Abstract
Whether mouse models of chronic asthma can be used to investigate the relationship between airway inflammation/remodeling and airway hyper-responsiveness (AHR) is a vexed question. It raises issues about the extent to which such models replicate key features of the human disease. Here, we review some of the characteristic pathological features of human asthma and their relationship to AHR and examine some limitations of mouse models that are commonly used to investigate these relationships. We compare these conventional models with our mouse model of chronic asthma involving long-term low-level inhalational challenge and review studies of the relationship between inflammation/remodeling and AHR in this model and its derivatives, including models of an acute exacerbation of chronic asthma and of the induction phase of childhood asthma. We conclude that while extrapolating from studies in mouse models to AHR in humans requires cautious interpretation, such experimental work can provide significant insights into the pathogenesis of airway responsiveness and its molecular and cellular regulation.
Highlights
Mouse models can certainly be employed to investigate the relationship between asthmatic inflammation/airway remodeling and airway hyper-responsiveness (AHR): they have been and continue to be used for such research
This review focuses on the first of those considerations: technical issues related to the measurement of AHR in mouse models and their relevance to physiological assessment in humans are examined elsewhere in this issue
In this model there is clearly a role for both Th2 and Th1 cytokines, as demonstrated in studies using genetargeted animals and neutralizing antibodies (Kumar et al, 2002, 2004a,c). This model has, been widely acknowledged to represent a significant improvement in terms of the fidelity with which it reproduces features of human asthma (Shore, 2003; Fulkerson et al, 2005; Nials and Uddin, 2008). Can this model be used to investigate the pathogenesis of AHR and, in particular, its relationship to airway remodeling? Our studies suggest that, at the very least, the cytokine mechanisms involved in development of AHR following low-level chronic challenge may be different to those demonstrated in short-term models assessed at early time points after challenge, because there appears to be less dependency on Th2 responses and a significant role for interferon-γ (Kumar et al, 2004c)
Summary
Mouse models can certainly be employed to investigate the relationship between asthmatic inflammation/airway remodeling and airway hyper-responsiveness (AHR): they have been and continue to be used for such research. Whether they should be, i.e., whether the models are sufficiently similar to the human disease to be suitable for the purpose, is a separate question altogether. Even in the earliest stages of mild clinical asthma, there is accumulation of chronic inflammatory cells in the mucosa of the larger conducting airways (Holgate et al, 1992; Laitinen et al, 1993) These include increased numbers of lymphocytes, plasma cells, mast cells, and macrophages.
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