Pharmacological Analysis of Antigen-Induced Late Airway Response in Rats

Abstract

Bronchial asthma is one of the most common allergic diseases in the world, and is considered a complex inflammatory disorder of the airways with various pathophysiological features.1) The exposure of asthmatics to specific antigens causes airway symptoms which can be generally distinguished into two predominant airway reactions, an immediate airway response (IAR) and a late airway response (LAR). 2,3)The pharmacological profiles of antigen-induced IAR and LAR have been determined using animal models, especially in the guinea pig. For example, it is known that antileukotrienes reduce LAR in guinea pig, while antihistamines do not. 4,5) On the other hand, inhalation of a b 2 -agonist like salbutamol, which directly inhibits the contraction of airway smooth muscle, diminishes IAR but not LAR.6) Further, anti-IL-5 monoclonal antibody decrease infiltration of eosinophils into the tracheal wall, and also markedly suppresses the development of LAR in guinea pig. 7)In recent years, the pharmaceutical targets for new asthmatic drugs have become more immunologically diverse and specific, and detailed immunological analysis of mechanisms in animal models is required to determine with precision the efficacies of new drug candidates. However, the guinea pig model is not sufficient for this purpose, since immunological and genetic research on guinea pigs has not been performed in detail.In this regard, we have examined the pharmacological and immunological characteristics of ovalbumin (OVA)-induced IAR and LAR in the rat. Briefly, rat IAR exhibits diverse immunological characteristics, i.e. a quick phase (3-6 min after challenge) caused by the exocytosis of mediators in CTMCs and an early phase (6-30 min after challenge) mediated by leukotriene (LT) and TXA 2 .8) In addition, repeated antigen inhalation by sensitized rats converts IAR to LAR, a reaction triggered by antigen-specific immunoglobulin G (IgG). 9)In the present study, the pharmacological profiles of rat LAR were examined using rat LAR model. To clarify the pharmacological profile of rat LAR, the effects of antiasthmatic drugs including salbutamol (b 2 -agonist), ketotifen (antihistamine), pranlukast (anti-leukotriene C 4 /D 4 /E 4 ), and prednisolone (steroid) were evaluated. In addition, the involvement of cell infiltration in bronchoalveolar lavage fluid (BALF) and pulmonary edema in LAR were investigated in the rat model. MATERIALS AND METHODS AnimalsMale Sprague-Dawley (SD) rats were purchased from Charles River Japan, Inc. (CRJ, Yokohama, Japan) and individually housed in plastic cages maintained under specific pathogen-free conditions at a room temperature of 23.0Ϯ3.0°C and air humidity of 55Ϯ15% in a 12-h light/dark cycle environment. The rats were given a standard laboratory chow diet (CRF-1, Oriental Yeast, Tokyo, Japan) and water ad libitum. All experiments complied with the Guidelines for Animal Experimentation of our laboratories.Compounds The antihistamine ketotifen (Sigma-Aldrich Co.); anti-LT (leukotriene C 4 /D 4 /E 4 receptor antagonist) pranlukas...

Pulmonary edema measured by MRI correlates with late-phase response to allergen challenge

“…This LAR edema can be significantly inhibited by corticosteroid treatment. Our re-sult confirms a previous study in rats where antigeninduced LAR was associated with pulmonary edema [18]. However, this appears to be the first study to show pulmonary edema correlating with the LAR, both of which can be attenuated by corticosteroid treatment in OVA-challenged guinea-pigs.…”