PI3K in LPS-induced coagulation and inflammation

Summary

Principal Investigator: James Luyendyk
Abstract: [unreadable] DESCRIPTION (provided by applicant): LPS-induced coagulation and inflammation are important components of the pathogenesis of bacterial sepsis. In the United States, sepsis is the leading cause of death in non-coronary intensive care units. The objective of this proposal is to determine the role of the PI3K-Akt signaling pathway in suppressing LPS- induced coagulation and inflammation. The overall hypothesis is that the PI3K-Akt pathway negatively regulates LPS-induced coagulation and inflammation. Specific Aim 1 will characterize the role of PI3K-Akt pathway activation in LPS-induced cytokine and tissue factor production by macrophages. We will employ a genetic approach that either increases (PTEN-/-) or decreases (p85alpha-/-) PI3K-Akt pathway activation. Specific Aim 2 will evaluate whether the inhibitory effect of simvastatin on LPS-induced coagulation and inflammation involves activation of PI3K-Akt signaling. We hypothesize that wortmannin, a PI3K inhibitor, will block the anti-inflammatory and anticoagulant effects of simvastatin in LPS-treated macrophages and in a mouse endotoxemia model. Ultimately, characterization of the involvement of this pathway in LPS-induced inflammation may allow for development of novel strategies that can be used to treat sepsis. [unreadable] [unreadable] [unreadable]
Funding Period: 2006-09-01 - 2007-06-04
more information: NIH RePORT

Top Publications

  1. ncbi A novel class of antioxidants inhibit LPS induction of tissue factor by selective inhibition of the activation of ASK1 and MAP kinases
    James P Luyendyk
    Department of Immunology, e Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Arterioscler Thromb Vasc Biol 27:1857-63. 2007
  2. ncbi Role of the coagulation system in acetaminophen-induced hepatotoxicity in mice
    Patricia E Ganey
    Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA
    Hepatology 46:1177-86. 2007
  3. pmc Genetic analysis of the role of the PI3K-Akt pathway in lipopolysaccharide-induced cytokine and tissue factor gene expression in monocytes/macrophages
    James P Luyendyk
    Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
    J Immunol 180:4218-26. 2008
  4. pmc Insulin activation of the phosphatidylinositol 3-kinase/protein kinase B (Akt) pathway reduces lipopolysaccharide-induced inflammation in mice
    Linda B Kidd
    The Department of Immunology, The Scripps Research Institute, La Jolla, California, USA
    J Pharmacol Exp Ther 326:348-53. 2008

Detail Information

Publications4

  1. ncbi A novel class of antioxidants inhibit LPS induction of tissue factor by selective inhibition of the activation of ASK1 and MAP kinases
    James P Luyendyk
    Department of Immunology, e Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Arterioscler Thromb Vasc Biol 27:1857-63. 2007
    ..The purpose of this study was to elucidate the mechanism by which 2 structurally-related antioxidants (AGI-1067 and AGI-1095) inhibit LPS induction of tissue factor (TF) expression in human monocytic cells and endothelial cells...
  2. ncbi Role of the coagulation system in acetaminophen-induced hepatotoxicity in mice
    Patricia E Ganey
    Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA
    Hepatology 46:1177-86. 2007
    ..CONCLUSION: Activation of the coagulation system and PAR-1 signaling contribute significantly to APAP-induced liver injury...
  3. pmc Genetic analysis of the role of the PI3K-Akt pathway in lipopolysaccharide-induced cytokine and tissue factor gene expression in monocytes/macrophages
    James P Luyendyk
    Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
    J Immunol 180:4218-26. 2008
    ..Taken together, our results indicate that the PI3K-Akt pathway negatively regulates LPS signaling and gene expression in monocytes/macrophages...
  4. pmc Insulin activation of the phosphatidylinositol 3-kinase/protein kinase B (Akt) pathway reduces lipopolysaccharide-induced inflammation in mice
    Linda B Kidd
    The Department of Immunology, The Scripps Research Institute, La Jolla, California, USA
    J Pharmacol Exp Ther 326:348-53. 2008
    ..We conclude that insulin reduces LPS-induced inflammation in mice in a PI3K/Akt-dependent manner without affecting blood glucose levels...