Downregulation of Sfrp5 in insulin resistant rats promotes macrophage-mediated pulmonary inflammation through activation of Wnt5a/JNK1 signaling
Downregulation of Sfrp5 in insulin resistant rats promotes macrophage-mediated pulmonary inflammation through activation of Wnt5a/JNK1 signaling
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DOI：
10.1016/j.bbrc.2018.09.070
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发表时间：
2018-10-28
影响因子：
3.1
通讯作者：
Song, Shuang
中科院分区：
文献类型：
--
作者：
Zhu, Zhen;Yin, Shaojun;Song, Shuang
背景：胰岛素抵抗(IR)是慢性阻塞性肺疾病(COPD)的常见并存疾病，可加重COPD患者的呼吸道炎症，但其机制尚不清楚。Sfrp5是一种新型的抗炎脂肪细胞因子，可抑制巨噬细胞介导的脂肪组织炎症反应，抑制IR。然而，关于Sfrp5在肺部炎症中的调节作用的研究很少。方法：本研究将30只SD大鼠随机分为两组：正常饮食组和高脂饮食组。采用口服葡萄糖耐量试验(OGTT)和胰岛素释放试验评价胰岛素抵抗大鼠模型的建立。检测Wnt5a/JNKI信号通路下游关键分子Sfrp5的表达。观察肺组织病理形态和巨噬细胞活化情况。并计数肺泡灌洗液(BALF)中炎性细胞数及炎性细胞因子水平。体外分离大鼠肺巨噬细胞，用Wnt5a、Sfrp5和/或JNK抑制剂SP600125处理。结果：IR大鼠肺组织中Sfrp5表达下调，Wnt5a/Inki通路激活，肺组织炎症反应增强。同时，Sfrp5显著抑制Wnt5a/JNKI诱导的巨噬细胞活化。结论：IR可降低肺组织Sfrp5的表达，激活Wnt5a/JNK1通路，促进巨噬细胞活化，参与肺的炎症反应。相反，Sfrp5通过抑制Wnt5a/JNKI通路抑制炎症反应，而Wnt5a/JNKI通路可能是COPD治疗的靶点。(C)2018 Elsevier Inc.保留所有权利。
Background: Insulin resistance (IR), a common co-morbidity of chronic obstructive pulmonary disease (COPD), aggravates airway inflammation in COPD patients, but its mechanism is unclear. Sfrp5, a novel anti-inflammatory adipocytokine, inhibits macrophage-mediated inflammation of adipose tissue and abrogates IR. However, few studies have been conducted on the regulatory role of Sfrp5 in lung inflammation.Methods: In the present study, 30 SD rats were divided into two groups: the normal food (NF) group and the high-fat diet (HFD) group. Oral glucose tolerance test (OGTT) and insulin release test were performed to assess whether a successful IR rat model was established. The expression of Sfrp5 and key downstream moleculars of Wnt5a/JNKI signaling was detected. Lung tissue pathomorphology and macrophage activation were observed. In addition, we counted the number of inflammatory cells and measured inflammatory cytokines in bronchoalveolar lavage fluid (BALF). In vitro, rat lung macrophages were isolated and treated with Wnt5a, Sfrp5, and/or JNK inhibitor SP600125. JNK activity and inflammatory cytokines expression were examined.Results: We found that in a rat model of IR, Sfrp5 expression of lung tissue was downregulated, while the Wnt5a/INKI pathway was activated and the lung inflammatory response was enhanced. Meanwhile, Sfrp5 significantly suppressed Wnt5a/JNKI-induced macrophage activation.Conclusions: Collectively, IR reduces Sfrp5 expression of lung tissue and activates the Wnt5a/JNK1 pathway, promoting macrophage activation and contributing to the lung's inflammatory response. In contrast, Sfrp5 suppresses the inflammatory response by inhibiting the Wnt5a/JNKI pathway, which could be a target of treatment of COPD. (C) 2018 Elsevier Inc. All rights reserved.