Gamma-aminobutyric acid (GABA) is an important neurotransmitter that, through the subtype A GABA receptor (GABAAR), induces inhibition in the adult brain. Here we show that an excitatory, rather than inhibitory, GABAergic system exists in airway epithelial cells. Both GABAARs and the GABA synthetic enzyme glutamic acid decarboxylase (GAD) are expressed in pulmonary epithelial cells. Activation of GABAARs depolarized these cells. The expression of GAD in the cytosol and GABAARs in the apical membranes of airway epithelial cells increased markedly when mice were sensitized and then challenged with ovalbumin, an approach for inducing allergic asthmatic reactions. Similarly, GAD and GABAARs in airway epithelial cells of humans with asthma increased after allergen inhalation challenge. Intranasal application of selective GABAAR inhibitors suppressed the hyperplasia of goblet cells and the overproduction of mucus induced by ovalbumin or interleukin-13 in mice. These findings show that a previously unknown epithelial GABAergic system has an essential role in asthma.

Asthma induced by the inhalation of various allergens in the clinical research laboratory, has been a model for studying pathophysiology and pathogenesis of this disease for many years [1][2][3][4]. The inhalation of a specific allergen by asthmatic subjects can cause three types of airway responses [5]: the isolated response, that develops within 10-30 min after allergen challenge; the isolated late response that develops 3-8 h after the challenge; and the dual response, where subjects develop both early and late airway responses. The late response is associated with allergeninduced increases in airway responsiveness [6] and with eosinophilic airway inflammation [7].The doses of allergen usually used to study experimentally induced asthma are of a magnitude that causes an early response of at least a 15% reduction in forced expiratory volume in one second (FEV1) and a late response of at least 20% [5]. A shortcoming of this method is that these doses of allergen may be much higher than those to which patients with asthma are exposed in their natural environments. This shortcoming has been addressed by IHRE and co-workers [8,9], who used airway challenge with a low-dose of allergen. At first, these investigators studied early and late responses after a single challenge with low-dose allergen [8]. Later, they used repeated lowdose allergen challenge and demonstrated a significant increase in airway hyperresponsiveness [9]. However, the role of airway inflammation in causing these changes, as well as the time course of these events, has not been studied previously.The purposes of the present study were: 1) to determine the effects of repeated low-dose allergen challenge on airway inflammation as measured by numbers of eosinophils and metachromatic cells in induced sputum, as well as markers of eosinophil activation and level of the eosinopoietic cytokine IL-5; 2) to evaluate the effects of repeated low-dose allergen challenge on the development of late responses and methacholine airway hyperresponsiveness and to examine the time course of the changes; and 3) to evaluate the effects of repeated low-dose challenge on asthma symptoms and β 2 -agonist use. Increases in airway eosinophils and interleukin-5 with minimal bronchoconstriction during repeated low-dose allergen challenge in atopic asthmatics. I. Sulakvelidze, M.D. Inman, T. Rerecich, P.M. O'Byrne. ©ERS Journals Ltd 1998.ABSTRACT: Repeated low-dose allergen challenge increases airway hyperresponsiveness in atopic asthmatics. However, it is not known whether low-dose allergen challenge increases airway inflammation.Eight atopic asthmatics were enrolled in a controlled, cross-over study to evaluate the effect and time course of repeated low-dose allergen challenge on airway inflammation and hyperresponsiveness. The dose of allergen to reduce forced expiratory volume in one second (FEV1) by approximately 5% was selected in a screening allergen challenge. The subjects then were challenged for five consecutive days with either diluent or the selected low-dose of a...

Both budesonide 100 microg and 400 microg inhaled once daily significantly reduces allergen-induced sputum eosinophilia after repeated low dose challenge; however, only the higher dose also attenuates the allergen-induced airway hyperresponsiveness.