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Febrile-range hyperthermia augments reversible TNF-α-induced hyperpermeability in human microvascular lung endothelial cells.
- Source :
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International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group [Int J Hyperthermia] 2012; Vol. 28 (7), pp. 627-35. Date of Electronic Publication: 2012 Jul 26. - Publication Year :
- 2012
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Abstract
- Fever commonly occurs in acute lung injury (ALI) and ALI occurs in 25% of victims of heat stroke. We have shown in mouse models of ALI that exposure to febrile-range hyperthermia (FRH), 39.5°C, increases non-cardiogenic pulmonary oedema. In this study we studied the direct effects of FRH on endothelial barrier integrity using human microvascular endothelial cells (HMVEC-Ls). We analysed the effect of exposure to culture temperatures between 38.5° and 41°C with and without tumour necrosis factor-α (TNF-α) up to 250 U/mL for 6-24 h. We found that exposure to 2.5-250 U/mL TNF-α increased HMVEC-L permeability by 4.1-15.8-fold at 37°C. Exposure to 39.5°C alone caused variable, modest, lot-specific increases in HMVEC-L permeability, however raising culture temperature to 39.5°C in the presence of TNF-α increased permeability an additional 1.6-4.5-fold compared with cells incubated with the same TNF-α concentration at 37°C. Permeability occurred without measurable cytotoxicity and was reversible upon removal of TNF-α and reduction in temperature to 37°C. Exposure to 39.5°C or TNF-α each stimulated rapid activation of p38 and ERK but the effects were not additive. Treatment with inhibitors of ERK (U0126) or p38 (SB203580) each reduced TNF-α-induced permeability in 39.5°C monolayers to levels in 37°C cells, but did not alter TNF-α-induced permeability in the 37°C cells. These results demonstrate that FRH directly increases paracellular pathway opening through a process that requires ERK and p38 MAPKs. A better understanding of this mechanism may provide new understanding about how fever may contribute to the pathogenesis of ALI and provide new therapeutic targets to improve clinical outcomes.
Details
- Language :
- English
- ISSN :
- 1464-5157
- Volume :
- 28
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
- Publication Type :
- Academic Journal
- Accession number :
- 22834633
- Full Text :
- https://doi.org/10.3109/02656736.2012.690547