Hansbro Philip M, Kim Richard Y, Starkey Malcolm R, Donovan Chantal, Dua Kamal, Mayall Jemma R, Liu Gang, Hansbro Nicole G, Simpson Jodie L, Wood Lisa G, Hirota Jeremy A, Knight Darryl A, Foster Paul S, Horvat Jay C
Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, NSW, Australia.
James Hogg Research Centre, University of British Columbia, Vancouver, BC, Canada.
Immunol Rev. 2017 Jul;278(1):41-62. doi: 10.1111/imr.12543.
Severe, steroid-resistant asthma is clinically and economically important since affected individuals do not respond to mainstay corticosteroid treatments for asthma. Patients with this disease experience more frequent exacerbations of asthma, are more likely to be hospitalized, and have a poorer quality of life. Effective therapies are urgently required, however, their development has been hampered by a lack of understanding of the pathological processes that underpin disease. A major obstacle to understanding the processes that drive severe, steroid-resistant asthma is that the several endotypes of the disease have been described that are characterized by different inflammatory and immunological phenotypes. This heterogeneity makes pinpointing processes that drive disease difficult in humans. Clinical studies strongly associate specific respiratory infections with severe, steroid-resistant asthma. In this review, we discuss key findings from our studies where we describe the development of representative experimental models to improve our understanding of the links between infection and severe, steroid-resistant forms of this disease. We also discuss their use in elucidating the mechanisms, and their potential for developing effective therapeutic strategies, for severe, steroid-resistant asthma. Finally, we highlight how the immune mechanisms and therapeutic targets we have identified may be applicable to obesity-or pollution-associated asthma.
重度、激素抵抗性哮喘在临床和经济方面都很重要，因为受影响的个体对哮喘的主要皮质类固醇治疗无反应。患有这种疾病的患者哮喘发作更频繁，更有可能住院，生活质量也更差。迫切需要有效的治疗方法，然而，由于对该疾病背后的病理过程缺乏了解，其开发受到了阻碍。理解导致重度、激素抵抗性哮喘的过程的一个主要障碍是，已经描述了该疾病的几种内型，其特征是不同的炎症和免疫表型。这种异质性使得在人类中确定导致疾病的过程变得困难。临床研究强烈将特定的呼吸道感染与重度、激素抵抗性哮喘联系起来。在这篇综述中，我们讨论了我们研究的关键发现，在这些研究中，我们描述了代表性实验模型的开发，以增进我们对感染与这种疾病的重度、激素抵抗形式之间联系的理解。我们还讨论了它们在阐明机制以及开发重度、激素抵抗性哮喘有效治疗策略方面的应用潜力。最后，我们强调了我们所确定的免疫机制和治疗靶点如何可能适用于肥胖或污染相关的哮喘。
