Breton Jean-Didier, Heydet Déborah, Starrs Lora M, Veldre Tim, Ghildyal Reena
Respiratory Virology Group, Centre for Research in Therapeutic Solutions, Faculty of Science and Technology, University of Canberra, Canberra, Australia.
ANU Medical School, The Australian National University, Canberra, Australia.
Physiol Rep. 2018 Apr;6(7):e13669. doi: 10.14814/phy2.13669.
Airway remodeling is an important process in response to repetitive inflammatory-mediated airway wall injuries. This is characterized by profound changes and reorganizations at the cellular and molecular levels of the lung tissue. It is of particular importance to understand the mechanisms involved in airway remodeling, as this is strongly associated with severe asthma leading to devastating airway dysfunction. In this study, we have investigated the transforming growth factor-β (TGFβ, a proinflammatory mediator)-activated fibroblast to myofibroblast transdifferentiation pathway, which plays a key role in asthma-related airway remodeling. We show that TGFβ induces fibroblast to myofibroblast transdifferentiation by the expression of αSMA, a specific myofibroblast marker. Furthermore, Smad2/Smad3 gene and protein expression patterns are different between fibroblasts and myofibroblasts. Such a change in expression patterns reveals an important role of these proteins in the cellular phenotype as well as their regulation by TGFβ during cellular transdifferentiation. Interestingly, our data show a myofibroblastic TGFβ-mediated increase in glucocorticoid receptor (GR) expression and a preferential localization of GR in the nucleus, compared to in fibroblasts. Furthermore, the GRβ (nonfunctional GR isoform) is increased relative to GRα (functional isoform) in myofibroblasts. These results are interesting as they support the idea of a GRβ-mediated glucocorticoid resistance observed in the severe asthmatic population. All together, we provide evidence that key players are involved in the TGFβ-mediated fibroblast to myofibroblast transdifferentiation pathway in a human lung fibroblast cell line. These players could be the targets of new treatments to limit airway remodeling and reverse glucocorticoid resistance in severe asthma.
气道重塑是对重复性炎症介导的气道壁损伤作出反应的一个重要过程。其特征是肺组织在细胞和分子水平上发生深刻变化和重组。了解气道重塑所涉及的机制尤为重要，因为这与导致严重气道功能障碍的重度哮喘密切相关。在本研究中，我们研究了转化生长因子-β（TGFβ，一种促炎介质）激活的成纤维细胞向肌成纤维细胞转分化途径，该途径在哮喘相关的气道重塑中起关键作用。我们发现，TGFβ通过特异性肌成纤维细胞标志物αSMA的表达诱导成纤维细胞向肌成纤维细胞转分化。此外，成纤维细胞和肌成纤维细胞之间的Smad2/Smad3基因和蛋白表达模式有所不同。这种表达模式的变化揭示了这些蛋白在细胞表型中的重要作用以及它们在细胞转分化过程中受TGFβ调控的情况。有趣的是，我们的数据显示，与成纤维细胞相比，肌成纤维细胞中TGFβ介导的糖皮质激素受体（GR）表达增加，且GR优先定位于细胞核。此外，肌成纤维细胞中GRβ（无功能的GR异构体）相对于GRα（有功能的异构体）增加。这些结果很有意思，因为它们支持了在重度哮喘患者中观察到的GRβ介导的糖皮质激素抵抗这一观点。总之，我们提供了证据表明关键参与者参与了人肺成纤维细胞系中TGFβ介导的成纤维细胞向肌成纤维细胞转分化途径。这些参与者可能是限制气道重塑和逆转重度哮喘中糖皮质激素抵抗的新治疗方法的靶点。
