Animal Models of Airway Sensitization

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Airway inflammation and airway hyperresponsiveness (AHR) are hallmarks and distinguishing features of bronchial asthma. In studying the pathophysiology of the inflammatory response and the development of AHR, for practical and ethical reasons it is frequently necessary to use animal models. In particular, murine models of allergen-induced AHR are widely used, since the immunology of mice is well described and many immunological tools and genetically altered strains are available.

In most models of induced allergic asthma, animals are systemically sensitized to specific antigens and then, after a period of time, challenged with the same allergen administered via the airways (see Basic Protocol). In most studies ovalbumin has been used as the standard allergen to sensitize and challenge animals, although other antigens, including ragweed and the recombinant major cat allergen, FelDl, have been used as well. Besides systemic sensitization to allergen followed by airway provocation, mice can be sensitized exclusively via the airways (see Alternate Protocol).

Methods of measuring airway reactivity in mice also vary. Two approaches that are commonly employed are (1) in vivo assessment of lung function in response to methacholine—either invasively, by measuring lung resistance in anesthesized, tra-cheostomized mice, or noninvasively by barometric plethysmography of unrestrained mice (see Support Protocol 1)—and (2) in vitro assessment of tracheal smooth muscle reactivity in response to electrical field stimulation (see Support Protocol 2). There are significant genetic differences between mouse strains in both IgE responses to ovalbumin and airway responses to methacholine (Levine and Vaz, 1970; Levitt and Mitzner, 1988; Martin et al., 1988). The strain of mice most often used is BALB/c, a "high-responder" strain in which both these responses are easily inducible.

To a large extent, AHR is genetically determined. However, T cell-mediated immune responses and the products of T cells have been implicated as contributing to airway inflammation and, as a result, to AHR. T cells of the so-called TH2 type play a central role in initiating and perpetuating the inflammatory response by secreting TH2-cytokines: interleukin 4 (IL-4) appears essential for isotype switching to an IgE response to antigen challenge and for maintenance of the immune response, while IL-5 plays a key role in the activation and the recruitment of eosinophils to the airways. In murine models of allergen-induced AHR, essential components appear to include a combination of local antigen challenge of the airways, production of antigen-specific IgE, and eosinophil accumulation in and around the airways. Aside from lung function, parameters that may be monitored to determine the quality and degree of sensitization and AHR include T cell responsiveness, T cell cytokine production, IgE responses, and airway inflammation (see Support Protocol 3; Hamelmann et al., 1997a,b).

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