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PLoS One. 2014 Oct 9;9(10):e108126. doi: 10.1371/journal.pone.0108126. eCollection 2014.

Loss of the endothelial glucocorticoid receptor prevents the therapeutic protection afforded by dexamethasone after LPS.

Author information

1
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, United States of America.
2
Department of Internal Medicine, Veterans Affairs Hospital, West Haven, Connecticut, United States of America.
3
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, United States of America; Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America.

Abstract

Glucocorticoids are normally regarded as anti-inflammatory therapy for a wide variety of conditions and have been used with some success in treating sepsis and sepsis-like syndromes. We previously demonstrated that mice lacking the glucocorticoid receptor in the endothelium (GR EC KO mice) are extremely sensitive to low-dose LPS and demonstrate prolonged activation and up regulation of NF-κB. In this study we pre-treated these GR EC KO mice with dexamethasone and assessed their response to an identical dose of LPS. Surprisingly, the GR EC KO mice fared even worse than when given LPS alone demonstrating increased mortality, increased levels of the inflammatory cytokines TNF-α and IL-6 and increased nitric oxide release after the dexamethasone pre-treatment. As expected, control animals pre-treated with dexamethasone showed improvement in all parameters assayed. Mechanistically we demonstrate that GR EC KO mice show increased iNOS production and NF-κB activation despite treatment with dexamethasone.

PMID:
25299055
PMCID:
PMC4191990
DOI:
10.1371/journal.pone.0108126
[Indexed for MEDLINE]
Free PMC Article

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