严重哮喘的激素抵抗：当前的机制研究和未来的治疗方向
2011/05/12
摘要
对于传统抗炎治疗无效的哮喘患者，其治疗成本与疗效明显不成比例，这也使得对糖皮质激素抵抗哮喘的机制研究成为哮喘研究的一个重要领域。无偏聚类分析显示，哮喘是一种综合征，具有不同的表现型，5～10%的哮喘患者对糖皮质激素治疗不敏感。这一小部分人群中糖皮质激素抵抗性哮喘，存在不同的发病机制，可能与遗传因素或环境暴露（吸烟和感染）触发的特异性激酶信号通路相关。虽然对哮喘机制有了进一步的了解，但目前仍然缺乏有效的治疗方法。目前已知的是，一些吸烟患者对糖皮质激素治疗不敏感，应该鼓励这些患者戒烟，以降低机体的氧化物负荷。寻找新的治疗手段，包括开发针对异常信号通路的新抗炎治疗，以及抑制信号通路以降低糖皮质激素受体功能和恢复糖皮质激素敏感性的治疗手段。有必要寻找到通路异常活化以及鉴别那些异常的糖皮质激素受体活化成分的无创生物标志物，以便未来针对上述问题，对哮喘进行特异性治疗。传统的联合治疗在将来将持续采用，针对炎症通路异常活化的辅助治疗联合糖皮质激素吸入，仍然是未来哮喘治疗的有效手段。
(刘国梁 审校)
Curr Pharm Des. 2011 Mar 15. [Epub ahead of print]
Steroid Resistance in Severe Asthma: Current Mechanisms and Future Treatment.
Durham A, Adcock IM, Tliba O.
Airways Disease Section, National Heart & Lung Institute, Dovehouse Street, London SW3 6LY UK. a.durham@imperial.ac.uk.
Abstract
The disproportionate cost of treating asthmatic patients who do not respond to conventional anti-inflammatory therapies makes delineation of the mechanism for glucocorticoid resistance an important field of asthma research. Unbiased cluster analysis indicates that asthma is a syndrome with a number of distinct phenotypes and 5-10% of asthmatics fall into this category of relative glucocorticoid insensitivity. This sub-population is itself divided into smaller subsets which have different underlying mechanisms for this relative glucocorticoid resistance ranging from an inherited genetic basis to specific kinase signalling pathways triggered by exposure to environmental stressors such as cigarette smoking or infection. Whilst the underlying mechanisms are becoming better understood there remains a lack of effective novel therapies. However it is clear that relative glucocorticoid insensitive patients who are smokers should be encouraged to quit, thereby reducing their oxidant load. Novel treatments will consist of either developing new anti-inflammatory treatments targeting pathways aberrantly activated in these patients or of suppressing signalling pathways that attenuate glucocorticoid receptor function and thereby restoring glucocorticoid sensitivity. It will be important to uncover non-invasive biomarkers for aberrant pathway activation and for discerning which components of glucocorticoid receptor activation are abnormal if future treatments are to be tailored to address these specific issues. Conventional combination therapies will continue to be used in the near future but additional add-on treatments using drugs directed against aberrantly expressed inflammatory pathways or mediators along with an inhaledglucocorticoid are likely to prove the most effective new therapies in the future.
Curr Pharm Des. 2011 Mar 15. [Epub ahead of print]
对于传统抗炎治疗无效的哮喘患者，其治疗成本与疗效明显不成比例，这也使得对糖皮质激素抵抗哮喘的机制研究成为哮喘研究的一个重要领域。无偏聚类分析显示，哮喘是一种综合征，具有不同的表现型，5～10%的哮喘患者对糖皮质激素治疗不敏感。这一小部分人群中糖皮质激素抵抗性哮喘，存在不同的发病机制，可能与遗传因素或环境暴露（吸烟和感染）触发的特异性激酶信号通路相关。虽然对哮喘机制有了进一步的了解，但目前仍然缺乏有效的治疗方法。目前已知的是，一些吸烟患者对糖皮质激素治疗不敏感，应该鼓励这些患者戒烟，以降低机体的氧化物负荷。寻找新的治疗手段，包括开发针对异常信号通路的新抗炎治疗，以及抑制信号通路以降低糖皮质激素受体功能和恢复糖皮质激素敏感性的治疗手段。有必要寻找到通路异常活化以及鉴别那些异常的糖皮质激素受体活化成分的无创生物标志物，以便未来针对上述问题，对哮喘进行特异性治疗。传统的联合治疗在将来将持续采用，针对炎症通路异常活化的辅助治疗联合糖皮质激素吸入，仍然是未来哮喘治疗的有效手段。
(刘国梁 审校)
Curr Pharm Des. 2011 Mar 15. [Epub ahead of print]
Steroid Resistance in Severe Asthma: Current Mechanisms and Future Treatment.
Durham A, Adcock IM, Tliba O.
Airways Disease Section, National Heart & Lung Institute, Dovehouse Street, London SW3 6LY UK. a.durham@imperial.ac.uk.
Abstract
The disproportionate cost of treating asthmatic patients who do not respond to conventional anti-inflammatory therapies makes delineation of the mechanism for glucocorticoid resistance an important field of asthma research. Unbiased cluster analysis indicates that asthma is a syndrome with a number of distinct phenotypes and 5-10% of asthmatics fall into this category of relative glucocorticoid insensitivity. This sub-population is itself divided into smaller subsets which have different underlying mechanisms for this relative glucocorticoid resistance ranging from an inherited genetic basis to specific kinase signalling pathways triggered by exposure to environmental stressors such as cigarette smoking or infection. Whilst the underlying mechanisms are becoming better understood there remains a lack of effective novel therapies. However it is clear that relative glucocorticoid insensitive patients who are smokers should be encouraged to quit, thereby reducing their oxidant load. Novel treatments will consist of either developing new anti-inflammatory treatments targeting pathways aberrantly activated in these patients or of suppressing signalling pathways that attenuate glucocorticoid receptor function and thereby restoring glucocorticoid sensitivity. It will be important to uncover non-invasive biomarkers for aberrant pathway activation and for discerning which components of glucocorticoid receptor activation are abnormal if future treatments are to be tailored to address these specific issues. Conventional combination therapies will continue to be used in the near future but additional add-on treatments using drugs directed against aberrantly expressed inflammatory pathways or mediators along with an inhaledglucocorticoid are likely to prove the most effective new therapies in the future.
Curr Pharm Des. 2011 Mar 15. [Epub ahead of print]
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针对嗜酸粒细胞生物学的哮喘治疗方法
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不同哮喘治疗方法对感冒诱发哮喘恶化风险的影响
