Involvement of A₁adenosine 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 A 1 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 ϩ aerosolized adenosine (SEN ϩ AD). Animals were sensitized with ragweed (200 g ip; days 1 and 6), followed by 1% ragweed aerosol challenges (days 11 to 13). On day 14, the SEN ϩ 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 A 1WT CON group, which was impaired in the A1WT SEN and SEN ϩ AD groups. All groups of A 1KO mice showed similar (no significant difference) concentration-dependent relaxation to NECA. The A 1WT SEN and SEN ϩ AD groups had a significantly higher contraction to selective A 1 agonist 2-chloro-N 6 -cyclopentyladenosine (CCPA) compared with the CON group. Western blot data showed that aortic A 1AR expression was significantly increased in WT SEN and SEN ϩ AD mice compared with CON mice. Gene expression of ICAM-1 and IL-5 was significantly increased in allergic A 1WT 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 A 1WT mice showed altered vascular reactivity, increased airway hyperresponsiveness, and systemic inflammation. These data suggest that A 1AR is proinflammatory systemically in this model of allergic asthma.

Adenosine receptors and vascular inflammation

“…CCR3 was predominantly expressed on macrophages and they suggest eotaxin may participate in mast cell activation or recruitment. In addition to this, in our most recent study [61] we have found significantly higher levels of IL-5 in aortic tissue of allergic A 1 WT mice. This may further support a role for IL-5 induced eotaxin effects in vasculature.…”

“…Recent work from our lab [61] using A 1 AR knock-out (A 1 AR KO) mice has shown the involvement of A 1 ARs in systemic and vascular inflammation. Data showed that the allergic A 1 WT mice (A 1 WT SEN and A 1 WT SEN+AD groups) had lower adenosine-mediated aortic relaxation to 5’-N-ethylcarboxamidoadenosine (NECA; non-selective adenosine analog) (Table 2) and higher contraction to 2-chloro-N6-cyclopentyladenosine (CCPA; selective A 1 AR agonist), with increased protein expression of A 1 AR in the aorta.…”

Effective treatment of experimental ragweed‐induced asthma with STAT‐6‐IP, a topically delivered cell‐penetrating peptide

“…In this model, mice were sensitized and challenged exclusively via the intranasal route, without the use of adjuvants. Unlike other published models , many of which sensitize by administration of ragweed plus adjuvant via the intraperitoneal route, we extended the sensitization period to 5 weeks of intranasal allergen exposure (5 days per week) to mimic as closely as possible the route and extent of sensitization in humans. Previous studies have shown that ragweed sensitization can be achieved by intranasal exposure in a shorter period of time if the environment is enriched with GM‐CSF or if multiple allergens are used in a chronic model.…”

Purinergic Signaling in Mast Cell Degranulation and Asthma

“… Hua et al (2007) demonstrated that adenosine-induced bronchoconstriction in mice is mediated via the A 1 AR. Ponnoth et al (2010) demonstrated using allergic WT and A 1 AR KO mice that this receptor is systemically proinflammatory and increases airway hyperresponsiveness. Use of DNA antisense against the A 1 AR in a rabbit model of asthma suggested that receptor subtype may promote bronchoconstriction ( Nyce and Metzger, 1997 ).…”