Animal models of late bronchial responses

In the laboratory, inhalation of allergen by sensitized subjects can induce a variety of changes in airflow resistance, including: isolated early bronchial responses, early and late bronchial responses, or isolated late bronchial responses. The development of late bronchial responses, may be the initial physiological sign of a chronic inflammatory process that leads to a prolonged increase in airway responsiveness and offers a means of testing potential compounds against end-points that may be important in the disease. Corticosteroids, probably the most potent therapeutic agents used in the treatment of asthma, inhibit the late bronchial response and increased airway hyperresponsiveness. In the development of new therapeutic agents, it is important to show comparative efficacy in experimental conditions in which steroids have been shown to have positive effects in human subjects. Up to the present time, rats, guinea-pigs, rabbits, dogs, sheep and primates have been reported to develop late bronchial responses and have been used for the preclinical evaluation of potential therapeutic agents. The ideal 'late phase' animal model should exhibit all features of the human response, including characteristic changes in airway resistance, reproducibility of the response, mediator and inflammatory cell profile, and the induction of a prolonged period of airway hyperresponsiveness following a single antigen challenge. The model should be easily manipulated, in order to facilitate understanding of the pathophysiological mechanisms involved, and should respond to known pharmacological agents in the appropriate manner, so that positive and/or negative findings can be viewed with confidence. It is important to ascertain if there is a difference between statistically significant effects and inhibition that can be translated to functional protection in man. Finally, one must consider dosing and the specificity of the compounds being tested. A positive result in an animal model at doses far beyond those applicable to man may be of limited value.