The Role of Tuftelin-1 in Mesomesenchymal Transition of Pleural Mesothelial Cells and the Progression of Pleural Fibrosis.

IF 5.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Ann Jeffers, Shuzi Owens, Wenyi Qin, Olamipejo Durojaye, Matt Florence, Peace Okeke, Luis Destarac, Shiva Keshava, Mitsuo Ikebe, Steven Idell, Torry A Tucker
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引用次数: 0

Abstract

Pleural conditions causing exudative effusions (empyema or complicated parapneumonia), can result in pathological pleural organization leading to pleural fibrosis (PF). Pleural mesothelial cells (PMCs) undergo mesenchymal transition (MesoMT) and acquire a profibrotic phenotype characterized by increased expression of α-smooth muscle actin (α-SMA), collagen 1 (Col-1) and phenotypic changes including elongation, stress fiber formation and contraction. Using RNA sequencing analysis, we identified Tuftelin1 (Tuft1) as a novel potential target. Although Prior studies have shown that Tuft1 expression is associated with aggressive cellular phenotypes, its role in pleural fibrosis (PF) is unknown. Our prior studies show that inhibition of PI3K/Akt, mTORC2, or GSK-3β blocks MesoMT. In this study, we build on previous findings and suggest that Tuft1 plays a key role in promoting MesoMT. In human (PMCs), various mediators that induce MesoMT result in upregulation of Tuft1 expression. Furthermore, we also found that Tuft1 was increased in human pleuritis tissues and in murine models of PF compared to normal lung. In our studies, TGF-β mediated increase in Tuft1 was blocked by the GSK-3β inhibitor 9-ING-41. Knockdown of Tuft1 in vitro, blocked TGFβ mediated MesoMT. Conversely, Tuft1 overexpression induced mTORC2 signaling and promoted MesoMT in the absence of TGF-β. In vivo analyses showed that mesothelial cell-specific Tuft1 knockout mice (Tuft1PMC-/-) were protected from S. pneumoniae-mediated pleural injury. Histological analysis showed that pleural thickening and profibrotic markers were significantly reduced in Tuft1PMC-/- mice compared to WT controls. These studies strongly support therapeutic targeting of Tuft1 as a novel means to mitigate PF.

Tuftelin-1在胸膜间皮细胞间充质转化和胸膜纤维化进展中的作用
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来源期刊
CiteScore
11.20
自引率
3.10%
发文量
370
审稿时长
3-8 weeks
期刊介绍: The American Journal of Respiratory Cell and Molecular Biology publishes papers that report significant and original observations in the area of pulmonary biology. The focus of the Journal includes, but is not limited to, cellular, biochemical, molecular, developmental, genetic, and immunologic studies of lung cells and molecules.
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