R I Ketchell1, M D'Amato, M W Jensen, B J O'Connor. 1. 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
Abstract
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).
RCT Entities:
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).
Authors: G M Gauvreau; J M Lee; R M Watson; A M Irani; L B Schwartz; P M O'Byrne Journal: Am J Respir Crit Care Med Date: 2000-05 Impact factor: 21.405
Authors: Joanna J Lukawska; Lefteris Livieratos; Barbara M Sawyer; Tak Lee; Michael O'Doherty; Philip J Blower; Martin Kofi; James R Ballinger; Christopher J Corrigan; Gopinath Gnanasegaran; Ehsan Sharif-Paghaleh; Gregory E D Mullen Journal: EBioMedicine Date: 2014-10-28 Impact factor: 8.143