Mouse models of severe asthma: Understanding the mechanisms of steroid resistance, tissue remodelling and disease exacerbation

Abstract

Severe asthma has significant disease burden and results in high healthcare costs. While existing therapies are effective for the majority of asthma patients, treatments for individuals with severe asthma are often ineffective. Mouse models are useful to identify mechanisms underlying disease pathogenesis and for the preclinical assessment of new therapies. In fact, existing mouse models have contributed significantly to our understanding of allergic/eosinophilic phenotypes of asthma and facilitated the development of novel targeted therapies (e.g. anti-IL-5 and anti-IgE). These therapies are effective in relevant subsets of severe asthma patients. Unfortunately, non-allergic/noneosinophilic asthma, steroid resistance and disease exacerbation remain areas of unmet clinical need. No mouse model encompasses all features of severe asthma. However, mouse models can provide insight into pathogenic pathways that are relevant to severe asthma. In this review, as examples, we highlight models relevant to understanding steroid resistance, chronic tissue remodelling and disease exacerbation. Although these models highlight the complexity of the immune pathways that may underlie severe asthma, they also provide insight into new potential therapeutic approaches.

Obesity and severe asthma

“…Indeed, in severe asthmatics with type2-high asthma who are obese, many continue to have high expression of type 2 cytokine-dependent gene expression in sputum cells, despite inhaled corticosteroid use (42). While these studies indicate that obesity does indeed reduce the response to steroids, there may be an important additional reason why obese asthmatics do not respond well to these agents: steroids target the immune processes that mediate allergic responses, but many obese subjects with severe asthma are non-atopic (43–45). …”

Eosinophil persistence in vivo and sustained viability ex vivo in response to respiratory challenge with fungal allergens

“…Mouse models of allergic airways disease have been used extensively to explore specific features of the human asthmatic response (reviewed in Ref …”

In vivo experimental models of infection and disease

“…Animal models provide a range of benefits to complement human experimental approaches. 139 Experimental animals can be readily manipulated to induce consistent disease outcomes, such as the induction of allergic airway disease (AAD) to model asthma or cigarette smokeÀinduced COPD. Animal models have less variability than human populations providing more consistent experimental outcomes and statistical power in intervention studies.…”