Pharmacological manipulation of the inflammatory cascade by the superoxide dismutase mimetic, M40403

1 M40403 is a low molecular weight, synthetic manganese containing superoxide dismutasemimetic (SODm) that removes superoxide anions (.O27) without interfering with other reactivespecies known to be involved in in¯ammatory responses (e.g. nitric oxide, NO and peroxynitrite,ONOO-).2 As such, M40403 represents an important pharmacological tool to dissect the roles of .O27 inacute and chronic in¯ammation. For this purpose, the pharmacological pro®le of M40403 wasevaluated in carrageenan-induced pleurisy.3 Injection of carrageenan into the pleural cavity of rats elicited an acute in¯ammatory responsecharacterized by: ¯uid accumulation in the pleural cavity which contained a large number ofneutrophils (PMNs) as well as an in®ltration of PMNs in lung tissues and subsequent lipidperoxidation, and increased production of nitrite/nitrate (NOx), prostaglandin E2 (PGE2), tumournecrosis factor a, (TNFa), interleukin-1b (IL-1b), interleukin-6 (IL-6) and interleukin-10 (IL-10).4 All parameters of in¯ammation were attenuated by M40403 except for NOx, PGE2 and IL-10which remained unaltered. Furthermore, carrageenan induced an upregulation of the adhesionmolecules ICAM-1 and P-selectin, as well as nitrotyrosine and poly (ADP-ribose) synthetase (PARS)as determined by immunohistochemical analysis of lung tissues.5 The degree of staining for the ICAM-1, P-selectin, nitrotyrosine and PARS was reduced byM40403.6 These results clearly indicate that .O27 plays a critical role in the development of thein¯ammatory response by altering key components of the in¯ammatory cascade. Therefore,synthetic enzymes of SOD such as M40403, o€ers a novel therapeutic approach for the managementof various in¯ammatory diseases where these radicals have been postulated to play a role.