Division of Infection, Inflammation and Immunity, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom.
J Allergy Clin Immunol. 2011 Sep;128(3):495-505. doi: 10.1016/j.jaci.2011.06.052. Epub 2011 Jul 31.
Current asthma therapy is based on the use of adrenergic bronchodilator and anti-inflammatory drugs the specificity, efficacy, duration of action, and safety of which have been derived through classical pharmacology and medicinal chemistry. That asthma is a T(H)2-type inflammatory disorder frequently associated with atopy and allergic comorbidities has led to a concentrated effort to find treatments that act selectively on this pathway. A systematic literature review was undertaken, as well as a review of the Web site Clinicaltrials.gov for ongoing trials. Targets have included T cells themselves and their associated cytokines, chemokines, and receptors mostly targeted with biological agents. With the exception of anti-human IgE, none of these have met the expectations predicted from animal models and human in vitro tests. For most of these new therapies, only a very small subpopulation appears to respond. A case is made for a different approach to drug discovery based on acquiring a greater understanding of asthma stratification, the relevant pathways involved, and the development of appropriate diagnostic tests enabling the targeting of selective treatments to those asthmatic phenotypes most likely to respond. The recognition that asthma is more than allergy mandates improved predictive animal models and an appreciation that many of the environmental insults that initiate, consolidate, and exacerbate asthma operate through an epithelium functioning in a disorderly fashion. An integrated model that places the epithelium at the forefront of asthma pathogenesis suggests that greater emphasis should be placed on therapeutics that increase the airways' resistance against the inhaled environment rather than focusing only on suppression of inflammation.
目前的哮喘治疗基于使用肾上腺素能支气管扩张剂和抗炎药物，其特异性、疗效、作用持续时间和安全性是通过经典药理学和药物化学得出的。哮喘是一种 T(H)2 型炎症性疾病，常与特应性和过敏合并症相关，这导致人们集中精力寻找选择性作用于该途径的治疗方法。进行了系统的文献回顾，并在 Clinicaltrials.gov 网站上审查了正在进行的试验。目标包括 T 细胞本身及其相关的细胞因子、趋化因子和受体，这些主要通过生物制剂靶向。除了抗人 IgE 之外，这些药物都没有达到从动物模型和人体体外试验预测的预期效果。对于大多数这些新疗法，只有一小部分患者似乎有反应。有人提出了一种不同的药物发现方法，即基于对哮喘分层、涉及的相关途径以及开发适当的诊断测试有更深入的了解，使选择性治疗能够针对最有可能有反应的哮喘表型。认识到哮喘不仅仅是过敏，需要改进预测性动物模型，并认识到许多引发、巩固和加重哮喘的环境刺激因素都是通过功能紊乱的上皮细胞起作用的。将上皮细胞置于哮喘发病机制前沿的综合模型表明，应该更加重视增加气道对吸入环境的抵抗力的治疗方法，而不仅仅是关注炎症的抑制。
