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Hypoxia and hypoxia-mimetics attenuate the inflammatory response during murine endotoxemia
Intensive Care Medicine Experimental volume 3, Article number: A421 (2015)
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.
To determine the immunomodulatory effects of various degrees of hypoxia and hypoxia mimetics during systemic inflammation in mice.
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.
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).
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.
Eltzschig HK, Carmeliet P: Hypoxia and Inflammation. N Engl J Med. 2011, 364: 656-665. 10.1056/NEJMra0910283.
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.
Eltzschig HK, Sitkovsky MV, Robson SC: Purinergic signaling during inflammation. N Engl J Med. 2012, 367: 2322-2333. 10.1056/NEJMra1205750.
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Kiers, D., Groeneveld, R., van der Hoeven, J. et al. Hypoxia and hypoxia-mimetics attenuate the inflammatory response during murine endotoxemia. ICMx 3 (Suppl 1), A421 (2015). https://doi.org/10.1186/2197-425X-3-S1-A421
- Vascular Endothelial Growth Factor
- Gene Vascular Endothelial Growth Factor
- Lower Body Temperature
- Systemic Hypoxia
- Immunological Phenotype