MicroRNA-27a alleviates LPS-induced acute lung injury in mice via inhibiting inFLammation and apoptosis through modulating TLR4/MyD88/NF-κB pathway
MicroRNA-27a alleviates LPS-induced acute lung injury in mice via inhibiting inFLammation and apoptosis through modulating TLR4/MyD88/NF-κB pathway
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DOI：
10.1080/15384101.2018.1509635
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发表时间：
2018-01-01
期刊：
影响因子：
4.3
通讯作者：
Luo, Zhe
中科院分区：
文献类型：
--
作者：
Ju, MinJie;Liu, BoFei;Luo, Zhe
急性肺损伤（acute lung injury，ALI）是一种严重的临床疾病，以过度的炎症反应和细胞凋亡为特征，死亡率高。近年来，研究发现microRNA（miRNAs）在改善包括ALI在内的多种炎症诱导的疾病中发挥重要作用。然而，miRNAs在ALI炎症和凋亡调控中的生物学功能及其调控机制尚不清楚。本研究的目的是鉴定和评估miRNAs在ALI中的潜在作用，并揭示其作用的潜在分子机制。在这里，我们分析了microRNA表达谱从LPS攻击小鼠肺组织中使用miRNA微阵列。由于microRNA-27 a（miR-27 a）是下调最显著的miRNAs之一，在炎症调节中具有重要作用，因此我们研究了其功能。通过agomir-27 a过表达miR-27 a改善肺损伤，如通过减少肺组织病理学变化、肺湿/干（W/D）比、肺微血管通透性和肺组织中的细胞凋亡以及改善ALI小鼠的存活率所证明的。这伴随着炎症的缓解，例如总BALF细胞和中性粒细胞计数减少，BAL液中肿瘤坏死因子α（TNF-α）、白细胞介素-1（IL-6）、白细胞介素-1 β（IL-1 β）和髓过氧化物酶（MPO）活性水平降低。Toll样受体4（TLR 4）是核因子κ B（NF-κ B）信号通路的重要调节因子，是miR-27 a在RAW 264. 7细胞中的新靶点。LPS刺激后MyD 88和NF-κ B p65（p-p65）表达增加，而核因子-κ B-α抑制因子（I kappa B-alpha）表达减少，提示NF-κ B信号通路激活。进一步研究发现，agomir-miR-27 a逆转了LPS对NF-κ B信号通路的促进作用。结果提示，miR-27 a通过阻断TLR 4/MyD 88/NF-κ B的活化，减少炎症和凋亡，从而减轻LPS诱导的小鼠ALI。
Acute lung injury (ALI) is a critical clinical condition with a high mortality rate, characterized with excessive uncontrolled inflammation and apoptosis. Recently, microRNAs (miRNAs) have been found to play crucial roles in the amelioration of various inflammation-induced diseases, including ALI. However, it remains unknown the biological function and regulatory mechanisms of miRNAs in the regulation of inFLammation and apoptosis in ALI. The aim of this study is to identify and evaluate the potential role of miRNAs in ALI and reveal the underlying molecular mechanisms of their effects. Here, we analyzed microRNA expression profiles in lung tissues from LPS-challenged mice using miRNA microarray. Because microRNA-27a (miR-27a) was one of the miRNAs being most significantly downregulated, which has an important role in regulation of inflammation, we investigated its function. Overexpression of miR-27a by agomir-27a improved lung injury, as evidenced by the reduced histopathological changes, lung wet/dry (W/D) ratio, lung microvascular permeability and apoptosis in the lung tissues, as well as ameliorative survival of ALI mice. This was accompanied by the alleviating of inflammation, such as the reduced total BALF cell and neutrophil counts, decreased levels of tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-6) interleukin-1 beta (IL-1 beta) and myeloperoxidase (MPO) activity in BAL fluid. Toll-like receptor 4 (TLR4), an important regulator of the nuclear factor kappa-B (NF-kappa B) signaling pathway, was identified as a novel target of miR-27a in RAW264.7 cells. Furthermore, our results showed that LPS stimulation increased the expression of MyD88 and NF-kappa B p65 (p-p65), but inhibited the expression of inhibitor of nuclear factor-kappa B-alpha (I kappa B-alpha), suggesting the activation of NF-kappa B signaling pathway. Further investigations revealed that agomir-miR-27a reversed the promoting effect of LPS on NF-kappa B signaling pathway. The results here suggested that miR-27a alleviates LPS-induced ALI in mice via reducing inFLammation and apoptosis through blocking TLR4/MyD88/NF-kappa B activation.