THE NOVEL INOSINE ANALOGUE INO-2002 EXERTS AN ANTI-INFLAMMATORY EFFECT IN A MURINE MODEL OF ACUTE LUNG INJURY

Endogenous purines, including inosine, have been shown to exert immunomodulatory and anti-inflammatory effects in a variety of disease models. The dosage of inosine required for these effects has been shown to be between 200 and 600 mg kg−1 because of the rapid metabolism of inosine in vivo. The aim of this study was to determine whether a metabolic resistant purine analog, INO-2002, exerts anti-inflammatory effects in an animal model of acute respiratory distress syndrome. Mice challenged with intratracheal LPS (50 &mgr;g) were treated with INO-2002 (30 or 100 mg kg−1, i.p.) in divided doses at either 1 and 12 h or at 5 and 16 h. After 24 h, bronchoalveolar lavage fluid was obtained to measure leukocyte infiltration by myeloperoxidase levels, lung edema by protein levels, and proinflammatory chemokine (macrophage inflammatory protein 1&agr;) and cytokine (TNF-&agr;, IL-1, and IL-6) levels. INO-2002 (30 and 100 mg kg−1) reduced the LPS-mediated infiltration of leukocytes and edema as evidenced by bronchoalveolar lavage fluid reduction in levels of myeloperoxidase and protein. INO-2002 also downregulated expression of the proinflammatory mediators macrophage inflammatory protein 1&agr;, TNF-&agr;, IL-1, and IL-6. Delaying the start of treatment by 5 h after LPS administration affected the potency of INO-2002 protective effects, with 100 but not 30 mg kg−1 having anti-inflammatory effects. The inosine analog INO-2002 largely suppressed LPS-induced inflammation in vivo at doses lower than those needed for the naturally occurring purine inosine. These data support the proposal that purine analogs, resistant to metabolic breakdown, may represent a useful addition to the therapy of acute respiratory distress syndrome.