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

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Abstract
M40403 is a low molecular weight, synthetic manganese containing superoxide dismutase mimetic (SODm) that removes superoxide anions (.O2−) without interfering with other reactive species known to be involved in inflammatory responses (e.g. nitric oxide, NO and peroxynitrite, ONOO‐). As such, M40403 represents an important pharmacological tool to dissect the roles of .O2− in acute and chronic inflammation. For this purpose, the pharmacological profile of M40403 was evaluated in carrageenan‐induced pleurisy. Injection of carrageenan into the pleural cavity of rats elicited an acute inflammatory response characterized by: fluid accumulation in the pleural cavity which contained a large number of neutrophils (PMNs) as well as an infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), prostaglandin E2 (PGE2), tumour necrosis factor α, (TNFα), interleukin‐1β (IL‐1β), interleukin‐6 (IL‐6) and interleukin‐10 (IL‐10). All parameters of inflammation were attenuated by M40403 except for NOx, PGE2 and IL‐10 which remained unaltered. Furthermore, carrageenan induced an upregulation of the adhesion molecules ICAM‐1 and P‐selectin, as well as nitrotyrosine and poly (ADP‐ribose) synthetase (PARS) as determined by immunohistochemical analysis of lung tissues. The degree of staining for the ICAM‐1, P‐selectin, nitrotyrosine and PARS was reduced by M40403. These results clearly indicate that .O2− plays a critical role in the development of the inflammatory response by altering key components of the inflammatory cascade. Therefore, synthetic enzymes of SOD such as M40403, offers a novel therapeutic approach for the management of various inflammatory diseases where these radicals have been postulated to play a role. British Journal of Pharmacology (2001) 132, 815–827; doi:10.1038/sj.bjp.0703841