Involvement of A1 adenosine receptors in altered vascular responses and inflammation in an allergic mouse model of asthma.
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.
Ponnoth
Dovenia S
DS
Department of Physiology and Pharmacology, Center for Cardiovascular and Respiratory Sciences, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26506, USA.
Nadeem
Ahmed
A
Tilley
Stephen
S
Mustafa
S Jamal
SJ
D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000280:Administration, Inhalation; D000336:Aerosols; D031164:Ambrosia / Q000276:immunology; D000818:Animals; D052179:Antigens, Plant / Q000276:immunology; D001011:Aorta / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D001249:Asthma / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D015153:Blotting, Western; D016535:Bronchial Hyperreactivity / Q000378:metabolism / Q000503:physiopathology; D016084:Bronchoconstriction; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D015848:Interleukin-5 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010993:Plethysmography, Whole Body; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects
D000336:Aerosols; D052179:Antigens, Plant; D018836:Inflammation Mediators; D015848:Interleukin-5; D012333:RNA, Messenger; D043682:Receptor, Adenosine A1; D018799:Intercellular Adhesion Molecule-1; D019830:Adenosine-5'-(N-ethylcarboxamide); C058394:2-chloro-N(6)cyclopentyladenosine; D000241:Adenosine
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