Carroll Olivia R, Pillar Amber L, Brown Alexandra C, Feng Min, Chen Hui, Donovan Chantal
Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia.
Faculty of Science, School of Life Sciences, University of Technology Sydney, Sydney, NSW, Australia.
Front Physiol. 2023 Mar 16;14:1099719. doi: 10.3389/fphys.2023.1099719. eCollection 2023.
Recent advances in mouse models of experimental asthma coupled with vast improvements in systems that assess respiratory physiology have considerably increased the accuracy and human relevance of the outputs from these studies. In fact, these models have become important pre-clinical testing platforms with proven value and their capacity to be rapidly adapted to interrogate emerging clinical concepts, including the recent discovery of different asthma phenotypes and endotypes, has accelerated the discovery of disease-causing mechanisms and increased our understanding of asthma pathogenesis and the associated effects on lung physiology. In this review, we discuss key distinctions in respiratory physiology between asthma and severe asthma, including the magnitude of airway hyperresponsiveness and recently discovered disease drivers that underpin this phenomenon such as structural changes, airway remodeling, airway smooth muscle hypertrophy, altered airway smooth muscle calcium signaling, and inflammation. We also explore state-of-the-art mouse lung function measurement techniques that accurately recapitulate the human scenario as well as recent advances in precision cut lung slices and cell culture systems. Furthermore, we consider how these techniques have been applied to recently developed mouse models of asthma, severe asthma, and asthma-chronic obstructive pulmonary disease overlap, to examine the effects of clinically relevant exposures (including ovalbumin, house dust mite antigen in the absence or presence of cigarette smoke, cockroach allergen, pollen, and respiratory microbes) and to increase our understanding of lung physiology in these diseases and identify new therapeutic targets. Lastly, we focus on recent studies that examine the effects of diet on asthma outcomes, including high fat diet and asthma, low iron diet during pregnancy and predisposition to asthma development in offspring, and environmental exposures on asthma outcomes. We conclude our review with a discussion of new clinical concepts in asthma and severe asthma that warrant investigation and how we could utilize mouse models and advanced lung physiology measurement systems to identify factors and mechanisms with potential for therapeutic targeting.
实验性哮喘小鼠模型的最新进展，以及评估呼吸生理学系统的大幅改进，显著提高了这些研究结果的准确性和与人类的相关性。事实上，这些模型已成为具有 proven value 的重要临床前测试平台，它们能够迅速适应探究新出现的临床概念，包括最近发现的不同哮喘表型和内型，这加速了致病机制的发现，并增进了我们对哮喘发病机制以及对肺生理学相关影响的理解。在本综述中，我们讨论了哮喘与重度哮喘在呼吸生理学方面的关键区别，包括气道高反应性的程度以及最近发现的支撑这一现象的疾病驱动因素，如结构变化、气道重塑、气道平滑肌肥大、气道平滑肌钙信号改变和炎症。我们还探讨了能够准确重现人类情况的最新小鼠肺功能测量技术，以及精密肺切片和细胞培养系统的最新进展。此外，我们考虑了这些技术如何应用于最近开发的哮喘、重度哮喘和哮喘 - 慢性阻塞性肺疾病重叠的小鼠模型，以研究临床相关暴露（包括卵清蛋白、有无香烟烟雾情况下的屋尘螨抗原、蟑螂过敏原、花粉和呼吸道微生物）的影响，并增进我们对这些疾病中肺生理学的理解以及确定新的治疗靶点。最后，我们重点关注最近研究饮食对哮喘结果的影响，包括高脂肪饮食与哮喘、孕期低铁饮食与后代患哮喘的易感性，以及环境暴露对哮喘结果的影响。我们在综述结尾讨论了哮喘和重度哮喘中值得研究的新临床概念，以及我们如何利用小鼠模型和先进的肺生理学测量系统来识别具有潜在治疗靶点的因素和机制。
