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Edema-inducing activity of phospholipase A2 purified from human synovial fluid and inhibition by aristolochic acid.

Abstract
A neutral-active, Ca2+-dependent phospholipase A2 (PLA2) purified 11,000-fold from human synovial fluid (HSF) induced edema when injected into the mouse foot pad. The edema produced by HSF-PLA2 was dose-dependent and was positively correlated with the dose-dependent in vitro expression of PLA2 activity. Maximum edema was achieved within 45 min after the injection and persisted for at least 6 h. Aristolochic acid [8-methoxy-6-nitrophenanthro(3,4-d)-1,3-dioxole-5-carboxylic acid], a major chemical component derived from various species of Aristolochia plant, produced a dose-dependent inhibition of in vitro phospholipid hydrolysis by HSF-PLA2, porcine pancreatic PLA2, snake venom (Naja naja) PLA2, and PLA2 isolated from human platelet. The sensitivity of these PLA2s to inhibition by aristolochic acid varied markedly: HSF-PLA2 greater than N. naja PLA2 greater than human platelet PLA2 greater than porcine pancreatic PLA2. The inhibition of HSF-PLA2 by aristolochic acid was independent of substrate concentration (18-144 microM) and Ca2+ concentration (0.1-4.0 mM). These observations indicate that inhibition of HSF-PLA2 by aristolochic acid may result from direct interaction with the enzyme. When aristolochic acid was mixed with HSF-PLA2 and then injected into the mouse foot pad, edema was inhibited in a dose-dependent manner and was positively correlated with in vitro inhibition of PLA2 activity. Alkylation of HSF-PLA2 with p-bromophenacyl bromide concomitantly inhibited both enzyme and edema-inducing activity. These results clearly demonstrate that the neutral-active, Ca2+-dependent PLA2 isolated from human synovial fluid is proinflammatory and that catalytic activity is positively correlated with in vivo proinflammatory effects.
AuthorsB S Vishwanath, A A Fawzy, R C Franson
JournalInflammation (Inflammation) Vol. 12 Issue 6 Pg. 549-61 (Dec 1988) ISSN: 0360-3997 [Print] United States
PMID3220517 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Acetophenones
  • Aristolochic Acids
  • Phenanthrenes
  • aristolochic acid I
  • Phospholipases
  • 4-bromophenacyl bromide
Topics
  • Acetophenones (metabolism, pharmacology)
  • Animals
  • Aristolochic Acids
  • Edema (chemically induced, drug therapy)
  • Enzyme Activation (drug effects)
  • Female
  • Humans
  • Male
  • Mice
  • Phenanthrenes (metabolism, pharmacology)
  • Phospholipases (antagonists & inhibitors, metabolism, toxicity)
  • Synovial Fluid (metabolism)

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