The JAK2 pathway is activated in idiopathic pulmonary fibrosis.
The JAK2 pathway is activated in idiopathic pulmonary fibrosis.
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DOI：
10.1186/s12931-018-0728-9
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发表时间：
2018-02-06
影响因子：
5.8
通讯作者：
Cortijo J
中科院分区：
文献类型：
--
作者：
Milara J;Hernandez G;Ballester B;Morell A;Roger I;Montero P;Escrivá J;Lloris JM;Molina-Molina M;Morcillo E;Cortijo J
特发性肺纤维化（IPF）是最迅速进展和致命的纤维化疾病，没有治愈的治疗方法。信号传导和转录激活因子3 （STAT3）蛋白在肺成纤维细胞和肺泡II型细胞（ATII）中被激活，从而促进IPF肺纤维化。虽然Janus激酶2 （JAK2）的激活与增殖性疾病有关，但其在IPF中的作用尚不清楚。本研究的目的是分析JAK2在IPF中的激活，并确定JAK2/STAT3抑制是否是该疾病的潜在治疗策略。采用实时荧光定量pcr、western blotting和免疫组织化学检测JAK2/p-JAK2和STAT3/pSTAT3的表达。与人类健康肺组织（n = 10）相比，IPF患者肺组织中这两种蛋白均上调（n = 12）。用转化生长因子β 1或白细胞介素(IL)-6/IL-13刺激原代ATII和肺成纤维细胞激活JAK2和STAT3，诱导上皮细胞向间充质细胞和成纤维细胞向肌成纤维细胞转变。JSI-124双重抑制p-JAK2/p-STAT3或沉默JAK2和STAT3基因抑制ATII和成纤维细胞向肌成纤维细胞的转变，比单独使用JAK2或STAT3抑制剂获得的效果总和更大。双重抑制比单一抑制更有效地抑制成纤维细胞迁移，防止成纤维细胞衰老和Bcl-2表达的增加，并改善受损的自噬。大鼠给予1 mg/kg/天剂量的JSI-124 （p-JAK2/p-STAT3的双重抑制剂），博莱霉素诱导的肺纤维化减少，肺内胶原沉积被抑制，JAK2和STAT3的激活以及一些纤维化、自噬、衰老和抗凋亡的标志物也被抑制。JAK2和STAT3在IPF中被激活，它们的双重抑制可能是治疗这种疾病的一种有吸引力的策略。本文的在线版本（10.1186/s12931-018-0728-9）包含补充材料，授权用户可以使用。
Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal fibrotic disorder, with no curative therapies. The signal transducer and activator of transcription 3 (STAT3) protein is activated in lung fibroblasts and alveolar type II cells (ATII), thereby contributing to lung fibrosis in IPF. Although activation of Janus kinase 2 (JAK2) has been implicated in proliferative disorders, its role in IPF is unknown. The aim of this study was to analyze JAK2 activation in IPF, and to determine whether JAK2/STAT3 inhibition is a potential therapeutic strategy for this disease. JAK2/p-JAK2 and STAT3/pSTAT3 expression was evaluated using quantitative real time-PCR, western blotting, and immunohistochemistry. Compared to human healthy lung tissue (n = 10) both proteins were upregulated in the lung tissue of IPF patients (n = 12). Stimulating primary ATII and lung fibroblasts with transforming growth factor beta 1 or interleukin (IL)-6/IL-13 activated JAK2 and STAT3, inducing epithelial to mesenchymal and fibroblast to myofibroblast transitions. Dual p-JAK2/p-STAT3 inhibition with JSI-124 or silencing of JAK2 and STAT3 genes suppressed ATII and the fibroblast to myofibroblast transition, with greater effects than the sum of those obtained using JAK2 or STAT3 inhibitors individually. Dual rather than single inhibition was also more effective for inhibiting fibroblast migration, preventing increases in fibroblast senescence and Bcl-2 expression, and ameliorating impaired autophagy. In rats administered JSI-124, a dual inhibitor of p-JAK2/p-STAT3, at a dose of 1 mg/kg/day, bleomycin-induced lung fibrosis was reduced and collagen deposition in the lung was inhibited, as were JAK2 and STAT3 activation and several markers of fibrosis, autophagy, senescence, and anti-apoptosis. JAK2 and STAT3 are activated in IPF, and their dual inhibition may be an attractive strategy for treating this disease. The online version of this article (10.1186/s12931-018-0728-9) contains supplementary material, which is available to authorized users.
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影响因子：
10
作者：
Mata, M;Sarriá, B;Morcillo, EJ
通讯作者：
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影响因子：
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作者：
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通讯作者：
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