In vitro sensitization of human bronchus by β₂-adrenergic agonists

Abstract

Ϫ7 M fenoterol induced sensitization characterized by an increase in maximal contraction to endothelin-1 (ET-1) and acetylcholine (ACh). Incubation of human bronchi with 10 Ϫ6 , 3 ϫ 10 Ϫ6 , and 10 Ϫ5 M forskolin (an adenyl cyclase activator) reproduced sensitization to ET-1 and ACh. The sensitizing effect of fenoterol was inhibited by coincubation with gliotoxine (a nuclear factor-B inhibitor), dexamethasone, indomethacin (a cyclooxygenase inhibitor), GR-32191 (a TP prostanoid receptor antagonist), MK-476 (a cysteinyl leukotriene type 1 receptor antagonist), SR-140333 ϩ SR-48968 ϩ SR-142801 (neurokinin types 1, 2, and 3 tachykinin receptor antagonists) with or without HOE-140 (a bradykinin B 2 receptor antagonist), SB-203580 (an inhibitor of the 38-kDa mitogen-activated protein kinase, p38 MAPK ), or calphostin C (a protein kinase C blocker). Our results suggest that chronic exposure to fenoterol induces proinflammatory effects mediated by nuclear factor-B and pathways involving leukotrienes, prostanoids, bradykinin, tachykinins, protein kinase C, and p38 MAPK , leading to the regulation of smooth muscle contraction to ET-1 and ACh.␤ 2-agonists; airway sensitization; airway smooth muscle; endothelin-1; asthma THE FATAL ACUTE ASTHMA CASES attributable to fenoterol abuse in the 1980s in New Zealand started a controversy concerning the potential worsening of the bronchial hyperresponsiveness by the ␤ 2 -adrenoceptor agonists (7,14,42). Studies in animals and humans showed that chronic exposure to fenoterol or salbutamol induces a nonspecific bronchial sensitization, whereas the relaxant effects of these ␤ 2 -agonists on the airway smooth muscle are not decreased (11,59,60). The bronchial sensitization induced by fenoterol is similar to the sensitization provoked by ovalbumin in sensitized guinea pigs (60). Chronic administration of salbutamol at low doses to guinea pigs increases airway reactivity to histamine and methacholine (11). In humans, long-term use of salbutamol increases the bronchial hyperresponsiveness to histamine but does not cause subsensitization of ␤ 2 -adrenoceptors to salbutamol (59). In a bovine tracheal model, Katsunuma and colleagues (36) showed that prolonged incubation with fenoterol induced an increased contractile responsiveness to neurokinin A (NKA). In 1995, Peters and colleagues (47) suggested that the continuous activation of the intracellular signal transduction caused by the ␤ 2 -adrenoceptor stimulation could induce a proinflammatory process mediated by nuclear transcription factors in rat lung. A recent study in our institution showed that the transcription factor nuclear factor-B (NF-B) is involved in fenoterol-induced hyperresponsiveness to NKA in guinea pig isolated trachea (52).Endothelin-1 (ET-1) is a 21-amino acid peptide recently implicated in chronic inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease (25,26,41,46). ET-1 is synthesized and metabolized in lung, and ET-1 receptors (ET A and ET B ) are widely distributed in airway cells (21,26...

Cysteinyl Leukotrienes Are Autocrine and Paracrine Regulators of Fibrocyte Function

“…One previous report demonstrates that addition of endothelin 1 or TGF␤1 to human circulating fibrocytes can stimulate BrdU incorporation over a period of 4 days (8). It is interesting to note that in other systems, endothelin 1 and TGF␤1 have been noted to up-regulate CysLT production (32,33). Thus, it is possible that CysLTs are common effector molecules for fibrocyte proliferation, but they do not enhance fibrocyte differentiation into fibroblasts in vitro.…”

Beyond the dogma: novel β2-adrenoceptor signalling in the airways

“…For example, chronic treatment of human bronchi with fenoterol enhances contractile responses to endothelin via an effect that may be due to the sensitisation of the transient receptor potential vallinoid 1 channel [171,172]. In addition, repression of eosinophil apoptosis [173,174], induction of neurokinin (NK)-2 receptor expression [175,176], and upregulation of histamine H 1 receptor expression [177] are all examples of responses that would be considered undesirable in the context of asthma pathogenesis.…”

Expression and coupling of neurokinin receptor subtypes to inositol phosphate and calcium signaling pathways in human airway smooth muscle cells

“…Moreover, functional evidence for the presence of NK 3 R exists in both animal and human airways (24,38,40,43). Although most functional studies suggest that the NK 3 R subtype is not directly involved in airway smooth muscle constriction (2,13,14,53), an NK 3 R antagonist was mildly potent at inhibiting a neurokinin A-induced contraction in human bronchus (51).…”