Rhinovirus induces MUC5AC in a human infection model and in vitro via NF-κB and EGFR pathways
Rhinovirus induces MUC5AC in a human infection model and in vitro via NF-κB and EGFR pathways
复制标题
DOI：
10.1183/09031936.00026910
复制
发表时间：
2010-12-01
影响因子：
24.3
通讯作者：
Johnston, S. L.
中科院分区：
文献类型：
--
作者：
Hewson, C. A.;Haas, J. J.;Johnston, S. L.
鼻病毒(RV)感染是哮喘加重的主要原因，也是哮喘发病和死亡的主要原因。MUC5AC是支气管上皮细胞产生的主要粘蛋白。RV感染是否在体内上调MUC5AC尚不清楚，其分子机制尚不完全清楚。我们研究了RV在体内和体外对MUC5AC的诱导作用，以确定开发治疗哮喘加重的新疗法的靶点。在实验感染RV-16的正常和哮喘志愿者中，RV感染增加了MUC5AC的释放，在哮喘患者中，这与病毒载量有关。在体外，MUC5AC的RV诱导是通过依赖核因子-kappa B诱导基质金属蛋白酶介导的转化生长因子-α的释放，从而激活依赖于表皮生长因子受体的级联反应，最终通过丝裂原活化的蛋白激酶激活，在MUC5AC启动子的特异性蛋白-1反式激活中达到高潮。RV诱导MUC5AC可能是RV诱导体内哮喘加重的重要机制。揭示所涉及的复杂的一系列信号级联，确定了药物干预治疗轮状病毒引起的疾病粘液高分泌的发展靶点。
Rhinovirus (RV) infections are the major cause of asthma exacerbations, the major cause of morbidity and mortality in asthma. MUC5AC is the major mucin produced by bronchial epithelial cells. Whether RV infection upregulates MUC5AC in vivo is unknown and the molecular mechanisms involved are incompletely understood.We investigated RV induction of MUC5AC in vivo and in vitro to identify targets for development of new therapies for asthma exacerbations.RV infection increased MUC5AC release in normal and asthmatic volunteers experimentally infected with RV-16, and in asthmatic, but not normal, subjects, this was related to virus load. Bronchial epithelial cells were confirmed a source of MUC5AC in vivo.RV induction of MUC5AC in bronchial epithelial cells in vitro occurred via nuclear factor-kappa B-dependent induction of matrix metalloproteinase-mediated transforming growth factor-a release, thereby activating an epidermal growth factor receptor-dependent cascade culminating, via mitogen-activated protein kinase activation, in specificity protein-1 transactivation of the MUC5AC promoter. RV induction of MUC5AC may be an important mechanism in RV-induced asthma exacerbations in vivo. Revealing the complex serial signalling cascade involved identifies targets for development of pharmacologic intervention to treat mucus hypersecretion in RV-induced illness.