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Volume 271, Number 42, Issue of October 18, 1996 pp. 26149-26156
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Manganese-based Superoxide Dismutase Mimetics Inhibit Neutrophil Infiltration in Vivo

(Received for publication, April 26, 1996, and in revised form, August 7, 1996)

Randy H. Weiss , Donald J. Fretland ^¶ , David A. Baron ^¶ , Una S. Ryan and Dennis P. Riley

From  Monsanto Corporate Research, St. Louis, Missouri 63167 and ^¶ Searle Research & Development, Skokie, Illinois 60077

In a previous study (Hardy et al. (1994) J. Biol. Chem. 269, 18535-18540), we observed that the manganese-based superoxide dismutase mimetic Mn(II)-dichloro(1,4,7,10,13-pentaazacyclopentadecane) (MnPAM) inhibited neutrophil-mediated cell injury in vitro. We have extended these studies with the low molecular weight superoxide dismutase mimic to evaluate the role of superoxide in neutrophil-mediated tissue injury in vivo. In a dose-dependent manner, MnPAM inhibited colonic tissue injury and neutrophil accumulation into the colonic tissue induced by the intracolonic instillation of dilute aqueous acetic acid in mice. Tissue injury was assessed by visual and histological analysis. Neutrophil infiltration was determined by tissue myeloperoxidase activity and confirmed by histological analysis. Two novel Mn(II) dichloro complexes of the carbon-substituted macrocycles 2-methyl-1,4,7,10,13-pentaazacyclopentadecane (MnMAM) and 2-(2-methylpropyl)-1,4,7,10,13-pentaazacyclopentadecane (MnBAM) effectively catalyzed the dismutation of superoxide with catalytic rate constants (k_cat) of 3.31 × 10⁷ M¹ s¹ and 1.91 × 10⁷ M¹ s¹, respectively, as determined by stopped-flow kinetic analysis at pH 8.1 and 21 °C. The superoxide dismutase mimetics MnMAM and MnBAM also attenuated dilute aqueous acetic acid-induced tissue injury and neutrophil infiltration into colonic tissue; however, two Mn(II) complexes that had little or no detectable SOD activity (k_cat  0.1 × 10⁷ M¹ s¹), specifically the Mn(II) dichloro complexes of 1,4,7,10,13-pentaazacyclohexadecane and 1,4,7,11,14-pentaazacycloheptadecane, failed to inhibit the colonic tissue injury or infiltration of neutrophils in mice treated intracolonically with dilute aqueous acetic acid. These results are consistent with a proinflammatory role for superoxide in the mediation of neutrophil infiltration in vivo.

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