d-609 and Shock--Septic

Excessive release of proinflammatory cytokines from cells stimulated with lipopolysaccharide (LPS) or staphylococcal exotoxin (SE) mediates the pathophysiologic manifestations of septic shock. Tricyclodecan-9-yl (D609), an inhibitor of phosphatidylcholine-specific phospholipase C, suppressed LPS- or SE-induced cytokines and chemokines in human peripheral blood mononuclear cells. These data suggest a potential role for D609 in the treatment of septic shock.

Topics: Bridged-Ring Compounds; Chemokine CCL2; Chemokine CCL4; Cytokines; Exotoxins; Humans; In Vitro Techniques; Interferon-gamma; Interleukin-1; Interleukin-6; Leukocytes, Mononuclear; Lipopolysaccharides; Macrophage Inflammatory Proteins; Norbornanes; Phosphodiesterase Inhibitors; Shock, Septic; Thiocarbamates; Thiones; Tumor Necrosis Factor-alpha; Type C Phospholipases

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.

Topics: Animals; Bridged-Ring Compounds; Female; Interleukin-1; Mice; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Norbornanes; Phosphatidylcholines; Phosphodiesterase Inhibitors; Shock, Septic; Thiocarbamates; Thiones; Tumor Necrosis Factor-alpha; Type C Phospholipases

Tumor necrosis factor (TNF) is a pleiotropic mediator of inflammation that has been implicated in the pathogenesis of devastating clinical syndromes including septic shock. We have investigated the role of a TNF-responsive phosphatidylcholine-specific phospholipase C (PC-PLC) for the cytotoxic and proinflammatory activity of TNF. We show here that the cytotoxicity signaled for by the so-called "death domain" of the p55 TNF receptor is associated with the activation of PC-PLC. The xanthogenate tricyclodecan-9-yl (D609), a specific and selective inhibitor of PC-PLC, blocked the cytotoxic action of TNF on L929 and Wehi164 cells. In vivo, D609 prevented both adhesion molecule expression in the pulmonary vasculature and the accompanying leukocyte infiltration in TNF-treated mice. More strikingly, D609 protects BALB/c mice from lethal shock induced either by TNF, lipopolysaccharide, or staphylococcal enterotoxin B. Together these findings imply PC-PLC as an important mediator of the pathogenic action of TNF, suggesting that PC-PLC may serve as a novel target for anti-inflammatory TNF antagonists.

Topics: Animals; Antigens, CD; Bridged-Ring Compounds; Cell Line; Enterotoxins; Enzyme Activation; Mice; Norbornanes; Phosphatidylcholines; Phosphodiesterase Inhibitors; Phospholipases A; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Shock, Septic; Signal Transduction; Thiocarbamates; Thiones; Type C Phospholipases