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Altered Guanine Nucleotide Protein Function: Potential Role in Endotoxin Tolerance

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Host Defense Dysfunction in Trauma, Shock and Sepsis

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Abstract

Endotoxin stimulates macrophages to synthesize and release a number of monokines including tumor necrosis factor (TNF), colony stimulating factor, platelet-activating factor, interleukin-1 (IL-1) and arachidonic acid metabolites [1–8]. In recent years arachidonic acid metabolites or eicosanoids, a group of inflammatory mediators, have generated considerable interest [9–14]. Arachidonic acid is esterified in the 2-position of specific cellular phospholipids including phosphatidylcholine (PC), phosphatidyl-ethanolamine (PE), and phosphatidylinositol (PI) [15–19]. The generation of free arachidonic acid from phospholipids is thought to be a rate-limiting step in the formation of arachidonic acid metabolites [20]. Endotoxin-stimulated cells mobilize their phospholipids through at least two major pathways [21]. In the first pathway, phospholipase C cleaves phosphatidylinositol 4,5-biphosphate, yielding inositol-1,4,5-triphosphate (IP3) and 1,2-diacylglycerol, both of which are second messengers [22–25]. IP3 mobilizes cytoplasmic calcium while 1,2-diacylglycerol stimulates protein kinase C [26–28]. A separate diglyceride lipase cleaves arachidonic acid from the diacylglycerol molecule [29, 30]. In the second pathway, phospholipase A2 (PLA2) directly releases arachidonic acid and other unsaturated fatty acids from phospholipids including PC, PE, and PI.

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Authors and Affiliations

  1. Department of Physiology, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC, 29425, USA

    K. Coffee, W. C. Wise & J. A. Cook

  2. Department of Pharmacology and Medicine, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC, 29425, USA

    P. V. Halushka

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  1. K. Coffee
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Editors and Affiliations

  1. Dept. of Surgery, Ludwig-Maximilians-University Munich, Klinikum Großhadern Marchioninistr. 15, 8000, Munich 70, Germany

    Eugen Faist  & Friedrich W. Schildberg  & 

  2. Dept. of Surgery, McGill University, Room 510.34 687 Pine Avenue West, Montreal, Quebec, H3A 1A1, Canada

    Jonathan L. Meakins M.D., D.Sc.

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Coffee, K., Halushka, P.V., Wise, W.C., Cook, J.A. (1993). Altered Guanine Nucleotide Protein Function: Potential Role in Endotoxin Tolerance. In: Faist, E., Meakins, J.L., Schildberg, F.W. (eds) Host Defense Dysfunction in Trauma, Shock and Sepsis. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-77405-8_109

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  • DOI: https://doi.org/10.1007/978-3-642-77405-8_109

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