adenosine-5--(n-ethylcarboxamide) and Bronchial-Hyperreactivity

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 (A(1)AR) and investigated the effects of aerosolized adenosine on vascular reactivity and inflammation, using A(1)AR knockout (A(1)KO) and corresponding wild-type (A(1)WT) 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 microg 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 A(1)WT CON group, which was impaired in the A(1)WT SEN and SEN + AD groups. All groups of A(1)KO mice showed similar (no significant difference) concentration-dependent relaxation to NECA. The A(1)WT SEN and SEN + 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(1)AR 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 A(1)WT aorta and were undetected in the A(1)KO groups. A(1)WT allergic mice had significantly higher airway hyperresponsiveness (enhanced pause) to NECA, with adenosine aerosol further enhancing it. In conclusion, allergic A(1)WT mice showed altered vascular reactivity, increased airway hyperresponsiveness, and systemic inflammation. These data suggest that A(1)AR is proinflammatory systemically in this model of allergic asthma.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Administration, Inhalation; Aerosols; Ambrosia; Animals; Antigens, Plant; Aorta; Asthma; Blotting, Western; Bronchial Hyperreactivity; Bronchoconstriction; Disease Models, Animal; Dose-Response Relationship, Drug; Inflammation; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-5; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Plethysmography, Whole Body; Polymerase Chain Reaction; Receptor, Adenosine A1; RNA, Messenger; Vasodilation

The mechanisms responsible for the development of airway hyperresponsiveness in asthma are poorly understood. Adenosine levels are high in the lungs of patients with asthma, but a role for adenosine in the development of this cardinal feature of asthma has not been previously reported.. To determine the capacity of adenosine to induce airway hyperresponsiveness, and to investigate the mechanisms behind these effects of adenosine on airway physiology.. Wild-type C57BL/6 mice were exposed to aerosolized adenosine analog adenosine-5' N-ethylcarboxamide (NECA), and subsequent hyperresponsiveness to methacholine was investigated by measuring airway mechanics after anesthesia and tracheostomy. Similar experiments were conducted with A(1)-deficient, A(3)-deficient, and mast cell-deficient mice, as well as with mast cell-deficient mice engrafted with wild-type (wt) or A(3)(-/-) mast cells. The effect of NECA on methacholine-induced tension development in ex vivo tracheal rings was also examined.. Exposure of wt mice to NECA resulted in the robust induction of airway hyperresponsiveness. NECA failed to induce hyperresponsiveness to methacholine in tracheal ring preps ex vivo, and NECA-induced airway hyperresponsiveness in vivo was not affected by the genetic inactivation of the A(1) adenosine receptor. In contrast, NECA-induced airway hyperresponsiveness was abolished in A(3) adenosine receptor-deficient mice and in mice deficient in mast cells. Reconstitution of mast cell-deficient mice with wt mast cells restored hyperresponsiveness, whereas reconstitution with A(3) receptor-deficient mast cells did not.. Adenosine induces airway hyperresponsiveness indirectly by activating A(3) receptors on mast cells.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Asthma; Bronchial Hyperreactivity; Female; Hexosaminidases; Lung; Mast Cells; Mice; Mice, Inbred C57BL; Receptor, Adenosine A3