title: Febrile-range hyperthermia augments reversible TNF-α-induced hyperpermeability in human microvascular lung endothelial cells.
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.
authors: Division of Pulmonary and Critical Care, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA. nshah1@medicine.umaryland.edu
authors: Nirav G
authors: NG
authors: Shah
authors: Mohan E
authors: ME
authors: Tulapurkar
authors: Mahendra
authors: M
authors: Damarla
authors: Ishwar S
authors: IS
authors: Singh
authors: Simeon E
authors: SE
authors: Goldblum
authors: Paul
authors: P
authors: Shapiro
authors: Jeffrey D
authors: JD
authors: Hasday
mesh_terms: D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology; D005334:Fever / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000166:cytology; D020935:MAP Kinase Signaling System / Q000502:physiology; D010539:Permeability; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases