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Cutting Edge: Essential Role of Hypoxia Inducible Factor-1α in Development of Lipopolysaccharide-Induced Sepsis

Division of Biological Sciences, School of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
The Journal of Immunology (Impact Factor: 5.36). 07/2007; 178(12):7516-9. DOI: 10.4049/jimmunol.178.12.7516
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ABSTRACT Sepsis, the leading cause of death in intensive care units, reflects a detrimental host response to infection in which bacteria or LPS act as potent activators of immune cells, including monocytes and macrophages. In this report, we show that LPS raises the level of the transcriptional regulator hypoxia-inducible factor-1alpha (HIF-1alpha) in macrophages, increasing HIF-1alpha and decreasing prolyl hydroxylase mRNA production in a TLR4-dependent fashion. Using murine conditional gene targeting of HIF-1alpha in the myeloid lineage, we demonstrate that HIF-1alpha is a critical determinant of the sepsis phenotype. HIF-1alpha promotes the production of inflammatory cytokines, including TNF-alpha, IL-1, IL-4, IL-6, and IL-12, that reach harmful levels in the host during early sepsis. HIF-1alpha deletion in macrophages is protective against LPS-induced mortality and blocks the development of clinical markers including hypotension and hypothermia. Inhibition of HIF-1alpha activity may thus represent a novel therapeutic target for LPS-induced sepsis.

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Available from: Randall S Johnson, Mar 31, 2014
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    • "HIF-1␣ is a transcriptional factor that upregulates the expression of various genes in response to hypoxia, inflammation, and oxidative stress (Heyman et al. 2011). Lipopolysaccharides have been demonstrated to induce the expression of HIF-1␣ protein and HIF-1 dependent gene, even in the absence of hypoxia, in macrophages and the hepatic tissue of rats (Peyssonnaux et al. 2007; Kan et al. 2008). In animals subjected to LPS treatment, a significant increase in hepatic HIF-1␣ levels was probably due to LPS-induced tissue hypoxia and (or) the secretion of proinflammatory cytokines . "
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    ABSTRACT: Plasma levels of asymmetric dimethylarginine (ADMA) are known to be elevated under pathological conditions, but reports on intracellular ADMA levels are scarce. In this study, we investigated whether lipopolysaccharide (LPS)-induced endotoxemia alters the intra- and extra-cellular partition of l-arginine and ADMA. The effect of H2S pretreatment was also researched. Wistar rats were given sodium hydrogen sulfide (NaHS, 1 mg·(kg body mass)(-1)) one hour before the LPS injections (20 mg·kg(-1)). Six hours after the LPS treatment, the animals were sacrificed. Myeloperoxidase (MPO) and dimethylarginine dimethylaminohydrolase (DDAH) activities and levels of hypoxia-inducible factor (HIF)-1α were measured in the liver. ADMA and arginine levels were determined using HPLC. LPS injection caused liver injury, as evidenced by the activities of alanine transaminase, aspartate transaminase, and arginase. LPS increased l-arginine content and decreased DDAH activity in the rat liver. MPO activity and HIF-1α levels indicated inflammation and hypoxia. Despite the accumulation of ADMA in the plasma, the level remained unchanged in the liver. NaHS pretreatment restored both the DDAH activity and intracellular l-arginine levels. It is concluded that increased H2S generation has a potency to restore hepatic l-arginine levels and ADMA handling in endotoxemia. Extra- and intra-cellular partitions of ADMA seem to depend on transport proteins as well as the DDAH activity.
    Canadian Journal of Physiology and Pharmacology 12/2013; 91(12):1071-5. DOI:10.1139/cjpp-2013-0114 · 1.55 Impact Factor
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    • "Neutrophil apoptosis was shown to be significantly attenuated in hypoxia by HIF1a (Walmsley et al, 2005) and more recently, PHD3 (Walmsley et al, 2011), although whether this latter effect occurs in a HIF1a-dependent or -independent manner remains unclear. HIFa also contributes to the production of a number of proinflammatory cytokines such as TNFa, interleukin (IL)-1a, IL-1b, IL-6, and IL-12, which are necessary for macrophage activation and phagocytic function, as well as lymphocyte proliferation (Peyssonnaux et al, 2005, 2007; Jantsch et al, 2008; Nizet and Johnson, 2009). "
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    The EMBO Journal 05/2012; 31(11):2448-60. DOI:10.1038/emboj.2012.125 · 10.75 Impact Factor
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    • "Thus, HIF proteins were shown to regulate all aspects of Mφ functions in response to hypoxia, including the shift to anaerobic glycolysis, mitochondrial impairment, angiogenesis, invasion, and immune suppression (Coffelt et al., 2009; Walmsley et al., 2009; Werno et al., 2010a). Moreover, HIFs are also induced in normoxia, and play a central role in immune recognition, phagocytosis, bacterial killing, and pro-inflammatory cytokine production (Cramer et al., 2003; Peyssonnaux et al., 2007). "
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