The role of the airway epithelium and its interaction with environmental factors in asthma pathogenesis.
The role of the airway epithelium and its interaction with environmental factors in asthma pathogenesis.
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DOI：
10.1513/pats.200907-072dp
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发表时间：
2009-12-01
期刊：
影响因子：
--
通讯作者：
Davies, Donna E
中科院分区：
文献类型：
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作者：
Holgate, Stephen T;Roberts, Graham;Davies, Donna E
哮喘是一种以th2型为主的气道炎症性疾病。正因为如此，大多数研究都集中在研究过敏途径的作用，以期发现新的治疗靶点。不幸的是，这种策略（已扩展到动物模型）未能确定除针对多年来已知目标的抗ige和白三烯修饰剂之外的任何治疗方式。似乎问题在于把过敏放在疾病发病机制的中心，而在实践中，其他环境因素在哮喘的诱发和发展中可能同样重要，如果不是更重要的话。另一种观点认为，哮喘主要是上皮屏障功能的缺陷，如特应性皮炎，使环境过敏原、微生物和有毒物质更容易进入气道组织。有证据表明，哮喘患者气道上皮的物理和功能屏障都存在缺陷，紧密连接被破坏，抗氧化活性降低，先天免疫受损。这解释了哮喘气道对呼吸道病毒的显著易感性以及空气污染物对哮喘加重的影响。它还提供了树突状细胞编程的机制，以驱动哮喘起源中的Th2反应。将哮喘主要视为一种上皮疾病，并采用慢性伤口情景，也为气道壁重塑和生命过程中不同的哮喘表型提供了途径。
Asthma is an inflammatory disorder of the airways dominated by a Th2-type pattern. Because of this, most research has focused on investigating the role of allergic pathways with the hope of discovering novel therapeutic targets. Unfortunately, this strategy (which has been extended to animal models) has failed to identify any therapeutic modalities other than anti-IgE and leukotriene modifiers directed to targets known about for many years. It seems that the problem lies in placing allergy at the center of disease pathogenesis, when in practice other environmental factors may be equally if not more important in the induction and then progression of asthma. An alternative view is that asthma is primarily a defect of epithelial barrier function that, as in atopic dermatitis, allows greater access of environmental allergens, microorganisms, and toxicants to the airway tissue. Evidence is provided to show that both the physical and functional barrier of the airway epithelium is defective in asthma with disrupted tight junctions, reduced antioxidant activity, and impaired innate immunity. This explains the remarkable susceptibility of asthmatic airways to respiratory viruses and the impact of air pollutants on asthma exacerbations. It also provides a mechanism for programming of dendritic cells to drive a Th2 response in the origins of asthma. Viewing asthma primarily as an epithelial disease with adoption of a chronic wound scenario also provides a route to airway wall remodeling and the varying asthma phenotypes over the life course.