Gene Knockout Models of Asthma
Authors: JOHAN C. KIPS, KURT G. TOURNOY, ROMAIN A. PAUWELS
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Airway morphology in asthma is characterized not only by features of an acute allergic inflammation, but also by structural airway changes including subepithelial fibrosis or smooth muscle hypertrophy and/or hyperplasia (1). The key functional abnormality of asthma is the presence of nonspecific bronchial hyperresponsiveness (BHR). This is reflected by an increase both in sensitivity and reactivity of the airways (2, 3). Hypersensitivity is characterized by a leftward shift of the dose–response curve of a bronchoconstrictor agonist, whereas hyperreactivity is reflected in a steeper slope of the dose– response curve and increased maximal airway narrowing. These morphological and functional characteristics are not fully mimicked in the currently developed murine models of allergic airway inflammation. First, no “gold standard” lung function index has been invariably accepted in mice. The indices used include lung resistance, based on the principles described by Amdur and Mead, overflow of insufflation pressure as described by Konzett and Rossler, and sometimes expressed as the airway pressure over time index (APTI), or the enhanced pause (Penh) value (4–7). These various indices reflect to a variable and ill-defined degree changes in airway sensitivity and reactivity. In the vast majority of murine models, these two components of bronchial hyperresponsiveness are not specifically examined. In addition, the overall increase in airway responsiveness obtained in murine models is smaller than the difference in airway responsiveness that exists between healthy subjects and subjects with asthma. This presumably relates, at least in part, to the differences observed at a morphological level. In most of the murine models of allergen exposure, only acute inflammatory changes are induced, without any concomitant structural change that might affect responsiveness to a larger degree. The distribution of the inflammation is also different from that of human asthma. In animal models, the inflammatory changes not only concentrate in or around the airways, but frequently also include lung parenchymal, mainly perivascular, changes. A serious limitation of the currently available knockout models is that most of these consist of constitutional deletions, precluding the evaluation of the gene of interest in a specific phase of the disease process. As the technology further improves, the possibilities for conditional deletions increase, thus allowing investigators to time the switching off of the gene of interest (8–10). This will, for example, allow an evaluation in adult life of the role of gene products that are essential during the early stage of development. In addition, conditional deletions will also enable researchers to dissect the role of gene products specifically during the primary antigen sensitization, or during the secondary antigen exposure to memory cells. Finally, it must be borne in mind that important differences exist between different mouse strains, both in the functional role of components of the immune system and the baseline degree of airway responsiveness (11–14). Moreover, the sensitization and exposure procedures used in the different models also vary greatly. These different issues must be taken into account, not only when comparing results from different experiments, but especially when trying to extrapolate data from murine models to human asthma.