathologically in vivo using hematoxylin and eosin and Masson's trichrome staining. The BLM-induced fibrosis was characterized by western blotting and immunohistochemical analyses for fibronectin, TGF-β1, E-cadherin (E-cad), and α-smooth muscle actin (SMA) in lung tissues.ResultsSFN reversed mesenchymal-like changes induced by TGF-β1 and restored cells to their epithelial-like morphology. The results confirmed that the expression of the epithelial marker, E-cadherin, increased after SFN treatment, while expression of the mesenchymal markers, N-cadherin, vimentin, and α-SMA decreased in A549 cells after SFN treatment. In addition, SFN inhibited TGF-β1-induced mRNA expression of the EMT-related transcription factors, Slug, Snail, and Twist. The SFN treatment attenuated TGF-β1-induced expression of fibrosis-related proteins, such as fibronection, collagen I, collagen IV, and α-SMA in MRC-5 cells. Furthermore, SFN reduced the TGF-β1-induced phosphorylation of SMAD2/3 protein in A549 cells and MRC-5 cells. BLM induced fibrosis in mouse lungs that was also attenuated by SFN treatment, and SFN treatment decreased BLM-induced fibronectin expression, TGF-β1 expression, and the levels of collagen I in the lungs of mice.ConclusionsSFN showed a significant anti-fibrotic effect in TGF-β-treated cell lines and BLM-induced fibrosis in mice. These findings showed that SFN has anti-fibrotic activity that may be considered in the treatment of IPF.

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Loss of Family with Sequence Similarity 13, Member A Exacerbates Pulmonary Fibrosis Potentially by Promoting Epithelial to Mesenchymal Transition.

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Loss of Family with Sequence Similarity 13, Member A Exacerbates Pulmonary Fibrosis Potentially by Promoting Epithelial to Mesenchymal Transition.

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