Regulation of Mitochondrial Function by Hypoxia and Inflammation in Sepsis: A Putative Role for Hypoxia Inducible Factor

  • T. Regueira
  • S. M. Jakob
  • S. Djafarzadeh
Conference paper


Sepsis-related organ failure is the leading cause of mortality in European intensive care units (ICU). Although the inflammatory cascade of mediators in response to infection is well known, the relationships between regional inflammation, microvascular heterogeneity, hypoxia and hypoxia-inducible gene expression, and finally, organ dysfunction, are unknown. Growing evidence suggests that not only low oxygen supply to the tissues secondary to macrovascular and microvascular alterations, but also altered cellular oxygen utilization is involved in the development of multiorgan dysfunction [1, 2, 3]. Microbial products and innate and adaptive dysregulated immune response to infection directly affect parenchymal cells of organs and may contribute to multiorgan dysfunction.


Vascular Endothelial Growth Factor Flavin Adenine Dinucleotide Respiratory Control Ratio Dependent Respiration European Intensive Care Unit 
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  1. 1.
    Kreymann G, Grosser S, Buggisch P, Gottschall C, Matthaei S, Greten H (1993) Oxygen consumption and resting metabolic rate in sepsis, sepsis syndrome, and septic shock. Crit Care Med 21:1012–1019PubMedCrossRefGoogle Scholar
  2. 2.
    Boekstegers P, Weidenhofer S, Kapsner T, Werdan K (1994) Skeletal muscle partial pressure of oxygen in patients with sepsis. Crit Care Med 22:640–650PubMedCrossRefGoogle Scholar
  3. 3.
    Hotchkiss RS, Swanson PE, Freeman BD, et al (1999) Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 27:1230–1251PubMedCrossRefGoogle Scholar
  4. 4.
    Schatz G (1995) Mitochondria: beyond oxidative phosphorylation. Biochim Biophys Acta 1271:123–126PubMedGoogle Scholar
  5. 5.
    Semenza GL (2007) Oxygen-dependent regulation of mitochondrial respiration by hypoxiainducible factor 1. Biochem J 405:1–9PubMedGoogle Scholar
  6. 6.
    Ivan M, Kondo K, Yang H, et al (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for 02 sensing. Science 292:464–468PubMedCrossRefGoogle Scholar
  7. 7.
    Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML (2002) Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295:858–861PubMedCrossRefGoogle Scholar
  8. 8.
    Mansfield KD, Guzy RD, Pan Y, et al (2005) Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metab 1:393–399PubMedCrossRefGoogle Scholar
  9. 9.
    Schumacker PT (2005) Hypoxia-inducible factor-1 (HIF-1). Crit Care Med 33:S423–425PubMedCrossRefGoogle Scholar
  10. 10.
    Cramer T, Yamanishi Y, Clausen BE, et al (2003) HIF-1 alpha is essential for myeloid cellmediated inflammation. Cell 112:645–657PubMedCrossRefGoogle Scholar
  11. 11.
    Kantrow SP, Taylor DE, Carraway MS, Piantadosi CA (1997) Oxidative metabolism in rat hepatocytes and mitochondria during sepsis. Arch Biochem Biophys 345:278–288PubMedCrossRefGoogle Scholar
  12. 12.
    Unno N, Wang H, Menconi MJ, et al (1997) Inhibition of inducible nitric oxide synthase ameliorates endotoxin-induced gut mucosal barrier dysfunction in rats. Gastroenterology 113:1246–1257PubMedCrossRefGoogle Scholar
  13. 13.
    Zingarelli B, Day BJ, Crapo JD, Salzman AL, Szabo C (1997) The potential role of peroxynitrite in the vascular contractile and cellular energetic failure in endotoxic shock. Br J Pharmacol 120:259–267PubMedCrossRefGoogle Scholar
  14. 14.
    Vary TC, Siegel JH, Nakatani T, Sato T, Aoyama H (1986) Effect of sepsis on activity of pyruvate dehydrogenase complex in skeletal muscle and liver. Am J Physiol 250:E634–640PubMedGoogle Scholar
  15. 15.
    Vary TC (1991) Increased pyruvate dehydrogenase kinase activity in response to sepsis. Am J Physiol 260:E669–674PubMedGoogle Scholar
  16. 16.
    Brealey D, Karyampudi S, Jacques TS, et al (2004) Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol 286:R491–497PubMedGoogle Scholar
  17. 17.
    Radi R, Rodriguez M, Castro L, Telleri R (1994) Inhibition of mitochondrial electron transport by peroxynitrite. Arch Biochem Biophys 308:89–95PubMedCrossRefGoogle Scholar
  18. 18.
    Szabo C (2007) Poly (ADP-ribose) polymerase activation and circulatory shock. Novartis Found Symp 280:92–103PubMedCrossRefGoogle Scholar
  19. 19.
    Goldfarb RD, Marton A, Szabo E, et al (2002) Protective effect of a novel, potent inhibitor of poly(adenosine 5′-diphosphate-ribose) synthetase in a porcine model of severe bacterial sepsis. Crit Care Med 30:974–980PubMedCrossRefGoogle Scholar
  20. 20.
    Khan AU, Delude RL, Han YY, et al (2002) Liposomal NAD(+) prevents diminished O(2) consumption by immunostimulated Caco-2 cells. Am J Physiol Lung Cell Mol Physiol 282:L1082–1091PubMedGoogle Scholar
  21. 21.
    Martin-Oliva D, Aguilar-Quesada R, O’Valle F, et al (2006) Inhibition of poly(ADP-ribose) polymerase modulates tumor-related gene expression, including hypoxia-inducible factor-1 activation, during skin carcinogenesis. Cancer Res 66:5744–5756PubMedCrossRefGoogle Scholar
  22. 22.
    Crouser ED, Julian MW, Huff JE, Struck J, Cook CH (2006) Carbamoyl phosphate synthase-1: a marker of mitochondrial damage and depletion in the liver during sepsis. Crit Care Med 34:2439–2446PubMedCrossRefGoogle Scholar
  23. 23.
    Blouin CC, Page EL, Soucy GM, Richard DE (2004) Hypoxic gene activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor lalpha. Blood 103:1124–1130PubMedCrossRefGoogle Scholar
  24. 24.
    Frede S, Stockmann C, Freitag P, Fandrey J (2006) Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-kappaB. Biochem J 396:517–527PubMedCrossRefGoogle Scholar
  25. 25.
    Kim HY, Kim YH, Nam BH, et al (2007) HIF-1 alpha expression in response to lipopolysaccaride mediates induction of hepatic inflammatory cytokine TNFalpha. Exp Cell Res 313:1866–1876PubMedCrossRefGoogle Scholar
  26. 26.
    Peyssonnaux C, Cejudo-Martin P, Doedens A, Zinkernagel AS, Johnson RS, Nizet V (2007) Cutting edge: Essential role of hypoxia inducible factor-lalpha in development of lipopolysaccharide-induced sepsis. J Immunol 178:7516–7519PubMedGoogle Scholar
  27. 27.
    Lukashev D, Klebanov B, Kojima H, et al (2006) Cutting edge: hypoxia-inducible factor lalpha and its activation-inducible short isoform I.1 negatively regulate functions of CD4+ and CD8+ T lymphocytes. J Immunol 177:4962–4965PubMedGoogle Scholar
  28. 28.
    Thiel M, Caldwell CC, Kreth S, et al (2007) Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflammed tissues and improves septic mice survival. PLoS ONE 2:e853PubMedCrossRefGoogle Scholar
  29. 29.
    Bateman RM, Tokunaga C, Kareco T, Dorscheid DR, Walley KR (2007) Myocardial hypoxiainducible HIF-1alpha, VEGF, and GLUT1 gene expression is associated with microvascular and ICAM-1 heterogeneity during endotoxemia. Am J Physiol Heart Circ Physiol 293:H448–456PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media Inc. 2008

Authors and Affiliations

  • T. Regueira
    • 1
  • S. M. Jakob
    • 1
  • S. Djafarzadeh
    • 1
  1. 1.Department of Intensive Care MedicineUniversity Hospital InselspitalBernSwitzerland

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