In Vivo Activation and Pro-Fibrotic Function of NF-κB in Fibroblastic Cells During Pulmonary Inflammation and Fibrosis Induced by Carbon Nanotubes
In Vivo Activation and Pro-Fibrotic Function of NF-κB in Fibroblastic Cells During Pulmonary Inflammation and Fibrosis Induced by Carbon Nanotubes
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DOI：
10.3389/fphar.2019.01140
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发表时间：
2019-10-02
影响因子：
5.6
通讯作者：
Ma, Qiang
中科院分区：
文献类型：
--
作者：
Dong, Jie;Ma, Qiang
暴露于肺中的不溶性颗粒会激发炎症反应，消除沉积的颗粒并修复受损的组织。过度或延长的反应会导致慢性疾病，如纤维化和恶性肿瘤，这些疾病通常是进行性的，对药物治疗无效，导致高致残率和死亡率。肺部炎症进展为慢性病理的分子事件，特别是向纤维化的转化，仍然知之甚少。已显示致纤维化多壁碳纳米管（MWCNT）刺激显著的急性炎症，其演变成以小鼠肺中的慢性炎症、间质纤维化和肉芽肿为特征的慢性病变。在这篇文章中，我们研究了多壁碳纳米管诱导的炎症和纤维化进展过程中成纤维细胞核因子-κ B（NF-κ B）信号的体内激活。通过咽部抽吸将野生型C57 BL/6 J雄性小鼠暴露于两种致纤维化MWCNT（Mitsui XNRI MWNT-7和长MWCNT）。在急性和慢性反应期间，两种多壁碳纳米管强烈刺激肺成纤维细胞和肌成纤维细胞中NF-κ B p65的核转位。在成纤维细胞核中，多壁碳纳米管显著诱导NF-κ B p65丝氨酸276处的磷酸化，NF-κ B活化的标志物。此外，在肺成纤维细胞和肌成纤维细胞中，分别编码促纤维化介质、金属蛋白酶组织抑制剂1（TIMP 1）和骨桥蛋白（OPN）的两种NF-κ B调节基因被显著诱导。这些结果表明，NF-κ B被激活介导的成纤维细胞中的促纤维化基因的转录在肺急性和慢性响应CNT，提供了一个机制框架，通过NF-κ B信号转导分析肺纤维化进展中的基因调控。
Exposure to insoluble particles in the lung elicits inflammatory responses that eliminate deposited particulates and repair damaged tissue. Overzealous or prolonged responses lead to chronic conditions, such as fibrosis and malignancy, which are frequently progressive and refractory to drug therapy leading to high rates of disability and mortality. The molecular events underlying the progression of lung inflammation to chronic pathology, in particular, the conversion to fibrosis, remain poorly understood. Fibrogenic multi-walled carbon nanotubes (MWCNTs) have been shown to stimulate prominent acute inflammation that evolves into chronic lesions characterized by chronic inflammation, interstitial fibrosis, and granulomas in mouse lungs. In this communication, we examined the in vivo activation of nuclear factor-kappa B (NF-kappa B) signaling in fibroblastic cells during the inflammatory and fibrotic progression induced by MWCNTs. Wild-type C57BL/6J male mice were exposed to two fibrogenic MWCNTs (Mitsui XNRI MWNT-7 and long MWCNTs) by pharyngeal aspiration. Both MWCNTs strongly stimulated the nuclear translocation of NF-kappa B p65 in lung fibroblasts and myofibroblasts during the acute and chronic responses. Phosphorylated NF-kappa B p65 at serine 276, a marker of NF-kappa B activation, was markedly induced by MWCNTs in the nucleus of fibroblastic cells. Moreover, two NF-kappa B-regulated genes encoding pro-fibrotic mediators, tissue inhibitor of metalloproteinase 1 (TIMP1), and osteopontin (OPN), respectively, were significantly induced in lung fibroblasts and myofibroblasts. These results demonstrate that NF-kappa B is activated to mediate transactivation of pro-fibrotic genes in fibroblastic cells during pulmonary acute and chronic responses to CNTs, providing a mechanistic framework for analyzing gene regulation in pulmonary fibrotic progression through NF-kappa B signaling.