Acute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. Atypical mitogen activated protein kinases (MAPKs) play critical roles in the development of tissues and have been proposed as promising therapeutic targets for various diseases. However, the potential role of atypical MAPKs in ALI remains elusive. In this study, we investigated the role of atypical MAPKs family member MAPK4 in ALI using LPS-induced murine ALI model. We found that MAPK4 deficiency mice exhibited prolonged survival time after LPS challenge, accompanied by alleviated pathology in lung tissues, decreased levels of pro-inflammatory cytokines and altered composition of immune cells in BALF. Furthermore, the transduction of related signaling pathways, including MK5, AKT, JNK, and p38 MAPK pathways, was reduced obviously in LPS-treated MAPK4−/− mice. Notably, the expression of MAPK4 was up-regulated in lung tissues of ALI model, which was not related with MAPK4 promoter methylation, but negatively orchestrated by transcriptional factors NFKB1 and NR3C1. Further studies have shown that the expression of MAPK4 was also increased in LPS-treated macrophages. Meanwhile, MAPK4 deficiency reduced the expression of related pro-inflammatory cytokines in macrophage in response to LPS treatment. Finally, MAPK4 knockdown using shRNA pre-treatment could ameliorate the pathology of lung tissues and prolong the survival time of mice after LPS challenge. Collectively, these findings reveal an important biological function of atypical MAPK in mediating the pathology of ALI, indicating that MAPK4 might be a novel potential therapeutic target for ALI treatment.

中文翻译：

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鉴定非典型丝裂原活化蛋白激酶 MAPK4 作为急性肺损伤的新型调节剂

急性肺损伤 (ALI) 是一种具有高发病率和死亡率的严重疾病，在全球范围内导致严重的健康问题。非典型有丝分裂原活化蛋白激酶 (MAPKs) 在组织发育中发挥关键作用，并已被提议作为各种疾病的有希望的治疗靶点。然而，非典型 MAPK 在 ALI 中的潜在作用仍然难以捉摸。在这项研究中，我们使用 LPS 诱导的小鼠 ALI 模型研究了非典型 MAPKs 家族成员 MAPK4 在 ALI 中的作用。我们发现 MAPK4 缺陷小鼠在 LPS 攻击后表现出延长的存活时间，伴随着肺组织病理学减轻，促炎细胞因子水平降低和 BALF 中免疫细胞组成改变。此外，相关信号通路的转导，包括 MK5、AKT、JNK 和 p38 MAPK 通路，在 LPS 处理的 MAPK4 - / - 小鼠中明显减少。值得注意的是，ALI模型肺组织中MAPK4的表达上调，这与MAPK4启动子甲基化无关，但受转录因子NFKB1和NR3C1的负调控。进一步的研究表明，LPS 处理的巨噬细胞中 MAPK4 的表达也增加了。同时，MAPK4 缺乏降低了巨噬细胞中相关促炎细胞因子的表达，以响应 LPS 治疗。最后，使用shRNA预处理敲低MAPK4可以改善肺组织的病理学并延长LPS攻击后小鼠的存活时间。总的来说，这些发现揭示了非典型 MAPK 在介导 ALI 病理学中的重要生物学功能，表明 MAPK4 可能是 ALI 治疗的一个新的潜在治疗靶点。