Environmental particulate (PM2.5) augments stiffness-induced alveolar epithelial cell mechanoactivation of transforming growth factor beta.
Environmental particulate (PM2.5) augments stiffness-induced alveolar epithelial cell mechanoactivation of transforming growth factor beta.
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DOI：
10.1371/journal.pone.0106821
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Barker TH
中科院分区：
文献类型：
--
作者：
Dysart MM;Galvis BR;Russell AG;Barker TH
肺稳态和修复功能失调，包括肺纤维化（PF）、慢性阻塞性肺病（COPD）和肿瘤发生等疾病在过去十年中不断增加，这一事实与环境影响密切相关。多项研究表明，为了响应转化生长因子 - β (TGFβ) 信号传导的增加，II 型肺泡 (ATII) 上皮细胞会发生表型变化，这可能导致 PF 的复杂病理学变化。我们之前已经证明，与 PF 相关的组织硬度增加是上皮细胞激活 TGFβ 的有效细胞外基质 (ECM) 信号。本文报道的工作探讨了组织硬度与暴露于环境刺激下 TGFβ 激活之间的关系。我们假设 ATII 细胞暴露于细颗粒物 (PM2.5) 将导致细胞收缩性增强、TGFβ 激活以及随后 ATII 细胞表型的变化。 ATII 细胞在添加或不添加 PM2.5 的情况下在逐渐变硬的基质上培养。暴露于 PM2.5 会导致 TGFβ 活化增加、细胞收缩性增加以及 ATII 细胞伸长。最值得注意的是，在 8 kPa 基质上，硬度大于正常但小于已形成的纤维化肺，添加 PM2.5 导致皮层细胞硬度增加、肌动蛋白染色增强和细胞伸长；这是在没有 PM2.5 的情况下不会出现的结果。我们的工作表明，PM2.5 暴露还增强了 ECM 硬度和 TGFβ 之间现有的相互作用，这一点已在之前报道过。此外，我们表明这种额外的增强可能是细胞内活性氧（ROS）导致 TGFβ 信号事件增加的结果。这些结果强调了微机械和生化环境在肺部疾病发生中的重要性，并表明处于纤维化过程中肺部重塑早期阶段的个体在暴露于环境损伤佐剂时可能比健康个体更容易受到影响。
Dysfunctional pulmonary homeostasis and repair, including diseases such as pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD), and tumorigenesis have been increasing over the past decade, a fact that heavily implicates environmental influences. Several investigations have suggested that in response to increased transforming growth factor - beta (TGFβ) signaling, the alveolar type II (ATII) epithelial cell undergoes phenotypic changes that may contribute to the complex pathobiology of PF. We have previously demonstrated that increased tissue stiffness associated with PF is a potent extracellular matrix (ECM) signal for epithelial cell activation of TGFβ. The work reported here explores the relationship between tissue stiffness and exposure to environmental stimuli in the activation of TGFβ. We hypothesized that exposure of ATII cells to fine particulate matter (PM2.5) will result in enhanced cell contractility, TGFβ activation, and subsequent changes to ATII cell phenotype. ATII cells were cultured on increasingly stiff substrates with or without addition of PM2.5. Exposure to PM2.5 resulted in increased activation of TGFβ, increased cell contractility, and elongation of ATII cells. Most notably, on 8 kPa substrates, a stiffness greater than normal but less than established fibrotic lung, addition of PM2.5 resulted in increased cortical cell stiffness, enhanced actin staining and cell elongation; a result not seen in the absence of PM2.5. Our work suggests that PM2.5 exposure additionally enhances the existing interaction between ECM stiffness and TGFβ that has been previously reported. Furthermore, we show that this additional enhancement is likely a consequence of intracellular reactive oxygen species (ROS) leading to increased TGFβ signaling events. These results highlight the importance of both the micromechanical and biochemical environment in lung disease initiation and suggest that individuals in early stages of lung remodeling during fibrosis may be more susceptible than healthy individuals when exposed to environmental injury adjuvants.
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影响因子：
2.9
作者：
ABE, M;HARPEL, JG;RIFKIN, DB
通讯作者：
RIFKIN, DB
影响因子：
64.5
作者：
Choquet, D;Felsenfeld, DP;Sheetz, MP
通讯作者：
Sheetz, MP
影响因子：
1.5
作者：
Bonner, James C.
通讯作者：
Bonner, James C.
影响因子：
3.3
作者：
Arnoux, Valerie;Nassour, Mayssaa;Savagner, Pierre
通讯作者：
Savagner, Pierre
DOI：
10.1083/jcb.200405004
发表时间：
2004-09-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
Engler AJ;Griffin MA;Sen S;Bönnemann CG;Sweeney HL;Discher DE
通讯作者：
Discher DE