Contrasting effects of allergen challenge on airway responsiveness to cysteinyl leukotriene D4 and methacholine in mild asthma

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 .

Bronchial responsiveness to leukotriene D4 is resistant to inhaled fluticasone propionate

“…Our data are in agreement with other studies that have shown the LTD 4 challenge to be highly reproducible. 20,21 Although the outcome was unexpected, it agrees with the result in 1 study of healthy subjects whose geometric mean LTD 4 PD 10 was unaffected after 6 days of budesonide. 12 Because similar 2-week courses of ICSs induce attenuation of bronchial hyperresponsiveness to most indirect stimuli, and albeit to a lesser degree also to direct stimuli, 22 the absence of an effect of fluticasone on the LTD 4 response is surprising, in particular because we at the same time in the same subjects were able to demonstrate that fluticasone caused a significant improvement of bronchial hyperresponsiveness to methacholine.…”

Odd couple: The unexpected partnership of glucocorticoid hormones and cysteinyl-leukotrienes in the extrinsic regulation of murine bone-marrow eosinopoiesis

“…To reconcile all of these apparent paradoxes, we propose a model in flow chart format (Figure 1 ) which has the following essential tenets: (1) GC and CysLT become functionally coupled in vivo as a consequence of allergen challenge, so that TNF-α-dependent GC signaling makes it possible for CysLT generated locally in the context of allergic challenge to induce bone-marrow eosinophilia; (2) because the upstream permissive element (GC) and the downstream effector element (CysLT) are coupled, blocking the former will prevent the actions of the latter; (3) as a result of this coupling, full maturation of the eosinophils produced can be achieved in vivo after challenge; and (4) nevertheless, this mechanism is not operating unchecked in vivo , for its operation makes it less effective in subsequent rounds of allergen challenge, as shown by the attenuation of the proallergic effects of CysLT ex vivo , and by the observation that the positive effects of GC on the eosinophil lineage tend to less marked following chronic (repeated challenge) than acute (single challenge) exposures. Attenuation of CysLT effects ex vivo in murine bone-marrow would be consistent with observations that allergen challenge leads to a large increase in CysLT production in humans, and that a mechanism of desensitization to CysLT effects may limit the untoward effects of these potent bronchoconstrictors[ 75 ], although at present it is unclear whether and how this applies to hemopoietic effects.…”

Relation between bronchial responsiveness to inhaled leukotriene D4 and markers of leukotriene biosynthesis

“…Interestingly, Ketchell et al found that bronchial responsiveness to MCh but not to LTD 4 was increased after allergen challenge, findings that indirectly are in line with Ädelroth's hypothesis and our findings. 29 Thus, although MCh and LTD 4 are both direct bronchoconstrictors, the difference in relative potency for the two classes of bronchoconstrictors in asthmatics with varying degree of hyperresponsiveness indicates that each bronchoconstrictor has unique effects on the airways in asthma. Our findings support the hypothesis 27 that subjects with asthma and a high degree of airway reactivity have developed tachyphylaxis to LTD 4 , presumably because of high exposure to endogenous LTD 4 in their inflamed airways.…”