Date of Graduation

1981

Document Type

Dissertation/Thesis

Abstract

The interaction of myeloperoxidase (MPO) with H(,2)O(,2) and Cl('-) provides a potent cytotoxic/antimicrobial system for polymorphonuclear leukocytes (PMNs). MPO-related cytotoxicity may be associated with the formation of toxic oxidant MPO intermediates, OCl('-), or both. MPO itself is able to oxidize drugs and cellular components. Non-steroidal anti-inflammatory drugs (NSAIDs) able to act as antioxidant free radical scavengers are shown in this study to inhibit luminol-enhanced chemiluminescence (CL) which results from the MPO-H(,2)O(,2)-Cl('-) interaction. CL is a measure of the production of oxygen-centered free radicals by this reaction. The source of CL which these NSAIDs affect is not OCl('-), once thought to be the primary MPO oxidant, but oxygen-centered free radicals formed by the initial MPO-H(,2)O(,2)-Cl('-) interaction. Oxygen-centered peroxidase-dependent free radicals are likely to make a major contribution to inflammation. PMNs release MPO, H(,2)O(,2) and these oxygen free radicals at the site of initial inflammation, promoting the inflammatory reaction. These radicals are cytotoxic to host as well as foreign tissue. An NSAID free radical scavenging mechanism directed against these radicals may be the reason for the drugs' anti-inflammatory effects. Other free radical scavengers such as phenol or vitamin E have anti-inflammatory capabilities. This study compares the effects of antioxidant NSAIDs, methyl-prednisone and free radical scavengers against OCl('-), MPO and PMN luminol-enhanced CL. Agents which affected OCl('-)-CL are not very good NSAIDs, suggesting that MPO oxidant intermediates are the site of NSAID effects. Most NSAIDs were more effective against MPO-CL. The effectiveness of these NSAIDs followed the profile of NSAIDs effective in this study against PMN-CL. One exception to this was methyprednisone, which had no effect on PMN or MPO-CL, yet inhibited OCl('-)-CL. This and other data suggest that MPO and not OCl('-)-related reactions are a major source of PMN-CL. This study also shows that the luminol intermediate is not susceptible to attack from radical scavengers such as NSAIDs, further validating the use of luminol-enhanced CL as an assay for free radical production. While both OCl('-) and MPO oxidant intermediates may be affected by NSAIDs, it appears that MPO oxygen-centered free radicals are the primary target for NSAID antioxidant free radical scavenging mechanisms. These antioxidants impair the major killing mechanism of the PMN, and may be the NSAIDs' primary anti-inflammatory mechanism. Studies using the anesthetic agent ketamine also suggested that phenolic-type structures could effectively scavenge MPO radicals. Other anesthetics also inhibit PMN-CL. Patient susceptibility to infection following general anesthesia could be partially due to a depression of PMN bactericidal mechanisms due to a scavenging of bactericidal MPO oxidants.

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