Involvement of A1 adenosine receptors in altered vascular responses and inflammation in an allergic mouse model of asthma

Abstract

Poor lung function and respiratory disorders like asthma have a positive correlation with the development of adverse cardiovascular events. Increased adenosine levels are associated with lung inflammation that could lead to altered vascular responses and systemic inflammation. We hypothesized that asthmatic lung inflammation has systemic effects through A1 adenosine receptors (A1AR) and investigated the effects of aerosolized adenosine on vascular reactivity and inflammation, using A1AR knockout (A1KO) and corresponding wild-type (A1WT) mice that were divided into three experimental groups each: control (CON), allergen sensitized and challenged (SEN), and SEN + aerosolized adenosine (SEN + AD). Animals were sensitized with ragweed (200 μg ip; days 1 and 6), followed by 1% ragweed aerosol challenges ( days 11 to 13). On day 14, the SEN + AD groups received one adenosine aerosol challenge (6 mg/ml) for 2 min, and aortae were collected on day 15. 5′- N-ethylcarboxamidoadenosine (NECA; nonselective adenosine analog) induced concentration-dependent aortic relaxation in the A1WT CON group, which was impaired in the A1WT SEN and SEN + AD groups. All groups of A1KO mice showed similar (no significant difference) concentration-dependent relaxation to NECA. The A1WT SEN and SEN + AD groups had a significantly higher contraction to selective A1 agonist 2-chloro- N6-cyclopentyladenosine (CCPA) compared with the CON group. Western blot data showed that aortic A1AR expression was significantly increased in WT SEN and SEN + AD mice compared with CON mice. Gene expression of ICAM-1 and IL-5 was significantly increased in allergic A1WT aorta and were undetected in the A1KO groups. A1WT allergic mice had significantly higher airway hyperresponsiveness (enhanced pause) to NECA, with adenosine aerosol further enhancing it. In conclusion, allergic A1WT mice showed altered vascular reactivity, increased airway hyperresponsiveness, and systemic inflammation. These data suggest that A1AR is proinflammatory systemically in this model of allergic asthma.