Febrile-range hyperthermia augments reversible TNF - Induced hyperpermeability in human microvascular lung endothelial cells

Nirav G. Shah, Mohan E. Tulapurkar, Mahendra Damarla, Ishwar S. Singh, Simeon E. Goldblum, Paul Shapiro, Jeffrey D. Hasday

Research output: Contribution to journalArticle

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- (TNF-) up to 250U/mL for 624h. We found that exposure to 2.5250U/mL TNF- increased HMVEC-L permeability by 4.115.8-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- increased permeability an additional 1.64.5-fold compared with cells incubated with the same TNF- concentration at 37°C. Permeability occurred without measurable cytotoxicity and was reversible upon removal of TNF- and reduction in temperature to 37°C. Exposure to 39.5°C or TNF- 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 - induced permeability in 39.5°C monolayers to levels in 37°C cells, but did not alter TNF - 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.

Original languageEnglish (US)
Pages (from-to)627-635
Number of pages9
JournalInternational Journal of Hyperthermia
Volume28
Issue number7
DOIs
StatePublished - Nov 1 2012

Keywords

  • Endothelial
  • Hyperpermeability
  • Hyperthermia
  • Lung
  • MAP kinases

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cancer Research

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