Contrasting effects of allergen challenge on airway responsiveness to cysteinyl leukotriene D-4 and methacholine in mild asthma

Background: Cysteinyl leukotrienes (cysteinyl-LTs) have been implicated in the pathogenesis of allergen induced airway responses. Airway responsiveness (AR) to inhaled cysteinyl-LTs is dramatically increased following allergen challenge in animal studies. The effect in man has not been evaluated. Methods: Ten mild steroid-naive asthmatic subjects with an isolated early asthmatic response (EAR) and 21 with an additional late asthmatic response (LAR) took part in a randomised controlled crossover study to assess AR to inhaled methacholine (MCh) and cysteinyl-LT D-4 (LTD4) 22 and 24 hours, respectively, after allergen challenge. Eight subjects had two further LTD4 challenges separated by a 2 week washout period to assess the reproducibility of inhaled LTD4 challenge. Results: In subjects with an isolated EAR, non-significant mean (SE) increases in AR of 0.4 (0.4) doubling doses (DD) for MCh and 0.4 (0.5) DD for LTD4 followed allergen challenge compared with cona trol. A significant correlation between AR to MCh and LTD4 followed both control (r=0.91, 95% CI 0.67 to 0.98; p=0.0002) and allergen challenge (r=0.79, 95% CI 0.32 to 0.95; p=0.0063). In subjects with an additional LAR there was a significant increase in AR to MCh (1.2 (0.3) DD, p=0.0005) following allergen challenge but no overall effect on AR to LTD4 (0.69 (0.4) DD, p=0.11). A significant correlation between AR to MCh and LTD4 was again observed (r=0.70; 95% CI 0.38 to 0.87; p=0.0004) following control, although it was reduced following allergen challenge (r=0.48; 95% CI 0.063 to 0.76% P=0.027). LTD, challenge was highly reproducible with a mean difference of 0.2 (0.3) DD between challenges. Conclusions: Allergen challenge significantly increases AR to inhaled MCh but not to LTD4 in subjects with LAR. The lack of a comparable increase in AR to LTD4 is surprising. Endogenous cysteinyl-LTs are produced in abundance following allergen challenge and may enhance AR to MCh or induce a degree of tachyphylaxis to LTD4.