title: The novel inosine analogue INO-2002 exerts an anti-inflammatory effect in a murine model of acute lung injury.
abstract: 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 microg) 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 1alpha) and cytokine (TNF-alpha, 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 1alpha, TNF-alpha, 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.
authors.affiliation: School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, UK. j.g.Mabley@brighton.ac.uk
authors.forename: Jon G
authors.initials: JG
authors.lastname: Mabley
authors.forename: Pal
authors.initials: P
authors.lastname: Pacher
authors.forename: Kanneganti G K
authors.initials: KG
authors.lastname: Murthy
authors.forename: William
authors.initials: W
authors.lastname: Williams
authors.forename: Garry J
authors.initials: GJ
authors.lastname: Southan
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Salzman
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D054405:Chemokine CCL3 / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D007288:Inosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009195:Peroxidase / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D007288:Inosine; D009195:Peroxidase