Mucus hypersecretion in asthma: causes and effects.
Mucus hypersecretion in asthma: causes and effects.
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DOI：
10.1097/mcp.0b013e32831da8d3
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发表时间：
2009-01
影响因子：
3.3
通讯作者：
Dickey BF
中科院分区：
文献类型：
--
作者：
Evans CM;Kim K;Tuvim MJ;Dickey BF
气道粘液堵塞长期以来被认为是哮喘死亡的主要原因。然而，直到最近人们才了解粘蛋白过量产生和分泌的分子机制。这些机制与正在进行的与肺病理生理学相关的研究一起进行审查。在哺乳动物的五种分泌型凝胶形成粘蛋白中，只有 MUC5AC 和 MUC5B 在肺内气道中大量产生。 MUC5B 是人类和小鼠小气道基线时主要的凝胶形成粘蛋白，因此可能执行大多数稳态清除功能。 MUC5AC 是气道炎症中上调的主要凝胶形成粘蛋白，受到叉头框 a2 的阴性控制和缺氧诱导因子 1 的阳性控制。粘蛋白分泌与产生分开调节，主要是通过细胞外三磷酸核苷酸结合气道分泌细胞腔表面上的 P2Y2 受体，产生激活胞吐蛋白 Munc13-2 和 synaptotagmin-2 的细胞内第二信使。 MUC5AC 的产生显着上调并刺激分泌，导致哮喘中的气流阻塞。由于 MUC5B 似乎介导体内平衡功能，因此有可能选择性抑制 MUC5AC 的产生而不损害气道功能。粘蛋白分泌过多在呼吸困难和咳嗽等哮喘症状以及气道高反应性等生理现象中的确切作用仍有待确定。
Airway mucus plugging has long been recognized as a principal cause of death in asthma. However, molecular mechanisms of mucin overproduction and secretion have not been understood until recently. These mechanisms are reviewed together with ongoing investigations relating them to lung pathophysiology. Of the five secreted gel-forming mucins in mammals, only MUC5AC and MUC5B are produced in significant quantities in intrapulmonary airways. MUC5B is the principal gel-forming mucin at baseline in small airways of humans and mice, and therefore likely performs most homeostatic clearance functions. MUC5AC is the principal gel-forming mucin upregulated in airway inflammation and is under negative control by forkhead box a2 and positive control by hypoxia inducible factor-1. Mucin secretion is regulated separately from production, principally by extracellular triphosphate nucleotides that bind P2Y2 receptors on the lumenal surface of airway secretory cells, generating intracellular second messengers that activate the exocytic proteins, Munc13-2 and synaptotagmin-2. Markedly upregulated production of MUC5AC together with stimulated secretion leads to airflow obstruction in asthma. As MUC5B appears to mediate homeostatic functions, it may be possible to selectively inhibit MUC5AC production without impairing airway function. The precise roles of mucin hypersecretion in asthma symptoms such as dyspnea and cough and in physiologic phenomena such as airway hyperresponsiveness remain to be defined.