Bronchial responsiveness is not always increased after allergen challenge.

Increased bronchial responsiveness has been reported at various time points following allergen challenge (AC), and may be related to the magnitude of the late response (LAR). We have studied 20 mild asthmatics, who were known to develop a late asthmatic response to inhalation of house dust mite extract (fall of > 15% from post-diluent baseline FEV1 from 2 to 7h after AC). The provocation concentration of methacholine causing a 20% fall in FEV1 (PC20 FEV1) was measured before and 24 h after challenge with house dust mite extract (HDM). The mean (SEM) change in log(PC20) was 0.08 (0.09) mg ml-1, and was not significant (P = 0.38; paired t-test). The change in PC20 for each subject was not significantly correlated with the size of LAR (r = -0.33; P > 0.05), but was significantly correlated with the absolute change from baseline FEV1 at 24 h (r = 0.67; P < 0.01). Our subjects had a high baseline responsiveness, when compared with previous studies. We suggest they may have been approaching a maximally responsive state prior to study, and allergen challenge may have had little effect in further increasing responsiveness. Exposure to allergen in late responders is not necessarily followed by an increase in non-specific bronchial responsiveness.

A novel animal model for investigating persistent airway hyperresponsiveness.

The present study investigates the development and maintenance of airway hyperresponsiveness in neonatally immunized rabbits. Rabbits were immunized within 24 hr of birth with the antigen Alternaria tenuis together with aluminum hydroxide as an adjuvant, followed by repeated antigen and adjuvant administration up to 3 months of age. Anesthetized, spontaneously breathing rabbits immunized according to this protocol exhibited a 3.7- (p < 0.01) and 1.8-fold (p < 0.05) increase in airway responsiveness to inhaled histamine when compared with groups of naive or sham-immunized rabbits, respectively. In the absence of further antigen challenge, these changes in airway responsiveness to histamine in a subpopulation of antigen-immunized rabbits persisted for up to 12 months of age. This hyperresponsiveness was not associated with an alteration in either total or differential inflammatory cell numbers as assessed by bronchoalveolar lavage (BAL), and no significant differences in isolated bronchial smooth muscle responsiveness to methacholine, histamine, theophylline, or electrical field stimulation were observed. These results demonstrate that neonatal immunization of rabbits with Alternaria tenuis can lead to the development of persistent airway hyperresponsiveness, and that the maintenance of this state is unrelated to either a detectable alteration in cellular infiltration within the airway lumen or changes in bronchial smooth muscle responsiveness. It is suggested that neonatal exposure to antigen and adjuvant may be important determinants for the development of persistent airway hyperresponsiveness. This animal model may provide a useful way to investigate the effects of drugs on airway hyperresponsiveness.

The thromboxane receptors of rat and guinea-pig lung.

The thromboxane (TXA2) receptors on rat and guinea-pig lung strips were compared using TXA2 agonists and TXA2 receptor antagonists. On rat lung strip several TXA2 mimetics were full agonists whilst the primary prostanoids lacked agonist activity. On guinea-pig lung strip the same agonists displayed markedly different efficacies. Both preparations contained homogeneous populations of TXA2 receptors as evidenced by BAY u3405 giving comparable pA2 values against four TXA2 mimetics. However, the observed pA2's of nine different TXA2 receptor antagonists, determined against U46619, did not correlate between the two preparations. These results point to the existence of TXA2 receptor subtypes.

BAY u3405, a potent and selective thromboxane A2 receptor antagonist on airway smooth muscle in vitro.

1. BAY u3405 (3(R)-[[(4-fluorophenyl) sulphonyl]amino]-1,2,3,4- tetrahydro-9H-carbazole-9-propanoic acid) has been evaluated on airway smooth muscle, from a number of species including man, for its thromboxane A2 (TXA2) antagonist activity. 2. BAY u3405 was a potent, and competitive, antagonist of the TXA2-mimetic U46619-induced contractions of human, guinea-pig, rat and ferret airway smooth muscle with pA2 values between 8.0 and 8.9 and with no inherent contractile activity (10(-9)-10(-4) M). 3. The TXA2 antagonist activity of BAY u3405 was stereoselective. Its (S)-enantiomer, BAY u3406, was approximately 50 fold less effective against U46619 on guinea-pig and human airway smooth muscle. 4. BAY u3405 also competitively antagonized contractions of guinea-pig airway smooth muscle induced by prostaglandin D2 (PGD2) or its metabolite 9 alpha, 11 beta-PGF2. On human and ferret airway smooth muscle it abolished contractions induced by PGD2, PGF2 alpha and 16,16-dimethyl-PGE2. 5. A high concentration (10(-6) M) of BAY u3405 had no effect on the contraction, or relaxation, of airway smooth muscle induced by a range of other agonists, nor did BAY u3405 have any effect on other prostanoid receptor types (DP, EP2, FP or IP). 6. BAY u3405, in contrast to some other TXA2 antagonists, is a potent and selective antagonist on a wide range of airways including human. This high affinity, and the oral activity of the compound described elsewhere, suggest it may be an appropriate tool to investigate the role of prostanoids in airway diseases such as asthma.

Effect of capsaicin on PAF-induced bronchial hyperresponsiveness and pulmonary cell accumulation in the rabbit.

1 Platelet activating factor (PAF), but not the carrier molecule bovine serum albumin (BSA) induced bronchoconstriction in the anaesthetized rabbit. This bronchoconstriction was not altered by prior treatment with capsaicin. 2 Rabbits demonstrated increased airways responsiveness to histamine 24h after exposure to PAF but not to BSA. PAF failed to increase airways responsiveness to histamine in animals pretreated with capsaicin (80 mg kg-1). 3 A significant increase in inflammatory cells was obtained in bronchoalveolar lavage (BAL) 24h after PAF exposure in vehicle-treated rabitts. This was associated with an increase in the numbers of neutrophils and eosinophils. Capsaicin treatment inhibited the PAF-induced influx of inflammatory cells found in BAL, although this was not associated with an inhibition of PAF-induced pulmonary eosinophilia. 4 Capsaicin-induced motor effects were modest in epithelium-intact rabbit bronchial preparations, but were significantly enhanced in epithelium-denuded preparations in the presence of thiorphan. The contractile response to capsaicin was significantly inhibited in tissues exposed to a consecutive dose of capsaicin. Furthermore, ruthenium red abolished capsaicin-induced contraction in epithelium-denuded preparations. 5 Tissue content of calcitonin gene-related peptide-like immunoreactivity and substance P-like immunoreactivity was not reduced in bronchus and iris obtained from capsaicin-treated rabbits, although capsaicin-induced contractile responses in rabbit bronchus obtained from animals previously treated with capsaicin were significantly reduced. Furthermore, airway responses to histamine, methacholine and electrical field stimulation in vitro, were not altered by pretreatment of rabbits in vivo for 3 days with capsaicin. 6. In conclusion, PAF-induced airways responsiveness and pulmonary cell accumulation is inhibited by in vivo capsaicin pretreatment in the rabbit, via a mechanism that may not involve depletion of sensory neuropeptides.