Beta‐adrenoceptors and asthma

Since Szentivanyi's proposal in 1968 that there may be a defect in J3-adrenoceptor function in atopy and asthma, there has been intensive debate about whether J3-receptor dysfunction may contribute to the pathophysiology of airway obstruction [IJ. Several early studies reported that cardiovascular and metabolic responses to infused J3-agonists were reduced in patients with asthma and that the number of J3-receptors on circulating leucocytes was reduced (reviewed in [2]). It later became clear that these abnormalities were likely to be due to tolerance induced by the J3-agonists used in therapy and could be replicated in normal individuals given the same therapy. Furthermore when J3-agonist therapy was withdrawn J3-adrenergic responsiveness usually returned to normal [3J. This suggested that the J3-adrenoceptor dysfunction reported in asthmatic patients was likely to be due to tolerance as a result of prior exposure to J3-agonists and was not due to an intrinsic abnormality in J3-receptor function in asthma. Studies on J3-receptor function in untreated asthmatic patients are conflicting, with some studies showing no difference in responsiveness compared to normal subjects [3,4J, whereas others have described reduced cardiovascular and metabolic responsiveness [5J or a reduced J3-receptor density and adenylyl cyclase response to J3-agonists in circulating leucocytes [6-8J. The magnitUde of these changes is very small, however, compared with the reduction in function of the same responses after J3-agonist therapy, and are unlikely to be of functional significance. An increase in circulating autoantibodies to the J3z-receptor was reported in asthmatic patients [9,IOJ. In the original report IgG autoantibodies that inhibited J3-receptor binding in calf lung were described in two asthmatic and one atopic patient of 10 patients tested, compared with no inhibition in four non-atopic controls [9J. Furthermore there appeared to be some relationship between antibody titre and reduced responsiveness to isoprenaline [IOJ. In this issue Potter and colleagues demonstrate that sera and purified IgG from both asthmatic and non-asthmatic subjects inhibit binding to cloned J3z-receptors and that there is no difference between the two groups, even in asthmatic patients with acute exacerbations [IIJ. However, in neither group of subjects did serum or IgG inhibit isoprenaline-induced cyclic AMP response in cloned human J3z-receptors, indicating that the blocking antibody is of no functional consequence. Polymorphism of the human J32-receptor gene has been reported using the restriction enzyme Ban-l [12J, which reveals two alleles. Potter et al. have found that BanI polymorphism of the J3rreceptor gene is unrelated to allergic disease [IIJ. These studies all suggest that an intrinsic defect in J3-receptors is unlikely in atopic or asthmatic subjects. Intuitively such an intrinsic defect in asthma is unlikely as chronic administration of J3-blockers to normal individuals does not result in atopy, airway hyperresponsiveness or asthma [2J. What is still uncertain is whether J3-receptor function may become abnormal as a consequence of asthmatic inflammation. A reduced cyclic AMP response to J3-agonists has been reported in lymphocytes from asthmatic patients following allergen challenge, suggesting that some factor may be released from inflammatory cells which may lead to this impaired responsiveness [13J. In guinea pigs sensitized to allergen and exposed to aerosolized allergen a reduction in J3-receptor density has been reported [14, 15], and in the Basenji greyhound model of airway hyperresponsiveness there is evidence for reduced J3-receptor function [I6J. There is also evidence that 13receptors may be dysfunctional in asthmatic airways, since the bronchodilator response to J3-agonists in vitro is impaired in airways taken from asthmatic patients who have died during an acute exacerbation [17,18J. Other studies in airways obtained from asthmatic patients at surgical lobectomy have also shown a reduction in relaxant response to isoprenaline in vitro [19J, although this has not always been observed [20,21]. In an autoradiographic study of a single patient with asthma who died from an asthmatic attack no change in J3-receptor density in airway smooth muscle was seen, despite a reduced relaxant response to isoprenaline [22]. Similarly, a normal airway distribution of J3-receptors was reported in four patients with fatal asthma [23]. In a recent report a paradoxical increase in both J3-receptor density and affinity was observed in airway smooth muscle in seven cases of fatal asthma [24J, and there was an inverse relationship between the impairment in relaxation response to isoprenaline and the increase in J3-receptor density. These studies suggest that there is uncoupling of airway smooth muscle J3-receptors in fatal asthma. The increase in J3-receptor density may be the result of increased J32-receptor gene transcription in response to some loss of negative feedback control of transcription. In a single case of fatal asthma a striking increase in J32-receptor messenger RNA in airway smooth muscle has been observed (Mak J.C.W. & Barnes P.J., unpublished observations). Although uncoupling of J3-receptors may occur in fatal asthma (and may be a terminal event), it is