Effect of NPC 15669, an inhibitor of neutrophil recruitment and neutrophil-mediated inflammation, on neutrophil function in vitro.
The new anti-inflammatory agent N-[9H-(2,7-dimethylfluorenyl-9-methoxy)carbonyl]-L-leucine (NPC 15669) inhibits inflammation in several animal models dependent upon neutrophil activation and recruitment into the inflammatory lesion. NPC 15669 appears to elicit its pharmacological action by inhibiting the cell surface expression of CD11b/CD18 (Mac-1) on the neutrophil and subsequent adhesion of the neutrophil to the vascular endothelium. The current study sought to further characterize the action of NPC 15669 on neutrophil function. In the range of 1-100 microM, this fluorene enhanced superoxide production in a concentration-dependent fashion. Using spin trapping/ESR spectroscopy, NPC 15669 was found to inhibit myeloperoxidase (MPO)-dependent hydroxyl radical primarily by scavenging hypochlorous acid, and secondarily by inhibiting agonist-stimulated degranulation as assessed by MPO and elastase release. These studies demonstrated that NPC 15669, in addition to inhibiting adhesion, alters other neutrophil functions. Whether the pharmacological activities described for NPC 15669 resulted directly from changes in Mac-1 expression or through some other mechanism is currently under investigation.
Pou
S
S
Department of Pharmacology and Toxicology, University of Maryland School of Pharmacy, Baltimore 21201.
Gunther
M R
MR
Pou
W S
WS
Cao
G L
GL
Bator
J M
JM
Cohen
M S
MS
Burch
R M
RM
Rosen
G M
GM
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D006878:Hydroxides / Q000378:metabolism; D017665:Hydroxyl Radical; D007249:Inflammation / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013268:Stimulation, Chemical; D013481:Superoxides / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006878:Hydroxides; D017382:Reactive Oxygen Species; D013481:Superoxides; C071244:N-(9H-(2,7-dimethylfluoren-9-ylmethoxy)carbonyl)leucine; D017665:Hydroxyl Radical; D007930:Leucine; D010100:Oxygen