Protection by dexamethasone of the functional desensitization to β₂‐adrenoceptor‐mediated responses in human lung mast cells

Abstract

1 The b-adrenoceptor agonist, isoprenaline, inhibited the IgE-mediated release of histamine from human lung mast cells (HLMC) in a dose-dependent manner. Maximal inhibitory e ects were obtained with 0.1 mM isoprenaline. However, the inhibition of histamine release from HLMC by isoprenaline (0.1 mM) was highly variable ranging from 33 to 97% inhibition (mean, 59+3%, n=27). 2 Long-term (24 h) incubation of HLMC with isoprenaline led to a subsequent reduction in the ability of a second exposure of isoprenaline to inhibit IgE-mediated histamine release from HLMC. The impairment in the ability of isoprenaline (0.1 mM) to inhibit histamine release following desensitizing conditions (1 mM isoprenaline for 24 h) was highly variable amongst HLMC preparations ranging from essentially negligible levels of desensitization in some preparations to complete abrogation of the inhibitory response in others (mean, 65+6% desensitization, n=27). 3 The ability of HLMC to recover from desensitization was investigated. Following desensitizing conditions (1 mM isoprenaline for 24 h), HLMC were washed and incubated for 24 h in bu er and the e ectiveness of isoprenaline (0.1 mM) to inhibit IgE-mediated histamine release from HLMC was assessed. The extent of recovery was highly variable with some HLMC preparations failing to recover and others displaying a complete restoration of responsiveness to isoprenaline (mean, 40+6% recovery, n=23).4 The e ects of the glucocorticoid, dexamethasone, were also investigated. Long-term (24 ± 72 h) treatments with dexamethasone (0.1 mM) had no e ect on IgE-mediated histamine release from HLMC. Additionally, long-term (24 ± 72 h) treatments with dexamethasone (0.1 mM) had no e ect on the e ectiveness of isoprenaline to inhibit histamine release. However, long-term (24 ± 72 h) treatments with dexamethasone (0.1 mM) protected against the functional desensitization induced by incubation (24 h) of HLMC with isoprenaline (1 mM). The protective e ect was time-dependent and pretreatment of HLMC with dexamethasone for either 24, 48 or 72 h prevented desensitization by either 15+7, 19+5 or 51+10%, respectively (n=5 ± 7). 5 HLMC preparations which were relatively refractory to isoprenaline even after withdrawal (24 h) from desensitizing conditions responded more e ectively to isoprenaline (0.1 mM) if dexamethasone (0.1 mM) was also included during the recovery period (19+9% recovery after 24 h in bu er; 50+8% recovery after 24 h with dexamethasone, n=5). 6 These data indicate that the responses of di erent HLMC preparations to isoprenaline, the susceptibility of HLMC to desensitization and the ability of HLMC to recover from desensitizing conditions varies markedly. Dexamethasone, which itself has no direct e ects on IgE-mediated histamine release from HLMC, protected HLMC from the functional desensitization to b-adrenoceptor agonists. Because b 2 -adrenoceptor agonists and glucocorticoids are important in the therapeutic management of asthma and as the HLMC is probably important in certain types of asthma, these ...

ADRB2 Gly16Arg polymorphism, asthma control and lung function decline

“…It has been suggested that genetically mediated paradoxical bronchial obstruction or hyperresponsiveness may occur with long-term use of b-agonists [22]. Steroids have shown in experimental in vitro and in vivo studies to reverse functional desensitisation of b 2 -AR [4,23,24], increase receptor expression and density, and enhance expression of G s a, producing a dose-dependent increase in cyclic adenosine monophosphate levels [25,26]. However, in humans, loss of bronchoprotection from regularly administered b 2 -agonists seems to reverse only with acute high doses of ICS [27,28] and it is not clear that this happens with chronic use of ICS at low or medium doses [29][30][31].…”

Scientific rationale for using a single inhaler for asthma control

“…In asthmatic patients, there is tolerance to the mast cell protective effect of b 2 -agonists (against adenosine and allergen), but not to the protective effect against direct bronchoconstrictors [43,44]. A corticosteroid can reverse the tolerance to b-agonists in mast cells in vitro [45]. This suggests that regular treatment with inhaled corticosteroids should prevent the tolerance to the mast cell stabilising effects of b 2 -agonists and this may be an important mechanisms in reducing asthma exacerbations, as in the FACET study, and with combination inhalers.…”

Beyond the dogma: novel 2-adrenoceptor signalling in the airways

“…Interestingly, glucocorticoids tend to reverse many of these effects, demonstrating the highly beneficial potential of combined b 2 -agonist/corticosteroid therapy [6]. Indeed, glucocorticoids enhance b 2 -adrenoceptor expression and function [178][179][180], resensitise b 2 -adrenoceptors [181], increase Gsa expression [182], enhance eosinophil apoptosis [173] and reverse the upregulation of NK-2 receptor expression [175].…”