Animal models of asthma

Abstract

Studies in animal models form the basis for much of our current understanding of the pathophysiology of asthma, and are central to the preclinical development of drug therapies. No animal model completely recapitulates all features of the human disease, however. Research has focused primarily on ways to generate allergic inflammation by sensitizing and challenging animals with a variety of foreign proteins, leading to an increased understanding of the immunological factors that mediate the inflammatory response and its physiological expression in the form of airways hyperresponsiveness. Animal models of exaggerated airway narrowing are also lending support to the notion that asthma may represent an abnormality of the airway smooth muscle. The mouse is now the species of choice for asthma research involving animals. This presents practical challenges for physiological study because the mouse is so small, but modern imaging methodologies, coupled with the forced oscillation technique for measuring lung mechanics, have allowed the asthma phenotype in mice to be precisely characterized.

Fig. 1.

The parameters of respiratory input impedance (R_N, G, and H) expressed as fractional changes above baseline (ΔR_N, ΔG, and ΔH, respectively) in control and allergically inflamed mice following a 40-s challenge with an aerosol of methacholine. MCh, the time of completion of delivery of methacholine. DI, the time of delivery of 2 deep lung inflations to 25 cmH₂O. [From Wagers et al. (87).]

Fig. 2.

Minimum intensity projection images of a normal mouse lung (left) and an allergically inflamed mouse lung (right) following ventilation with pure oxygen obtained using microcomputed tomography. The missing basal air spaces in the inflamed lung (arrows) represent atelectatic regions that became consolidated after absorption of the oxygen by the capillary blood. Note the large bulbous appearance of the central airways and the asymmetrical branching pattern of the airway tree, which is typical of the mouse but very different in the human. [Adapted with permission from Lundblad et al. (59).]

Fig. 3.

The time course of bronchoconstriction in BALB/c mice following aerosolization of 3.125, 12.5, and 50 mg/ml methacholine. The open circles are saline-treated animals; the closed circles are animals treated with poly-l-lysine. The vertical dotted lines bracket parameter values obtained following deep lung inflations given to reestablish baseline conditions. Note the exaggerated response in R_N compared with G and H in the animals treated with poly-l-lysine compared with controls. This contrasts with the effects of allergic inflammation shown in Fig. 1. *Significant difference in magnitude of response; +significant difference in timing of peak. P < 0.05. [From Bates et al. (15).]

Fig. 4.

Mechanical and geometric mechanisms for airways hyperresponsiveness. A: a modest degree of shortening of the airway smooth muscle (black ring) impinging on an airway wall that thickened is due to epithelial hypertrophy and/or mucus hypersecretion (gray annulus) and leads to a substantial degree in luminal area (white). B: the same degree of luminal narrowing can be caused by accentuated smooth muscle shortening in the presence of a normal airway lining. C: both mechanisms together lead to a dramatic reduction in luminal area and may even lead to complete airway closure.