Lk. Chong et al., PROTECTION BY DEXAMETHASONE OF THE FUNCTIONAL DESENSITIZATION TO BETA(2)-ADRENOCEPTOR-MEDIATED RESPONSES IN HUMAN LUNG MAST-CELLS, British Journal of Pharmacology, 121(4), 1997, pp. 717-722
1 The beta-adrenoceptor agonist, isoprenaline, inhibited the IgE-media
ted release of histamine from human lung mast cells (HLMC) in a dose-d
ependent manner. Maximal inhibitory effects were obtained with 0.1 mu
M isoprenaline. However, the inhibition of histamine release from HLMC
by isoprenaline (0.1 mu M) was highly variable ranging from 33 to 97%
inhibition (mean, 59 +/- 3%, n = 27). 2 Long-term (24 h) incubation o
f 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
mu M) to inhibit histamine release following desensitizing conditions
(1 mu M isoprenaline for 24 h) was highly variable amongst HLMC prepa
rations 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 dese
nsitizing conditions (1 mu M isoprenaline for 24 h), HLMC were washed
and incubated for 24 h in buffer and the effectiveness of isoprenaline
(0.1 mu M) to inhibit IgE-mediated histamine release from HLMC was as
sessed. The extent of recovery was highly variable with some HLMC prep
arations failing to recover and others displaying a complete restorati
on of responsiveness to isoprenaline (mean, 40 +/- 6% recovery, n = 23
). 4 The effects of the glucocorticoid, dexamethasone, were also inves
tigated. Long-term (24-72 h) treatments with dexamethasone (0.1 mu M)
had no effect on IgE-mediated histamine release from HLMC. Additionall
y, long-term (24-72 h) treatments with dexamethasone (0.1 mu M) had no
effect on the effectiveness of isoprenaline to inhibit histamine rele
ase. However, long-term (24-72 h) treatments with dexamethasone (0.1 m
u M) protected against the functional desensitization induced by incub
ation (24 h) of HLMC with isoprenaline (1 mu M). The protective effect
was time-dependent and pretreatment of HLMC with dexamethasone for ei
ther 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 effectively to isoprena
line (0.1 mu M) if dexamethasone (0.1 mu M) was also included during t
he recovery period (19 +/- 9% recovery after 24 h in buffer; 50 +/- 8%
recovery after 24 h with dexamethasone, n = 5). 6 These data indicate
that the responses of different HLMC preparations to isoprenaline, th
e susceptibility of HLMC to desensitization and the ability of HLMC to
recover from desensitizing conditions varies markedly. Dexamethasone,
which itself has no direct effects on IgE-mediated histamine release
from HLMC, protected HLMC from the functional desensitization to beta-
adrenoceptor agonists. Because beta(2)-adrenoceptor agonists and gluco
corticoids are important in the therapeutic management of asthma and a
s the HLMC is probably important in certain types of asthma, these fin
dings may have wider clinical implications.