Zinc tetrakis(N-methyl-4 '-pyridyl) porphyrinato is an effective inhibitorof stimulant-induced activation of RAW 264.7 cells

One proposed mechanism for the development of silica-induced fibrosis is pr olonged pulmonary inflammation and lung damage resulting from the secretion of reactive mediators from alveolar macrophages. Metalloporphyrins have an tioxidative and antiinflammatory activities. However, the molecular basis f or the antiinflammatory action of zinc tetrakis(N-methyl-4 ' -pyridyl) porp hyrinato (ZnTMPyP) has not been elucidated. The objective of this study was to determine whether ZnTMPyP exhibited the ability to inhibit the producti on of reactive oxygen species (ROS), the activation of NF-KB, or the secret ion of IL-1 in RAW 264.7 cells, and whether such inhibitory activity was re lated to the ROS-scavenging ability of ZnTMPyP. The results indicate that, although ZnTMPyP is not cytotoxic to RAW 264.7 cells, it is a potent inhibi tor in ROS production by RAW 264.7 cells in response to various stimulants, such as silica, zymosan, or phorbol myristate acetate. ZnTMPyP is also eff ective in reducing stimulant-induced DNA-binding activity of NF-KB and sili ca-induced tyrosine phosphorylation of I kappaB-alpha. ZnTMPyP also inhibit s LPS-induced IL-1 production. However, ZnTMPyP exhibits relatively weak ab ility to directly scavenge hyroxyl or superoxide radicals. On the basis of effective concentrations of ZnTMyP, these results suggest that ZnTMPyP dire ctly acts as an inhibitor of cellular activation in addition to exhibiting an antioxidant effect. Therefore, it is suggested that further studies conc erning the effects of ZnTMPyP using in vivo oxidative stress models or its effects on the cytotoxic process of human diseases associated with lung inf lammation and injury are warranted. In addition, ZnTMPyP may be a useful to ol to investigate the molecular mechanisms involved in stimulant-induced si gnal pathways. (C) 2001 Academic Press.