Enhanced airway reactivity and inflammation in A2A adenosine receptor-deficient allergic mice.
A(2A) adenosine receptor (A(2A)AR) has potent anti-inflammatory properties, which may be important in the regulation of airway reactivity and inflammation. Inflammatory cells that possess A(2A)AR also produce nitrosative stress, which is associated with pathophysiology of asthma, so we hypothesized that A(2A)AR deficiency may lead to increased airway reactivity and inflammation through nitrosative stress. Thus the present study was carried out to investigate the role of A(2A)AR on airway reactivity, inflammation, NF-kappaB signaling, and nitrosative stress in A(2A)AR knockout (KO) and wild-type (WT) mice using our murine model of asthma. Animals were sensitized intraperitoneally on days 1 and 6 with 200 microg of ragweed, followed by aerosolized challenges with 0.5% ragweed on days 11, 12, and 13, twice a day. On day 14, airway reactivity to methacholine was assessed as enhanced pause (Penh) using whole body plethysmography followed by bronchoalveolar lavage (BAL) and lung collection for various analyses. Allergen challenge caused a significant decrease in expression of A(2A)AR in A(2A) WT sensitized mice, with A(2A)AR expression being undetected in A(2A) KO sensitized group leading to decreased lung cAMP levels in both groups. A(2A)AR deletion/downregulation led to an increase in Penh to methacholine and influx of total cells, eosinophils, lymphocytes, and neutrophils in BAL with highest values in A(2A) KO sensitized group. A(2A) KO sensitized group further had increased NF-kappaB expression and nitrosative stress compared with WT sensitized group. These data suggest that A(2A)AR deficiency leads to airway inflammation and airway hyperresponsiveness, possibly via involvement of nitrosative stress in this model of asthma.
Nadeem
Ahmed
A
Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, West Virginia 26505-9229, USA.
Fan
Ming
M
Ansari
Habib R
HR
Ledent
Catherine
C
Jamal Mustafa
S
S
D031164:Ambrosia / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D020672:I-kappa B Proteins / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology; D015227:Lipid Peroxidation / Q000276:immunology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D010766:Phosphorylation; D010993:Plethysmography, Whole Body; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D016085:Bronchoconstrictor Agents; D020672:I-kappa B Proteins; C000606205:Nfkbia protein, mouse; D026361:Reactive Nitrogen Species; D043705:Receptor, Adenosine A2A; D051996:Transcription Factor RelA; D016210:Methacholine Chloride; D000072000:NF-KappaB Inhibitor alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D000242:Cyclic AMP; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse