(S)-Albuterol Increases the Production of Histamine and IL-4 in Mast Cells

Abstract

Background: Racemic albuterol is an equimolar mixture of (R)-albuterol and (S)-albuterol. Previous studies indicated that (S)-albuterol may exert proinflammatory effects. We investigated the effect of (S)-albuterol in the production of mast cell mediators such as histamine and interleukin (IL)-4. Methods: Murine mast cells were either unstimulated or stimulated by IgE-receptor crosslinking. Both groups of mast cells were pretreated with either (R)- or (S)-albuterol. Histamine release and IL-4 secretion were measured by ELISA. Expression of L-histidine decarboxylase (L-HDC) and IL-4 was analyzed by semiquantitative reverse transcription-polymerase chain re- action. Results: In the overnight IgE-stimulated group, secreted histamine and total histamine were approximately 19.9 and 18.3% greater in cells co-treated with (S)-albuterol than untreated cells, respectively (n = 4, p < 0.002, p < 0.02), whereas there was no significant difference between the cells treated with (R)-albuterol and untreated cells. When the IgE-stimulated cells were treated with (S)-albuterol for 6 and 24 h, histamine release was approximately 18.3 and 24% greater, respectively (n = 4, p < 0.01). L-HDC is an essential enzyme for synthesizing histamine and its message was significantly induced in mast cells treated with (S)-albuterol. Both IL-4 message and protein were also significantly increased after treatment with (S)-albuterol. In the overnight IgE-stimulated group, IL-4 secretion was increased by approximately 58.8% upon exposure to (S)-albuterol (n = 5, p < 0.01). (R)-albuterol had no effect on mast cell mediator release. Conclusion: (S)-albuterol may have adverse effects in asthma control by activating mast cells to produce inflammatory mediators such as histamine and IL-4.

Evaluation of the effects of the R- and S-enantiomers of salbutamol on equine isolated bronchi

“…These findings were also confirmed in other animal models of bronchial hyperresponsiveness. Thus it has been reported that Ssalbutamol potentiates the pro-constrictory activity of histamine and IL-4 in sensitized guinea pigs [24], by stimulating the production of IL-2 and IL-13 in T-cells [25]. Over all, these cytokines shift the coupling of the β 2 -adrenergic receptors to pro-constrictory G proteins such as G iα-1 protein [19].…”

(R)-Albuterol Elicits Antiinflammatory Effects in Human Airway Epithelial Cells via iNOS

“…Based on this, many of the beneficial effects of racemic albuterol have been attributed to the "active" enantiomer, (R)-albuterol, discounting the (S)-enantiomer, which has been considered largely pharmacologically inactive. However, several recent reports suggest that (S)-albuterol may have deleterious effects, counteracting many of the therapeutic effects of (R)-albuterol when the racemic mixture is administered to patients (34)(35)(36). A recent study in cultured airway smooth muscle cells showed that (S)-albuterol could partially counteract the suppression of GM-CSF production mediated by the corticosteroid, dexamethasone, whereas (R)-albuterol elicited additional suppression (37).…”

Levalbuterol toxicity: no reason to be jittery

“…Studies have demonstrated that the S-levalbuterol not only increases intracellular-free calcium, which is an agonist in airway smooth muscle contraction, but also has significant proinflammatory effects, including increasing the production of histamine and interleukin-4 in mast cells [3][4][5]. These results support the concept that the S-levalbuterol may have significant detrimental effects on pulmonary function in an acute asthma exacerbation.…”