Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling.
Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling.
复制标题
DOI：
10.1067/mai.2003.25
复制
发表时间：
2003-01-01
影响因子：
14.2
通讯作者：
Henderson, William R., Jr.
中科院分区：
文献类型：
--
作者：
Holgate, Stephen T.;Peters-Golden, Marc;Henderson, William R., Jr.
提出了一种哮喘发病机制的新范式，其中呼吸道的过度炎症和重塑是受试者对吸入环境成分的易感性引起的异常损伤和修复反应的结果。一个上皮-间充质营养单位被激活，通过复杂的细胞因子相互作用来驱动病理重塑和平滑肌增殖。组胺、前列腺素和半胱氨酸白三烯(CysLts)是一种有效的气道平滑肌收缩激动剂。CysLTs似乎在调节人类ASM运动张力和表型改变方面发挥着中心作用，在慢性重度哮喘中表现为肥大和增生。CysLTs通过激活CysLT受体增强生长因子诱导的ASM有丝分裂。尽管它们通过增加磷脂酰肌醇的周转率和诱导细胞内钙离子的增加来调节其收缩效应，但新的数据表明，部分收缩效应可能不依赖于钙动员。前列腺素E2是呼吸道上皮细胞的主要二十烷类产物，是一种有效的有丝分裂、胶原合成和间充质细胞趋化的抑制剂，因此可以抑制炎症和成纤维细胞的激活。上皮细胞合成CysLT的能力与其产生PGE2的能力呈负相关。ASM能够表达白三烯合成酶和CysLT受体，细胞因子上调受体的表达。这可能是CysLts促进哮喘患者气道高反应性的原因之一。CysLTs在持续性哮喘的气道重塑中起重要作用，包括气道杯状细胞、粘液、血管、平滑肌、肌纤维母细胞和气道纤维化的增加。来自哮喘小鼠模型的证据表明，CysLT1受体拮抗剂抑制了气道重塑过程，包括嗜酸性粒细胞向肺的运输、嗜酸性粒细胞脱颗粒、TH2细胞因子释放、粘液腺增生、粘液高分泌、平滑肌细胞增生、胶原沉积和肺纤维化。
A new paradigm for asthma pathogenesis is presented in which exaggerated inflammation and remodeling in the airways are a consequence of abnormal injury and repair responses arising from a subject's susceptibility to components of the inhaled environment. An epithelial-mesenchymal trophic unit becomes activated to drive pathologic remodeling and smooth muscle proliferation through complex cytokine interactions. Histamine, prostanoids, and cysteinyl leukotrienes (CysLTs) are potent contractile agonists of airway smooth muscle (ASM). The CysLTs appear to play a central role in regulating human ASM motor tone and phenotypic alterations, manifested as hypertrophy and hyperplasia in chronic severe asthma. The CysLTs augment growth factor-induced ASM mitogenesis through activation of CysLT receptors. Although they mediate their contractile effects by increasing phosphoinositide turnover and inducing increased cytosolic calcium, new data suggest that part of the contractile effect may be independent of calcium mobilization. Prostaglandin E2, the predominant eicosanoid product of the airway epithelium, is a potent inhibitor of mitogenesis, collagen synthesis, and mesenchymal cell chemotaxis and therefore can suppress inflammation and fibroblast activation. The capacity of the epithelium for CysLT synthesis is inversely related to its ability to make PGE2. The ASM is capable of expressing both leukotriene-synthesizing enzymes and CysLT receptors, and cytokines upregulate the receptor expression. This may be an explanation for the CysLTs promoting airway hyperresponsiveness in asthma. The CysLTs play an important role in the airway remodeling seen in persistent asthma that includes increases of airway goblet cells, mucus, blood vessels, smooth muscle, myofibroblasts, and airway fibrosis. Evidence from a mouse model of asthma demonstrated that CysLT1 receptor antagonists inhibit the airway remodeling processes, including eosinophil trafficking to the lungs, eosinophil degranulation, TH2 cytokine release, mucus gland hyperplasia, mucus hypersecretion, smooth muscle cell hyperplasia, collagen deposition, and lung fibrosis.