Open AccessImpact of disrupting adenosine A 3 receptors (A 3 −/− AR) on colonic motility or progression of colitis in the mouse
Author(s) -
Ren Tianhua,
Grants Iveta,
Alhaj Mazin,
McKiernan Matt,
Jacobson Marlene,
Hassanain Hamdy H.,
Frankel Wendy,
Wunderlich Jacqueline,
Christofi Fievos L.
Publication year - 2011
Publication title -
inflammatory bowel diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.932
H-Index - 146
eISSN - 1536-4844
pISSN - 1078-0998
DOI - 10.1002/ibd.21553
Subject(s) - colitis , motility , medicine , histopathology , western blot , chemistry , pathology , immunology , biology , biochemistry , gene , genetics
Background: Pharmacological studies suggest that adenosine A 3 AR influences motility and colitis. Functional A 3 −/− AR knockout mice were used to prove whether A 3 AR activation is involved in modulating either motility or colitis. Methods: A 3 AR was probed by polymerase chain reaction (PCR) genotyping, Western blot, and immunochemistry. Motility was assessed in vivo by artificial bead‐expulsion, stool‐frequency, and FITC‐dextran transit. Colitis was induced with dextran sodium sulfate (DSS) in A 3 −/− AR or wildtype (WT) age‐ and sex‐matched controls. Progression of colitis was evaluated by histopathology, changes in myeloperoxidase (MPO), colon length, CD4 + ‐cells, weight‐loss, diarrhea, and the guaiac test. Results: Goat anti‐hu‐A 3 antiserum identified a 66 kDa immunogenic band in colon. A 3 AR‐immunoreactivity is expressed in SYN + ‐nerve varicosities, s‐100 + ‐glia, and crypt cells, but not 5‐HT + (EC), CD4 + (T), tryptase + (MC), or muscle cells. A 3 AR immunoreactivity in myenteric ganglia of distal colon ≫ proximal colon by a ratio of 2:1. Intestinal transit and bead expulsion were accelerated in A 3 −/− AR mice compared to WT; stool retention was lower by 40%–60% and stool frequency by 67%. DSS downregulated A 3 AR in epithelia. DSS histopathology scores indicated less mucosal damage in A 3 −/− AR mice than WT. A 3 −/− AR phenotype protected against DSS‐induced weight loss, neutrophil (MPO), or CD4 + ‐T cell infiltration, colon shortening, change in splenic weight, diarrhea, or occult‐fecal blood. Conclusions: Functional disruption of A 3 AR in A 3 −/− AR mice alters intestinal motility. We postulate that ongoing release of adenosine and activation of presynaptic‐inhibitory A 3 AR can slow down transit and inhibit the defecation reflex. A 3 AR may be involved in gliotransmission. In separate studies, A 3 −/− AR protects against DSS colitis, consistent with a novel hypothesis that A 3 AR activation contributes to development of colitis. (Inflamm Bowel Dis 2010)