Acute Inflammation Induces Insulin-like Growth Factor-1 to Mediate Bcl-2 and Muc5ac Expression in Airway Epithelial Cells
Acute Inflammation Induces Insulin-like Growth Factor-1 to Mediate Bcl-2 and Muc5ac Expression in Airway Epithelial Cells
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DOI：
10.1165/rcmb.2012-0079oc
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发表时间：
2012-12-01
影响因子：
6.4
通讯作者：
Tesfaigzi, Yohannes
中科院分区：
文献类型：
--
作者：
Chand, Hitendra S.;Woldegiorgis, Zekarias;Tesfaigzi, Yohannes
一般来说，人体呼吸道暴露于脂多糖以气雾剂的形式发生，并通过促进气道重塑和相关的病理改变而引起急性炎症反应或加重现有的慢性炎症状况。本研究评估了哪些炎性介质可能与雾化内毒素暴露小鼠的Bcl2表达和粘液细胞化生有关。暴露后3天，雾化吸入估计肺沉积剂量分别为0、0.02、0.2、1.4和20.2毫克的脂多糖(20-40分钟)可见中性粒细胞呈剂量依赖性增加。IL-1β、TNF-α、IL-6、生长相关癌基因或角质形成细胞衍生细胞因子、干扰素-γ诱导蛋白-10、单核细胞趋化蛋白-1和巨噬细胞炎性蛋白-1α等促炎介质在高剂量组显著升高。除了呼吸道上皮细胞数量增加外，粘液细胞数量和粘液产量也呈剂量依赖性增加。增生性上皮细胞表达胰岛素样生长因子(IGF)-1，与以前的研究类似，增加了生存蛋白Bcl-2的表达，并诱导了Muc5ac的表达。利用逆转录病毒shRNA抑制IGF-1的表达可阻断人和小鼠呼吸道上皮细胞中Bcl2的表达，以及原代小鼠呼吸道上皮细胞中Muc5ac的表达。这些结果表明，急性炎症诱导IGF-1介导气道上皮细胞表达Bcl2和Muc5ac。
Generally, exposure to LPS in human airways occurs in the form of aerosols and causes an acute inflammatory response or exacerbates existing chronic inflammatory conditions by enhancing airway remodeling and associated pathologies. The present study evaluated which inflammatory mediators may be responsible for the expression of Bcl-2 and mucus cell metaplasia when mice are exposed to aerosolized LPS. At 3 days after exposure, aerosolized LPS (for 20-40min) with the estimated lung deposited dosage of 0, 0.02, 0.2, 1.4, and 20.2 mu g showed a characteristic dose-dependent increase in polymorphonuclear neutrophils. Significant increases of proinflammatory mediators, including IL-1 beta, TNF-alpha, IL-6, growth-related oncogene or keratinocyte-derived cytokine, IFN-gamma-induced protein-10, monocyte chemotactic protein-1, and macrophage inflammatory protein-1 alpha, were detected at the highest doses. In addition to increased numbers of airway epithelial cells, mucus cell numbers and mucus production were increased in a dose-dependent manner. Hyperplastic epithelial cells expressed insulin-like growth factor (IGF)-1 and, similar to previous studies, increased expression of the prosurvival protein Bcl-2 and induced expression of Muc5ac. Suppression of IGF-1 expression using retroviral shRNA blocked Bcl-2 expression in human and murine airway epithelial cells andMuc5ac in primary murine airway epithelial cells. These findings show that acute inflammation induces IGF-1 to mediate Bcl-2 and Muc5ac expression in airway epithelial cells.