Animal models of allergic airways disease: where are we and where to next?

Abstract

In a complex inflammatory airways disease such as asthma, abnormalities in a plethora of molecular and cellular pathways ultimately culminate in characteristic impairments in respiratory function. The ability to study disease pathophysiology in the setting of a functioning immune and respiratory system therefore makes mouse models an invaluable tool in translational research. Despite the vast understanding of inflammatory airways diseases gained from mouse models to date, concern over the validity of mouse models continues to grow. Therefore the aim of this review is twofold; firstly, to evaluate mouse models of asthma in light of current clinical definitions, and secondly, to provide a framework by which mouse models can be continually refined so that they continue to stand at the forefront of translational science. Indeed, it is in viewing mouse models as a continual work in progress that we will be able to target our research to those patient populations in whom current therapies are insufficient.

Keywords: AIRWAY HYPERRESPONSIVENESS; ANIMAL MODELS; ASTHMA.

Figure 1. Comparison of lung anatomy between human and mouse

Computed tomography (CT) lung slice images from a 26 year old male (a) and a BALB/c control mouse (b, with μCT) showing the substantially greater relative airway caliber in mice. Maximum intensity projection images from a control mouse (c) and a mouse challenged with ovalbumin (d), both exposed to room air. Again note the large airway size relative to total lung size and the monopodial branching pattern, in which one daughter airway is much larger than the other. The human lung image was provided by Dr Jeffrey Klein, Department of Radiology, University of Vermont College of Medicine. Mouse lung images were provided by Dr Lennart K. Lundblad, Department of Medicine, University of Vermont College of Medicine (see Lundblad et al (64) for methodological details).

Figure 2. Airway hyperresponsiveness (AHR) to methacholine in human subjects and in mice

The response to increasing doses of methacholine in an asthmatic patient ( , 20 year old male, baseline FEV₁ of 97% predicted) and a healthy, non-asthmatic subject (■, 27 year old male, baseline FEV₁ of 92% predicted). Note that the asthmatic patient has a provocative dose causing a 20% fall in forced expiratory volume in one second (PD20FEV₁) of 0.3μmol of methacholine whereas the non-asthmatic subject does not reach a 20% fall even at a dose > 500-fold higher. The response to methacholine in mice following either 15 instillations of control (PBS, ■) or house dust mite (HDM, ) measured as central airway narrowing (Rn), peripheral tissue resistance (G) and tissue elastance (H). In contrast to ovalbumin models, house dust mite challenge results in greater central airway (Rn) effects whereas AHR following ovalbumin challenge is predominantly characterized by airway closure (H).

Figure 3. Representation of the different types of airway hyperresponsiveness (AHR) induced by antigen-dependent and several antigen-independent models of allergic airways disease

Antigen-dependent models, such as ovalbumin sensitization and re-exposure, predominantly induce an increase in the maximal response plateau. Similarly, ozone and chlorine exposure lead to an increase in the maximal response plateau; however, high doses of chlorine appear to also replicate the increased sensitivity (leftward shift) that is characteristic of AHR in patients with asthma. In contrast, cationic proteins cause an increase in sensitivity to bronchoconstricting stimulus without altering the maximal response plateau.