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Inflammation research : official journal of the European Histamine Research Society ... [et al.]2010; 59(9); 689-698; doi: 10.1007/s00011-010-0180-x

Endotoxin-induced HIF-1alpha stabilisation in equine endothelial cells: synergistic action with hypoxia.

Abstract: Hypoxia may enhance the deleterious effects of lipopolysaccharide (LPS) in the endotoxaemic horse. This study has examined some of the actions of LPS and hypoxia, alone and in combination, on cultured equine digital vein endothelial cells (EDVEC) and the signalling molecules involved. Methods: EDVEC were exposed to LPS, 5% O(2) and LPS then 5% O(2) for up to 24 h. HIF-1alpha stabilisation, neutrophil adhesion and EDVEC permeability were assessed by immunoblotting, measurement of myeloperoxidase and movement of FITC-dextran, respectively. Pharmacological inhibitors were used to assess the roles of p38 MAPK and HIF-1alpha. Results: LPS and hypoxia significantly increased HIF-1alpha stabilisation, neutrophil adhesion and EDVEC permeability and the effects of the two stimuli in combination on HIF-1alpha stabilisation and neutrophil adhesion were more than additive. The effect of LPS, but not 5% O(2), on neutrophil adherence required activation of p38 MAPK, whereas EDVEC permeability in response to both stimuli was dependent on p38 MAPK and HIF-1alpha. Conclusions: Exposure of EDVEC to LPS prior to induction of hypoxia up-regulates responses that may enhance LPS-induced tissue damage in the endotoxaemic horse. Inhibitors of p38 MAPK or HIF-1alpha could reduce such unwanted effects.
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Publication Date: 2010-03-17 PubMed ID: 20237827DOI: 10.1007/s00011-010-0180-xGoogle Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research study investigates the combined effects of blood oxygen deprivation (hypoxia) and a bacterial toxin (lipopolysaccharide-LPS) on horse vein cells, with findings suggesting that hypoxia exacerbates the negative outcomes induced by the bacteria, potentially leading to more tissue damage in horses with blood poisoning (endotoxemia). Potentially, blocking certain pathways or molecules could mitigate these harmful effects.

Research Context and Objective

The researchers were particularly interested in studying the combined effects of low oxygen levels (hypoxia), and a bacterial toxin called lipopolysaccharide (LPS) on equine venous cells. This interest arises from the understanding that in situations like endotoxemia – a condition associated with bacterial infections in horses and other animals – these two conditions can occur simultaneously. Exploring the interactions between these two factors may provide insights into how they could worsen tissue damage, and potentially offer targets for intervention.

  • The research objective was to analyze the effects of LPS and hypoxia, both individually and in combination, on equine digital vein endothelial cells (EDVEC), and the signaling molecules involved.

Research Methods

EDVEC were exposed to three conditions: LPS only, 5% Oxygen (O2) only, and LPS followed by 5% O2, for a period of up to 24 hours. Various outcomes were measured:

  • The stabilization of a protein called hypoxia-inducible factor 1-alpha (HIF-1alpha),
  • The adhesion of neutrophils (a type of white blood cell),
  • The permeability of the EDVEC.

The roles of p38 mitogen-activated protein kinases (MAPK) – a signaling molecule – and HIF-1alpha were assessed using specific pharmacological inhibitors.

Results

The experiments showed that both LPS and hypoxia individually increased the stabilization of HIF-1alpha, adhesion of neutrophils, and EDVEC permeability. Moreover, when LPS was followed by hypoxia, these effects were exaggerated beyond their independent actions, particularly for HIF-1alpha stabilization and neutrophil adhesion.

The effects on neutrophil adhesion were dependent on the activation of p38 MAPK for LPS, but not for hypoxia. The permeability of EDVEC in response to both stimuli, however, depended on both p38 MAPK and HIF-1alpha.

Conclusion

The study concluded that exposure of EDVEC to LPS prior to hypoxia significantly increased responses that could exacerbate tissue damage in horses with endotoxemia. Therefore, inhibiting either p38 MAPK or HIF-1alpha could be potential strategies to reduce such adverse effects.

Cite This Article

APA
Brooks AC, Menzies-Gow N, Bailey SR, Cunningham FM, Elliott J. (2010). Endotoxin-induced HIF-1alpha stabilisation in equine endothelial cells: synergistic action with hypoxia. Inflamm Res, 59(9), 689-698. https://doi.org/10.1007/s00011-010-0180-x

Publication

Inflammation research : official journal of the European Histamine Research Society ... [et al.]
ISSN: 1420-908X
NlmUniqueID: 9508160
Country: Switzerland
Language: English
Volume: 59
Issue: 9
Pages: 689-698

Researcher Affiliations

Brooks, A C
  • Department of Veterinary Basic Sciences, The Royal Veterinary College, North Mymms, Hertfordshire, UK. abrooks@rvc.ac.uk
Menzies-Gow, N
    Bailey, S R
      Cunningham, F M
        Elliott, J

          MeSH Terms

          • Animals
          • Capillary Permeability / drug effects
          • Cell Adhesion / drug effects
          • Cell Hypoxia / drug effects
          • Cells, Cultured
          • Endothelial Cells / drug effects
          • Endothelial Cells / metabolism
          • Endotoxemia / metabolism
          • Endotoxemia / veterinary
          • Female
          • Horse Diseases / metabolism
          • Horses
          • Hypoxia / metabolism
          • Hypoxia / veterinary
          • Hypoxia-Inducible Factor 1, alpha Subunit / chemistry
          • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
          • Lipopolysaccharides / toxicity
          • Male
          • Neutrophils / drug effects
          • Up-Regulation / drug effects
          • p38 Mitogen-Activated Protein Kinases / analysis

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