Abstract
The protein C (PC) pathway plays an important role in vascular function, and acquired deficiency during sepsis is associated with increased mortality. We have explored the role of PC suppression in modulating early inflammatory events in a model of polymicrobial sepsis. We show that increased levels of organ damage and dysfunction are associated with decreased levels of endogenous PC. Notably, animals with low PC had correspondingly high levels of pulmonary iNOS expression, which correlated with chemokines KC/Gro and MIP2, previously shown to predict outcome in thismodel. Treatment with activated protein C (aPC) not only reduced the pathology score, leukocyte infiltration and markers of organ dysfunction, but also suppressed the induction of iNOS, and the chemokine response (including KC/Gro, MIP2, IP-10, RANTES, GCP-2 and lymphotactin), and increased apoA1. aPC treatment also suppressed the induction of VEGF, a marker recently suggested to play a pathophysiological role in sepsis. These data demonstrate a clear link between low protein C and degree of organ damage and dysfunction in sepsis, as well as the early reversal with aPC treatment. Moreover, our data show a direct role of aPC in broadly modulating monocyte and T-cell chemokines following systemic inflammatory response.
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References
D. Angus, W.T. Linde-Zwirble, J. Lidicker, G. Clermont, J. Carcillo, M.R. Pinsky, Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care, Crit Care Med 291;303–1310 (2001).
B. Grinnell and D.E. Joyce, Recombinant human activated protein C: A system modulator of vascular function for treatment of severe sepsis, Crit Care Med 29;S53–S61 (2001).
C.J. Fisher and S.B. Yan, Protein C levels as a prognostic indicator of outcome in sepsis and related diseases, Crit Care Med 28(9);S49–S56 (2000).
W.L. Macias and D.R. Nelson, Severes protein C deficiency predicts early death in severe sepsis, Crit Care Med 32;S223–S228 (2004).
J.G. Heuer, G.R. Sharma, B. Gerlitz, T. Zhang, D.L. Bailey, C. Ding, D.T. Berg, D. Perkins, E.J. Stephens, K.C. Holmes, R.L. Grubbs, K.A. Fynboe, Y.F. Chen, B. Grinnell, and J.A. Jakubowski, Evaluation of protein C and other biomarkers as predictors of mortality in a rat cecal ligation and puncture model of sepsis. [see comment], Crit Care Med 32(7);1570–1578 (2004).
D. Berg, B. Gerlitz, G. Sharma, M. Richardson, E. Stephens, R. Grubbs, K. Holmes, D. Montani, T. Zhang, M. Cramer, S. Engle, J. Jakubowski, H. JG, and B. Grinnell, FoxA2 Involvement in Suppression of Protein C, an Outcome Predictor in Experimental Sepsis, Clinical Vaccine Immunol. 13;426–432 (2006).
C.T. Esmon, J.M. Gu, J. Xu, D. Qu, D.J. Stearns-Kurosawa, and S. Kurosawa, Regulation and functions of the protein C anticoagulant pathway, Haematologica 84(4);363–8 (1999).
D.E. Joyce, L. Gelbert, A. Ciaccia, B. Dehoff, and B.W. Grinnell, Gene Expression Profile of Antithrombotic Protein C Defines New Mechanisms Modulating Inflammation and Apoptosis, J Biol Chem 276;11199–11203 (2001).
L.O. Mosnier and J.H. Griffin, Inhibition of staurosporine-induced apoptosis of endothelial cells by activated protein C requires protease activated receptor-1 and endothelial cell protein C receptor, Biochem J 8(2003).
M. Riewald, R. Petrovan, A. Donner, B. Mueller, and W. Ruf, Activation of endothelial cell protease activated receptor 1 by the protein C pathway, Science 296;1880–1882 (2002).
D.E. Joyce, D.R. Nelson, and B.W. Grinnell, Leukocyte and endothelial cell interactions in sepsis: relevance of the protein C pathway, Crit Care Med 32(5 Suppl),(2004).
J.N. Hoffmann, B. Vollmar, M.W. Laschke, D. Inthorn, J. Fertmann, F.W. Schildberg, and M.D. Menger, Microhemodynamic and cellular mechanisms of activated protein C action during endotoxemia.[see comment], Crit Care Med 32(4);1011–1017 (2004).
B. Gerlitz and B.W. Grinnell, Mutation of protease domain residues Lys37-39 in human Protein C inhibits activation by the thrombomodulin-thrombin complex without affecting activation by free thrombin, J Biol Chem 271(37);22285–22288 (1996).
D.T. Berg, L.J. Myers, M.A. Richardson, G. Sandusky, and B.W. Grinnell, Smad6s regulates plasminogen activator inhibitor-1 through a protein kinase C-beta-dependent up-regulation of transforming growth factor-beta, J Biol Chem 280(15);14943–7 (2005).
Y. Bishop, S. Feinberg, and H. PW, Discrete multivariate analysis: Theory and practice, Cambridge: The MIT Press (1975).
L. Dugo, S. Marzocco, E. Mazzon, R. Di Paola, T. Genovese, A.P. Caputi, and S. Cuzzocrea, Effects of GW274150, a novel and selective inhibitor of iNOS activity, in acute lung inflammation, Br J Pharmacol 141(6);979–987 (2004).
H. Toga, T. Tobe, Y. Ueda, G.H. Yang, K. Osanai, M. Ishigaki, H. Okazaki, S. Katsuda, K. Takahashi, and N. Ohya, Inducible nitric oxide synthase expression and nuclear factor-kappaB activation in alveolar type II cells in lung injury, Experimental Lung Research 27(6);485–504 (2001).
L.W. Chen, B. Hwang, W.J. Chang, J.S. Wang, J.S. Chen, and C.M. Hsu, Inducible nitric oxide synthase inhibitor reverses exacerbating effects of hypertonic saline on lung injury in burn, Shock 22(5);472–477 (2004).
M. Navab, G. Anantharamaiah, and A. Fogelman, The role of high-density lipoprotein in inflammation, Trends Cardiovasc Med 15;158–161 (2005).
K. Yano, P. Liaw, J. Mullington, S. Shih, H. Okada, N. Bodyak, P. Kang, L. Tolt, B. Belikoff, J. Buras, B. Simms, J. Mizgerd, P. Carmeliet, S. Karumanchi, and W. Aird, Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality, J Exp Med 203(6);1447–1458 (2006).
D.E. Joyce and B.W. Grinnell, Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-kappaB, Crit Care Med 30;S288–293 (2002).
T. Cheng, D. Liu, J. Griffin, J. Fernandez, F. Castellino, E. Rosen, K. Fukudome, and B. Zlokovic, Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective, Nat Med 9;338–342 (2003).
M. Uchiba, K. Okajima, Y. Oike, Y. Ito, K. Fukudome, H. Isobe, and T. Suda, Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo, Circulation Research 95(1);34–41 (2004).
K. Okajima, Prevention of endothelial cell injury by activated protein C: the molecular mechanism(s) and therapeutic implications, Current Vascular Pharmacology 2(2);125–133 (2004).
D.H. Sturn, N.C. Kaneider, C. Feistritzer, A. Djanani, K. Fukudome, and C.J. Wiedermann, Expression and function of the endothelial protein C receptor in human neutrophils, Blood 102(4);1499–1505 (2003).
C. Feistritzer, D.H. Sturn, N.C. Kaneider, A. Djanani, and C.J. Wiedermann, Endothelial protein C receptor-dependent inhibition of human eosinophil chemotaxis by protein C, J Allergy Clin Immunol 112(2);375–381 (2003).
A. Mantovani, A. Sica, S. Sozzani, P. Allavena, A. Vecchi, and M. Locati, The chemokine system in diverse forms of macrophage activation and polarization, Trends in Immunology 25(12);677–686 (2004).
J.Y. Kim, D. Kim, E.M. Lee, I. Choi, C.G. Park, K.S. Kim, J. Ha, S.J. Kim, J. Yang, Y.S. Kim, J.S. Han, S. Kim, J.S. Lee, and C. Ahn, Inducible nitric oxide synthase inhibitors prolonged the survival of skin xenografts through selective down-regulation of pro-inflammatory cytokine and CC-chemokine expressions, Transplant Immunology 12(1);63–72 (2003).
M. Rosenkilde and T. Schwartz, The chemokine system – a major regulator of angiogenesis in health and disease, APMIS 112(7–8);481–495 (2004).
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Sharma, G.R. et al. (2008). Activated Protein C Modulates Chemokine Response and Tissue Injury in Experimental Sepsis. In: Kang, K.A., Harrison, D.K., Bruley, D.F. (eds) Oxygen Transport to Tissue XXIX. Advances In Experimental Medicine And Biology, vol 614. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-74911-2_10
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DOI: https://doi.org/10.1007/978-0-387-74911-2_10
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