(S,S)-Formoterol Increases the Production of IL-4 in Mast Cells and the Airways of a Murine Asthma Model

Abstract

Background: Racemic formoterol is an equimolar mixture of (R,R)- and (S,S)-formoterol. Several studies have shown (S,S)-formoterol to have proinflammatory effects. We previously reported that (S)-albuterol increased the secretion of histamine and interleukin (IL)-4 in murine mast cells. We thus hypothesized that (S,S)-formoterol promotes asthma by enhancing IL-4 production in mast cells of the asthmatic airway. Methods: Murine and human mast cells were stimulated by high affinity IgE receptor (FcΕRI) cross-linking or with phorbol myristate acetate/calcium ionophore A23187 (PMA/A23187). Jurkat T cells were stimulated with PMA. Cells were pretreated with either (R,R)- or (S,S)-formoterol. Ovalbumin (OVA)-sensitized BALB/c mice were pretreated with (R,R)- or (S,S)-formoterol before each intranasal OVA challenge for 10 days. Bronchoalveolar lavage fluid was obtained from the mice. The levels of IL-4, histamine and PGD₂ were measured. Early and late allergic responses (EAR and LAR, respectively) to OVA challenge and airway hyperresponsiveness (AHR) were measured. Results: (S,S)-formoterol enhanced the production of IL-4, histamine, and PGD₂ in mast cells, whereas (R,R)-formoterol had no effect. Neither (S,S)- nor (R,R)-formoterol had effect on IL-4 production in Jurkat T cells. In OVA-challenged mice, (S,S)-formoterol increased IL-4 secretion, whereas (R,R)-formoterol had no effect. Finally, (S,S)-formoterol enhanced the inflammatory changes in the peribronchial and perivascular areas without affecting EAR, LAR or AHR, whereas (R,R)-formoterol reduced EAR, LAR and AHR as well as cellular infiltration in the lung tissue of these mice. Conclusion: (S,S)-formoterol may exert adverse effects in asthma control by activating mast cells to produce proinflammatory mediators such as IL-4.

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

“…In agreement with these findings, racemic salbutamol induced an exaggerated conctractile response to histamine in airway tissues obtained from sensitized from guinea pigs [21]. It has been speculated that the pro-inflammatory and pro-constrictory activity of S-isomer, are mediated by the activation of transcriptional nuclear factor κB (NF-κB) as has been demonstrated in human isolated airways [23],. These findings were also confirmed in other animal models of bronchial hyperresponsiveness.…”

Effects of Formoterol on Contraction and Ca2+ Signaling of Mouse Airway Smooth Muscle Cells

“…However, others studies suggest that (S,S)-formoterol may not be biologically inactive as previously thought, but may reduce the relaxant efficacy of the racemic mixture (10). In addition, (S,S)-formoterol may promote inflammation (11).…”

Murine Th Clones Confer Late Asthmatic Response upon Antigen Challenge

“…Airflow limitation was determined by a dimensionless parameter: P enh , which is believed a suitable parameter for the continuous measurement of airflow limitation [26, 27]. P enh value of T6-2-transferred mice before challenge (baseline) was not statistically different from that obtained before cell transfer (data not shown), or 30 min after OVA challenge (fig.…”

“…Unrestrained plethysmography is ideally suited for long-term measurements of conscious animals, and P enh value was employed to evaluate both IAR and LAR in murine models [26, 27]. There is a controversy regarding the validity of P enh , because it is not a direct measurement of lower respiratory tract [46].…”