Adenosine receptors and asthma in humans

Abstract

According to an executive summary of the GINA dissemination committee report, it is now estimated that approximately 300 million people (5% of the global population or 1 in 20 persons) have asthma. Despite the scientific progress made over the past several decades toward improving our understanding of the pathophysiology of asthma, there is still a great need for improved therapies, particularly oral therapies that enhance patient compliance and that target new mechanisms of action. Adenosine is an important signalling molecule in human asthma. By acting on extracellular G-protein-coupled ARs on a number of different cell types important in the pathophysiology of human asthma, adenosine affects bronchial reactivity, inflammation and airway remodelling. Four AR subtypes (A(1), A(2a), A(2b) and A(3)) have been cloned in humans, are expressed in the lung, and are all targets for drug development for human asthma. This review summarizes what is known about these AR subtypes and their function in human asthma as well as the pros and cons of therapeutic approaches to these AR targets. A number of molecules with high affinity and high selectivity for the human AR subtypes have entered clinical trials or are poised to enter clinical trials as anti-asthma treatments. With the availability of these molecules for testing in humans, the function of ARs in human asthma, as well as the safety and efficacy of approaches to the different AR targets, can now be determined.

Figure 1

Representative photomicrographs showing positive immunostaining of asthmatic bronchial biopsy sections with an A₁ receptor antibody (a), with high expression of the A₁ receptor on the epithelium (b) and smooth muscle (c), shown at higher magnification. Positive immunostaining appears brown against a blue background as a result of the Mayer's haematoxylin counterstain. Scale bars=25 μm. Reprinted with permission from Brown et al. (2008).

Figure 2

Representative photomicrographs showing positive immunostaining of healthy bronchial biopsy sections with an A₁ receptor antibody (a), with weak expression of the A₁ receptor on the epithelium (b) and virtually no positive immunostaining of smooth muscle (c), shown at higher magnification. Positive immunostaining appears brown against a blue background as a result of the Mayer's haematoxylin counterstain. Scale bars=25 μm. Reprinted with permission from Brown et al. (2008).

Figure 3

Image analysis of asthmatic (open columns) and healthy (filled columns) bronchial biopsy sections immunostained with an A₁ receptor antibody. The intensity of positive staining specifically on the epithelium and smooth muscle areas of bronchial biopsy sections from 11 asthmatic volunteers and seven healthy individuals (one section per volunteer) was quantified using a Zeiss Vision KS400 software, from four different views of both epithelium and smooth muscle at a magnification of × 1000. Data are presented as mean±s.e.m. ^**P<0.01 versus healthy individuals. Reprinted with permission from Brown et al. (2008).