Elevated expression of adenosine A1 receptor in bronchial biopsy specimens from asthmatic subjects

Abstract

Asthmatics, unlike healthy subjects, experience bronchoconstriction in response to inhaled adenosine, and extracellular adenosine concentrations are elevated in the bronchoalveolar lavage fluid and exhaled breath condensate of asthmatic subjects. However, little is known about the location and expression of adenosine receptors in asthmatic airways. The aim of the present study was to investigate the distribution of adenosine A 1 receptors in bronchial biopsy specimens from mildly asthmatic steroid-naïve subjects and then compare the degree of expression with that of healthy subjects.Biopsy sections were immunostained using an adenosine A 1 receptor antibody, the selectivity of which was validated in specific experiments. Image analysis was then performed in order to determine differences in immunostaining intensity.Immunostaining of biopsy sections from the asthmatic subjects revealed strong expression of the A 1 receptor, located predominantly in the bronchial epithelium and bronchial smooth muscle. In comparison, very weak immunostaining was observed in biopsy specimens obtained from healthy subjects. Image analysis revealed that the intensity of positive staining of the asthmatic bronchial epithelium and smooth muscle regions was significantly greater than that observed for the healthy epithelium and smooth muscle.In conclusion, the sensitivity of asthmatics to inhaled adenosine coupled with increased adenosine A 1 receptor expression implies that these receptors play a role in the pathophysiology of this disease. KEYWORDS: Adenosine, adenosine A 1 receptor, adenosine A 1 receptor expression, asthma A denosine is a purine nucleoside that is expressed in all cells of the body and involved in a wide range of physiological processes. The effects of adenosine are mediated predominantly through specific cell surface receptors, of which four subtypes (A 1 , A 2A , A 2B and A 3 ) have been described. It is now well recognised that extracellular levels of adenosine markedly increase under metabolically stressful conditions, such as hypoxia and inflammation, and, although an acutely elevated level of extracellular adenosine is considered to mediate anti-inflammatory and protective effects, chronic accumulation has been associated with pathological consequences [1].In asthmatic subjects, it has been demonstrated that adenosine levels in bronchoalveolar lavage fluid and exhaled breath condensate are significantly higher than those occurring in healthy subjects [2,3], and current evidence strongly suggests that they may contribute to the pathophysiology of asthma. For example, it has been recognised since the mid-1980s that inhalation of adenosine 59-monophosphate (AMP; 5'-nucleotidase rapidly hydrolyses AMP to adenosine in the lung) in asthmatic but not healthy subjects results in dose-related bronchoconstriction [4]. This is considered to be mediated predominantly, but not exclusively, by mast cell degranulation via A 2B receptor activation (reviewed in [5]). Furthermore, inhalation of AMP has been shown to i...

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