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-naïve 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) (LTD(4)) 22 and 24 hours, respectively, after allergen challenge. Eight subjects had two further LTD(4) challenges separated by a 2 week washout period to assess the reproducibility of inhaled LTD(4) 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 LTD(4) followed allergen challenge compared with control. A significant correlation between AR to MCh and LTD(4) 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 LTD(4) (0.69 (0.4) DD, p=0.11). A significant correlation between AR to MCh and LTD(4) 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(4) 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 LTD(4) in subjects with LAR. The lack of a comparable increase in AR to LTD(4) 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 LTD(4).
Ketchell
R I
RI
Department of Respiratory Medicine and Allergy, Guys, King's & St Thomas' School of Medicine, King's College, London SE5 9PJ, UK. ian.ketchell@kcl.ac.uk
D'Amato
M
M
Jensen
M W
MW
O'Connor
B J
BJ
D000280:Administration, Inhalation; D000328:Adult; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D001249:Asthma / Q000276:immunology*; D001980:Bronchi / Q000187:drug effects* / Q000276:immunology; D001985:Bronchial Provocation Tests; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D017998:Leukotriene D4 / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage / Q000494:pharmacology*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
D000485:Allergens; D016085:Bronchoconstrictor Agents; D016210:Methacholine Chloride; D017998:Leukotriene D4