Modulation of mouse endotoxin shock by inhibition of phosphatidylcholine-specific phospholipase C.
During Gram-negative bacterial infections, lipopolysaccharide (LPS) interacts with monocyte/macrophage receptors, resulting in a host defense response. Activation of intracellular signal transduction pathways implicating various protein kinase and phospholipases is crucial in activating the transcription of genes encoding proinflammatory cytokines and inducible nitric oxide synthase (iNOS). In this article, we demonstrate that in mouse, endotoxin shock activation of phosphatidylcholine-specific phospholipase C (PC-PLC) plays a major role in controlling the inflammatory response. Inhibition of PC-PLC by the specific inhibitor tricyclodecan-9-yl-xanthogenate (D609) before LPS reduced the release of interleukin-1 beta, interleukin-6 and nitric oxide (NO) in vivo. In contrast, tumor necrosis factor-alpha serum levels were not altered by the pretreatment with D609. Consequently, survival from endotoxin shock of D609-treated animals was significantly improved compared with control animals (45% vs. 20%). Thus, inhibition of PC-PLC can reduce the inflammatory response to LPS and may serve as a novel approach to therapy of sepsis.
Tschaikowsky
K
K
Department of Anesthesiology, University of Erlangen-Nürnberg, Germany. klaus.tschaikowsky@rzmail.uni-erlangen.de
Schmidt
J
J
Meisner
M
M
D000818:Animals; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D005260:Female; D007375:Interleukin-1 / Q000502:physiology; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D009636:Norbornanes; D010713:Phosphatidylcholines / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D012772:Shock, Septic / Q000209:etiology*; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors*
D001952:Bridged-Ring Compounds; D007375:Interleukin-1; D009636:Norbornanes; D010713:Phosphatidylcholines; D010726:Phosphodiesterase Inhibitors; D013859:Thiocarbamates; D013871:Thiones; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C046498:tricyclodecane-9-yl-xanthogenate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C