Skip to main content

Advertisement

Volume 3 Supplement 1

ESICM LIVES 2015

Hypoxia and hypoxia-mimetics attenuate the inflammatory response during murine endotoxemia

Article metrics

Introduction

Hypoxia has been shown to exert immunomodulatory effects1. As oxygenation is daily practice in critical care, and the majority of critically ill patients suffer from inflammatory-related conditions, permissive hypoxia might be a novel therapeutic strategy. In addition, there are pharmacologic hypoxia-mimetics available that can replicate the hypoxia-effects without the potential drawbacks of systemic hypoxia. The hypoxic immunomodulatory effects are thought to be mediated through a group of transcription factors called hypoxia-inducible factors (HIFs)2. However, in vitro studies have demonstrated that, depending on the cell-type, these effects can be both pro- and anti-inflammatory. The net effects of hypoxia during systemic inflammation in vivo are therefore unknown.

Objectives

To determine the immunomodulatory effects of various degrees of hypoxia and hypoxia mimetics during systemic inflammation in mice.

Methods

BALB/c mice (n = 8 per group) were placed in an air-tight cage with variable degrees of oxygen (normal (21%), 12%, 9%, and 6%), or were injected with the hypoxia-mimetic cobalt chloride (CoCl2, 30mg/kg i.p.). After 1 hour, LPS (5 mg/kg E. Coli endotoxin, serotype 0111:B4) or placebo (NaCl 0.9%) was administered i.p. Ninety minutes after LPS/placebo administration, rectal temperature was measured and animals were sacrificed. Blood plasma was analyzed for cytokine concentrations. Furthermore, mRNA expression of interleukin (IL)-10 and the HIF-1α target gene vascular endothelial growth factor (VEGF) were determined in spleen samples.

Results

As expected, LPS administration resulted in hypothermia. Hypoxia and CoCl2 also lowered body temperature, in a dose-dependent fashion (Figure 1). Hypoxia itself did not result in elevated cytokine levels in plasma. Endotoxemia resulted in increased levels of circulating pro-inflammatory cytokines Tumor Necrosis Factor (TNF)-α, IL-6, IL-8, as well as anti-inflammatory IL-10 (Figure 2). Hypoxia and CoCl2 attenuated the endotoxin-induced pro-inflammatory cytokine response in a dose-dependent manner, while IL-10 protein levels were relatively unaffected. Furthermore, hypoxia resulted in a dose-dependent upregulation of splenic VEGF and IL-10 mRNA expression (Figure 3).

Figure 1
figure1

Rectal temperature in degrees Celsius (°C). Data are shown as mean ± SEM. Stastistical analysis was performed using two-way analysis of variance with Bonferonni post-hoc tests. * p < 0.05 compared with normoxia (21% with same LPS/placebo) # p < 0.05 compared with placebo (same % oxygen or CoCl2).

Figure 2
figure2

Plasma cytokines (Tumor Necrosis Factor (TNF)α, Interleukin(IL)-6, IL-8 and IL-10). Data are shown as mean ± SEM. Statistical analysis was performed using two-way analysis of variance with Bonferonni post-hoc tests. * p < 0.05 compared with normoxia (21% with same LPS/placebo). # p < 0.05 compared with placebo (same % oxygen of CoCl2)

Figure 3
figure3

Splenic mRNA expression of Interleukin 10 (IL-10) and vascular endothelial growth factor (VEGF). Data are shown as mean ± SEM. Statistical analysis was performed using two-way analysis of variance with Bonferonni post-hoc tests. * p < 0.05 compared with normoxia (21% with same LPS/placebo). # p < 0.05 compared with placebo (same % oxygen of CoCl2)

Conclusions

Hypoxia results in hypothermia and attenuation of the systemic pro-inflammatory response in a dose-dependent fashion, while preserving or enhancing the anti-inflammatory response. Administration of the hypoxia-mimetic CoCl2 results in a similar immunological phenotype. Our results suggest that permissive hypoxia is a novel non-pharmacological anti-inflammatory therapeutic strategy.

References

  1. 1.

    Eltzschig HK, Carmeliet P: Hypoxia and Inflammation. N Engl J Med. 2011, 364: 656-665. 10.1056/NEJMra0910283.

  2. 2.

    Palazon A, Goldrath AW, Nizet V, Johnson RS: HIF Transcription Factors, Inflammation, and Immunity. Immunity. 2014, 41 (4): 518-528. 10.1016/j.immuni.2014.09.008.

  3. 3.

    Eltzschig HK, Sitkovsky MV, Robson SC: Purinergic signaling during inflammation. N Engl J Med. 2012, 367: 2322-2333. 10.1056/NEJMra1205750.

Download references

Author information

Correspondence to D Kiers.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kiers, D., Groeneveld, R., van der Hoeven, J. et al. Hypoxia and hypoxia-mimetics attenuate the inflammatory response during murine endotoxemia. ICMx 3, A421 (2015) doi:10.1186/2197-425X-3-S1-A421

Download citation

Keywords

  • Vascular Endothelial Growth Factor
  • Gene Vascular Endothelial Growth Factor
  • Lower Body Temperature
  • Systemic Hypoxia
  • Immunological Phenotype