No abstract

Platelet-activating factor (PAF) is a lipid-derived mediator that has been implicated in the pathophysiology of airway inflammation in asthma. Its actions include chemotaxis and activation of inflammatory cells, particularly eosinophils. Inhaled PAF causes bronchoconstriction and increased airway responsiveness in human subjects. However, PAF antagonists have so far failed to show benefits in allergen challenge or in the treatment of chronic asthma. SR27417A is a novel PAF antagonist with increased potency compared with previously tested compounds. Twelve asthmatic subjects received treatment with either SR27417A or placebo for 1 wk in a double-blind crossover study. After treatment each subject underwent allergen challenge. Effects were assessed in terms of early and late asthmatic responses and allergen-induced effects on airway responsiveness. Baseline lung function and airway responsiveness were also examined. Treatment with SR27417A significantly attenuated the late asthmatic response (AUC LAR4-10h: 107 +/- 24 after placebo, 79 +/- 17 after SR27417A, p < 0.05; mean maximal percent fall in FEV1 LAR: 29 +/- 6% after placebo, 23.5 +/- 5.4% after SR27417A, p < 0.05). There were no effects on early asthmatic responses, allergen-induced airway responsiveness, or baseline lung measurements. SR27417A is the most potent PAF antagonist to date, and it has a modest inhibitory effect on the late asthmatic response. This suggests that PAF has a small role in allergic inflammation.

The capacity of peripheral blood monocytes and alveolar macrophages (AM) obtained by bronchoalveolar lavage (BAL) to present recall antigens, namely, tuberculin purified protein derivative (PPD) or streptokinase-streptodornase (SKSD), to highly purified autologous T-cells has been studied in 11 asthmatic and 11 healthy, nonatopic normal subjects. In the asthmatic group, AM accessory cell function was variable, and most subjects were unable to present either recall antigen as effectively as blood monocytes, although one asthmatic subject demonstrated larger proliferative responses than blood monocytes for both antigens. AM accessory cell activity was not antigen-specific, and there was a correlation between accessory cell efficacy for the two antigens (r = 0.92; confidence interval, 0.53 to 0.98). Furthermore, a correlation existed between the percentage lymphocyte count in the BAL fluid and the ratio of macrophage to monocyte antigen-presenting capability for both PPD (r = 0.92; 95% confidence interval, 0.83 to 0.99) and SKSD (r = 0.90; 95% confidence interval, 0.45 to 0.98). In the normal subjects, AM were also unable to act effectively as accessory cells for the presentation of PPD and SKSD in the majority of subjects. No correlation existed between the percentage lymphocytes in BAL fluid and the ratio of AM to monocyte accessory cell function. These results suggest an association between AM accessory function and the presence of BAL lymphocytes in bronchial asthma.