The relevance of murine animal models to study the development of allergic bronchial asthma.

Bronchial asthma (BA) develops on the basis of a genetic predisposition and involves a characteristic sequence of changes in immune functions. In the immunopathogenesis, several phases can be distinguished: the initial stage is defined as the development of allergic sensitization. This step is dependent on: (i) T cell activation; (ii) IL-4 production; (ii) IgE synthesis; and (iv) mediator release by effector cells. The second phase of allergic inflammation as a consequence of the T cell dependent sensitization is characterized by IL-5 production and eosinophil activation and recruitment. Airway mucosa remodelling is the consequence of chronic inflammatory processes and represents the final stage of BA. In this article animal models will be discussed with regard to their relevance for these different phases in development of chronic allergic BA.

Murine animal models to study the central role of T cells in immediate-type hypersensitivity responses.

The development of allergic sensitization and inflammation is dependent on activation and stimulation of T cells that exhibit pro-allergic functions. A mouse model system was developed to study the role of T cells in allergic sensitization in more detail. Local sensitization of mice stimulates an allergen specific IgE/IgG1 response that is associated with the development of immediate type skin test responses and increased airway responsiveness (AR). Strains of mice are identified that are high or low responder animals for allergens including ovalbumin and house dust mite. Each allergen stimulates a different pattern of T-cell receptor V beta expressing T cells in local draining lymph nodes. To induce a state of increased AR, at least two separate events are required. The first event is the presence of allergen specific IgE/IgG1. The second event is characterized as a local allergen challenge at the site of the response. These T cells play a critical role in the regulation of the allergic immune response including IgE production and increased AR. Based on these results intervention strategies can be developed which specifically target the development and function of these allergen specific T-cell populations and modify their pro-allergic activities.

Propranolol inhibits nonexocytotic noradrenaline release in myocardial ischemia.

Ischemic induces a nonexocytotic noradrenaline release in the heart, which leads to high and potentially harmful interstitial noradrenaline concentrations. The effect of beta-adrenoceptor antagonists on noradrenaline release in ischemia has been investigated in the present study. DL-Propranolol (1-100 mumol/l) concentration-dependently reduced noradrenaline release during 20 min of global and total ischemia in the perfused rat heart. Other beta-adrenoceptor blocking agents such as atenolol, metoprolol, and timolol (10 mumol/l each), however, did not share this effect. Moreover, both stereoisomers of propranolol were equipotent in suppression of ischemia-induced noradrenaline release, indicating a property of propranolol independent from interaction with beta-adrenoceptors. The well known local anesthetic action of propranolol was not likely to cause its inhibitory effect on ischemia-induced noradrenaline release, as lidocaine (10 mumol/l) did not affect noradrenaline overflow in ischemia. The effect of propranolol was further examined in cyanide intoxication, an experimental model of energy depletion. In this experimental setting the release of dihydroxyphenylethyleneglycol--the major neuronal metabolite of noradrenaline--served as indicator of increased axoplasmic noradrenaline levels which are present during nonexocytotic noradrenaline release. In cyanide intoxication DL-propranolol also reduced noradrenaline overflow but did not affect release of dihydroxyphenylethylene glycol. The latter finding suggests an interaction of propranolol with the neuronal membrane transport of noradrenaline. In ischemia and cyanide intoxication, transport of noradrenaline across the plasma membrane is known to be driven by the noradrenaline carrier (uptake1) working in reverse of its normal direction--from inside to outside. Consequently, inhibitors of the noradrenaline carrier like desipramine were shown to suppress nonexocytotic noradrenaline release in ischemia and cyanide intoxication.(ABSTRACT TRUNCATED AT 250 WORDS)