Department of Pediatrics, Renmin Hospital of Hubei University of Medicine, Shiyan, 442000, China.
Department of Pediatrics, Pediatrics of Traditional Chinese Medicine Hospital of Baoji City, Baoji, 721001, China.
Biochem Biophys Res Commun. 2019 Mar 26;511(1):49-56. doi: 10.1016/j.bbrc.2019.01.041. Epub 2019 Feb 11.
Acute lung injury (ALI) is served as a severe life-threatening disease. However, the pathogenesis that contributes to ALI has not been fully understood. Tumor necrosis factor receptor-associated factor 1 (TRAF1) interacts with multiple regulators, performing its diverse role in biological functions. However, the effects of TRAF1 on ALI remain unknown. In this study, we attempted to explore the role of TRAF1 in ALI progression. The findings suggested that TRAF1-knockout (KO) markedly attenuated LPS-induced severe mortality rate in murine animals. LPS-elicited histological alterations in pulmonary tissues were significantly alleviated by TRAF1-deletion. Additionally, TRAF1 knockout effectively attenuated lung injury, as evidenced by the reduced lung wet/dry (W/D) weight ratio, as well as decreased bronchoalveolar lavage fluid (BALF) protein levels and neutrophil infiltration. Meanwhile, TRAF1 deletion markedly lessened inflammation, oxidative stress and apoptosis in BALF and/or lung tissues. The levels of pro-inflammatory cytokines stimulated by LPS were down-regulated by TRAF1 ablation, along with the inactivation of nuclear factor κB (NF-κB). LPS-promoted reactive oxygen species (ROS) generation was decreased in TRAF1-KO mice, partly through the improvement of anti-oxidants. Apoptosis was also inhibited by TRAF1 deletion in lung tissues of LPS-challenged mice through the suppression of cleaved Caspase-3. Moreover, TRAF1 knockout significantly decreased c-Jun N-terminal kinase (JNK) activation and its down-streaming signal of c-Jun in pulmonary samples of LPS-induced mice. Importantly, the in vitro study suggested that promoting JNK activation markedly abrogated TRAF1 knockdown-attenuated inflammation, ROS production and apoptosis in LPS-exposed A549 cells. Therefore, our experimental results provided evidence that TRAF1 suppression effectively protected LPS-induced ALI against inflammation, oxidative stress and apoptosis through the suppression of JNK activity.
急性肺损伤（ALI）是一种严重的危及生命的疾病。然而，导致 ALI 的发病机制尚未完全阐明。肿瘤坏死因子受体相关因子 1（TRAF1）与多种调节剂相互作用，在生物学功能中发挥其多种作用。然而，TRAF1 对 ALI 的影响尚不清楚。在这项研究中，我们试图探讨 TRAF1 在 ALI 进展中的作用。研究结果表明，TRAF1 敲除（KO）显著降低了 LPS 诱导的小鼠动物严重死亡率。TRAF1 缺失显著减轻了 LPS 引起的肺组织组织学改变。此外，TRAF1 敲除有效地减轻了肺损伤，表现为肺湿/干（W/D）重量比降低，支气管肺泡灌洗液（BALF）蛋白水平和中性粒细胞浸润减少。同时，TRAF1 缺失显着减轻了 BALF 和/或肺组织中的炎症、氧化应激和细胞凋亡。TRAF1 缺失使 LPS 刺激的促炎细胞因子水平下调，核因子 κB（NF-κB）失活。TRAF1-KO 小鼠中 LPS 促进的活性氧（ROS）生成减少，部分是通过改善抗氧化剂来实现的。TRAF1 缺失通过抑制裂解 Caspase-3 也抑制了 LPS 挑战的小鼠肺组织中的细胞凋亡。此外，TRAF1 缺失显着降低了 LPS 诱导的小鼠肺组织中 c-Jun N-末端激酶（JNK）的激活及其下游信号 c-Jun。重要的是，体外研究表明，促进 JNK 激活显着削弱了 TRAF1 敲低减轻的 LPS 暴露的 A549 细胞中的炎症、ROS 产生和细胞凋亡。因此，我们的实验结果表明，通过抑制 JNK 活性，TRAF1 抑制可有效保护 LPS 诱导的 ALI 免受炎症、氧化应激和细胞凋亡。
