Study of a new adenosine receptor A2A agonist, ATL313, on Clostridium difficile toxin A-induced enteritis in ileal pouch isolated of mice / Estudo do efeito de um novo agonista do receptor a2a de adenosina, atl313, sobre a enterite induzida pela toxina a do clostridium difficile em alça ileal isolada de camundongos

AUTOR(ES)
DATA DE PUBLICAÇÃO

2005

RESUMO

C. difficile toxin A (TxA) plays an important pathogenic role in antibiotic-induced diarrhea and pseudomembranous colitis, a condition characterized by intense mucosal inflammation and secretion. Agonist activity at A2A adenosine receptors (A2A ARs) attenuates inflammation and damage in many tissues. This study evaluated the effect of a new selective A2A AR agonist (4-{3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl]prop-2-ynyl}piperidine-1-carboxylic acid methyl ester; ATL313) on TxA-induced enteritis in murine ileal loops. ATL313 (0.05-5 nM) and/or the A2A AR antagonist (ZM241385; 5 nM) or PBS were injected inside ileal loops immediately prior to challenge with TxA (1-10 mg/loop) or PBS. Intestinal fluid volume/length and weight/length ratios were calculated 3 h later. Ileal tissue samples were collected for measurement of myeloperoxidase (MPO) content, evaluation of ADA activity, for histopathology and apoptotic immunohistochemistry (ApopTagâ) and for assessment of TNF-α levels by ELISA. TxA (1-10 g/loop) significantly (p<0.05) increased volume/length and weight/length, reaching maximum values at 5g/loop dosage. ATL313 (5 nM) treatment significantly (p<0.05) reduced TxA-induced volume/length and weight/length, as well as prevented mucosal disruption and TxA-induced apoptosis. These protective effects were reversed by ZM241385 (5 nM), the A2A AR antagonist. ATL313 (5 nM) also reduced neutrophil infiltration, as measured by MPO content; reduced the toxin A-induced increase in ADA activity. Prior to the challenge with TxA, a systemic injection of fucoidin, but not PBS, also reduced tissue destruction and toxin A-induced increase in ADA activity. In conclusion, the A2A AR agonist ATL313 has a great antiinflammatory effect in TxA-induced mice enteritis, significantly reducing tissue destruction and ADA activity. In addition, our data suggested that TxA-induced increase in ADA activity and tissue damage in murine ileal loops are related to the neutrophil infiltration induced by this toxin.

ASSUNTO(S)

enterite inflamação neutrófilo receptor a2b de adenosina inflammation enteritis farmacologia adenosina desaminase migração e rolagem de leucócitos adenosina clostridium difficile adenosine toxina a receptor a2 de adenosina bactérias gram-positivas formadoras de endosporo toxin type a clostridium difficile neutrophil activation

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