Detrimental effects of albuterol on airway responsiveness requires airway inflammation and is independent of β-receptor affinity in murine models of asthma

Abstract

BackgroundInhaled short acting β2-agonists (SABA), e.g. albuterol, are used for quick reversal of bronchoconstriction in asthmatics. While SABA are not recommended for maintenance therapy, it is not uncommon to find patients who frequently use SABA over a long period of time and there is a suspicion that long term exposure to SABA could be detrimental to lung function. To test this hypothesis we studied the effect of long-term inhaled albuterol stereoisomers on immediate allergic response (IAR) and airway hyperresponsiveness (AHR) in mouse models of asthma.MethodsBalb/C mice were sensitized and challenged with ovalbumin (OVA) and then we studied the IAR to inhaled allergen and the AHR to inhaled methacholine. The mice were pretreated with nebulizations of either racemic (RS)-albuterol or the single isomers (S)- and (R)-albuterol twice daily over 7 days prior to harvest.ResultsWe found that all forms of albuterol produced a significant increase of IAR measured as respiratory elastance. Similarly, we found that AHR was elevated by albuterol. At the same time a mouse strain that is intrinsically hyperresponsive (A/J mouse) was not affected by the albuterol isomers nor was AHR induced by epithelial disruption with Poly-L-lysine affected by albuterol.ConclusionsWe conclude that long term inhalation treatment with either isomer of albuterol is capable of precipitating IAR and AHR in allergically inflamed airways but not in intrinsically hyperresponsive mice or immunologically naïve mice. Because (S)-albuterol, which lacks affinity for the β2-receptor, did not differ from (R)-albuterol, we speculate that isomer-independent properties of the albuterol molecule, other than β2-agonism, are responsible for the effect on AHR.

Antigen-induced mast cell expansion and bronchoconstriction in a mouse model of asthma

“…Because their model of transfer impedance in conscious mice involved applying pressure oscillations around the body generating flow through the nose, it was unavoidable that any restriction of air flow in the nose would affect the measurement of respiratory mechanics (16). Indeed, when Zosky et al (54) used the same input impedance technique as we used in our present study they failed to find any OVA-induced bronchoconstriction, similar to what we found with OVA in a previous study (27). While it is possible that inhaled OVA triggered mast cell degranulation in the study by Hessel et al, it is, due to technical limitations of their study, impossible to resolve if the increase in respiratory resistance emanated from the nose or the lung.…”

“…In a recent study we attempted to induce bronchoconstriction using an OVA model in mice. This was not successful in that inhaled OVA failed to induce any significant bronchoconstriction (27). In retrospect we did stain histological cuts from five OVA-sensitized mice for mast cells but found no expansion of mast cells (data not shown).…”

“…Next the mice were paralyzed with pancuronium bromide (0.8 g/kg ip). The depth of anesthesia was monitored with EKG throughout the experiment as previously described (27,28,30). The animals were stabilized over about 10 min of regular ventilation at a positive end-expiratory pressure (PEEP) of 3 cmH 2O.…”

Long-Acting Beta Agonists Enhance Allergic Airway Disease

“…In comparison to these animals, whereas addition of the SABA albuterol had no effect on A. Genotype matched wild type and β 2 -AR-and ßarr2-deficient mice were challenged with salmeterol or DLPC alone i.n. and assessed for airway niger-induced airway hyperresponsiveness, confirming a prior study of mice sensitized against ovalbumin [44], mice challenged with the LABA salmeterol and A. niger developed significantly greater airway hyperresponsiveness (Fig 1b). Given the relatively long duration of the challenge protocol, we considered the possibility that salmeterol was downregulating expression of the ß 2 -AR, a process termed tachyphylaxis [45], thereby potentially suppressing the ability of endogenous adrenaline to limit expression of airway hyperresponsiveness.…”

Ablation of Arg1 in hematopoietic cells improves respiratory function of lung parenchyma, but not that of larger airways or inflammation in asthmatic mice

“…R N in the large airways of OVA/OVA-treated Arg1-deficient mice was not different from that in similarly treated animals without the deletion, but H and G were markedly lower in the Arg-KO Tie2 mice. H and G primarily reflect peripheral lung function (1) and may, in allergic asthma, reflect "closure" of peripheral airways by mucous bridges (30,31,55). In agreement, the mRNA abundance of Clca3 (Gob5), which regulates mucus production, and the mucin Muc5ac were lower in OVA/OVAtreated Arg1-KO Tie2 than Arg1-Con mice.…”