A missing piece of the puzzle in pulmonary fibrosis: anoikis resistance promotes fibroblast activation.
A missing piece of the puzzle in pulmonary fibrosis: anoikis resistance promotes fibroblast activation.
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DOI：
10.1186/s13578-022-00761-2
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发表时间：
2022-02-25
影响因子：
7.5
通讯作者：
Chao J
中科院分区：
文献类型：
--
作者：
Yin J;Wang J;Zhang X;Liao Y;Luo W;Wang S;Ding J;Huang J;Chen M;Wang W;Fang S;Chao J
肺纤维化引发肺炎级联反应，导致以过度增殖为特征的成纤维细胞功能障碍。失巢凋亡是一种确保组织发育和体内平衡的生理过程。研究人员还没有明确确定失巢凋亡的破坏是否与肺纤维化有关。在这里，我们研究了二氧化硅通过抗失巢凋亡和随后的纤维化诱导成纤维细胞活化的机制。采用CCK-8、Western blot、细胞计数和流式细胞术检测肺纤维化过程中肺成纤维细胞、肺泡上皮细胞和内皮细胞的失巢凋亡。虽然这三种细胞类型显示出相似的增殖增加，但作为抗失巢凋亡标志物的NTRK 2的表达在成纤维细胞中特异性上调，表明肺纤维化中成纤维细胞独特的增殖机制，这可能与抗失巢凋亡有关。此外，还利用CRISPR/Cas9系统探讨了失巢凋亡抵抗的分子机制; SiO2诱导的炎症反应激活了肺成纤维细胞中的MAPK/PI 3 K信号通路，进而诱导ZC 3 H4蛋白的表达，从而特异性介导失巢凋亡抵抗，随后导致肺纤维化。目前的研究揭示了成纤维细胞增殖的特定模式，靶向抗失巢凋亡的策略可能会抑制肺纤维化的病理过程。这一结果为治疗肺纤维化提供了一种新的方法，并为ZC 3 H4在开发减轻肺纤维化的新治疗策略中的潜在应用提供了新的见解。在线版本包含补充材料，可通过10.1186/s13578-022-00761-2获得。
Pulmonary fibrosis initiates a pneumonic cascade that leads to fibroblast dysfunction characterized by excess proliferation. Anoikis is a physiological process that ensures tissue development and homeostasis. Researchers have not clearly determined whether disruption of anoikis is involved in pulmonary fibrosis. Here, we investigated the mechanism by which silica induces fibroblast activation via anoikis resistance and subsequent fibrosis. Anoikis of lung fibroblasts, alveolar epithelial cells and endothelial cells during the process of fibrosis was detected using CCK-8, western blot, cell count and flow cytometry (FCM) assays. Although the three cell types showed similar increases in proliferation, the expression of NTRK2, a marker of anoikis resistance, was upregulated specifically in fibroblasts, indicating the unique proliferation mechanism of fibroblasts in pulmonary fibrosis, which may be related to anoikis resistance. Furthermore, the CRISPR/Cas9 system was used to investigate the molecular mechanism of anoikis resistance; the SiO2-induced inflammatory response activated the MAPK/PI3K signaling pathway in lung fibroblasts and then induced the expression of the ZC3H4 protein, which specifically mediated anoikis resistance, followed by pulmonary fibrosis. The current study revealed a specific pattern of fibroblast proliferation, and strategies targeting anoikis resistance may inhibit the pathological process of pulmonary fibrosis. This result provides a new approach for treating pulmonary fibrosis and new insights into the potential application of ZC3H4 in the development of novel therapeutic strategies for mitigating pulmonary fibrosis. The online version contains supplementary material available at 10.1186/s13578-022-00761-2.
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通讯作者：
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作者：
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作者：
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