Autoradiographic Localization of Beta-Adrenoceptors in Asthmatic Human Lung

Abstract

The autoradiographic distribution and density of beta-adrenoceptors in human non-diseased and asthmatic bronchi were investigated using [125I]iodocyanopindolol (I-CYP). Analysis of the effects of the beta-adrenoceptor antagonists on I-CYP binding demonstrated that betaxolol (20 nM, beta 1-selective) had no significant effect on specific grain density in either nonasthmatic or asthmatic human bronchus, whereas ICI-118551 (20 nM, beta 2-selective) inhibited I-CYP binding by 85 +/- 9% and 89 +/- 3%, respectively. Thus, homogeneous populations of beta 2-adrenoceptors existed in bronchi from both sources. Large populations of beta-adrenoceptors were localized to the bronchial epithelium, submucosal glands, and airway smooth muscle. Asthmatic bronchial tissue featured epithelial damage with exfoliated cells associated with luminal mucus plugs. A thickened basement membrane and airway smooth muscle hyperplasia were also evident. High levels of specific I-CYP binding were also detected over asthmatic bronchial smooth muscle, as assessed by autoradiography and quantitation of specific grain densities. Isoproterenol and fenoterol were 10- and 13-fold less potent, respectively, in bronchi from asthmatic lung than in those from nonasthmatic lung. However, this attenuated responsiveness to beta-adrenoceptor agonists was not caused by reduced beta-adrenoceptor density in asthmatic airways. A defect may exist in the coupling between beta-adrenoceptors and postreceptor mechanisms in severely asthmatic lung.

Lung Deposition of BDP/Formoterol HFA pMDI in Healthy Volunteers, Asthmatic, and COPD Patients

“…(10) Additionally, in COPD the peripheral airways are the main site of obstruction. (11) Second, corticosteroid receptors and b 2 -adrenergic receptors are present throughout the airways; (31,32) thus, the ICS=LABA synergistic interaction at the molecular level might occur at various cellular types in the lungs. Last, extrafine BDP alone has already been shown to reduce candidate markers of small airway inflammation.…”

Autocrine role of interleukin 1beta in altered responsiveness of atopic asthmatic sensitized airway smooth muscle.

“…Note the marked induction of IL-1␤ expression in both the atopic/asthmatic serum-sensitized (S) rabbit (A) and human (B) tissues as compared to their respective controls (C), whereas expression of GAPDH, ␣-actin, and RPL7 were similar in both tissue samples. strated that the attenuated ␤-adrenoceptor responsiveness in asthmatic airways could not be accounted for by a decrease in ␤-adrenergic receptor density or affinity (33)(34)(35), but rather, likely reflects a disruption of the ␤-adrenoceptor/adenylate cyclase-coupled transmembrane signaling mechanism. Indeed, in support of this concept, we recently reported that the induced impairment of ␤-adrenoceptor-mediated relaxation in rabbit ASM passively sensitized with human atopic/asthmatic serum is attributed to enhanced muscarinic M 2 receptor/G i protein-coupled expression and interaction, leading to attenuated receptor-coupled cAMP accumulation (22).…”

Pharmacological modulation of β-adrenoceptor function in patients with coexisting chronic obstructive pulmonary disease and chronic heart failure

“…Radioligand binding studies on lobectomy specimens have shown β 2 -AR density to increase with increasing airway generation, with high levels in the alveolar region [18]. β 2 -ARs are also expressed on many pro-inflammatory and immune cells, including mast cells, macrophages, neutrophils, lymphocytes, eosinophils, epithelial and endothelial cells, and both type I and type II alveolar cells.…”