Roles of mitogen-activated protein kinases in the modulation of endothelial cell function following thermal injury.
Several mitogen-activated protein kinases (MAPKs) are activated during thermal injury, and the p38 MAPK is specifically involved in endothelial cell (EC) actin and myosin rearrangement (stress-fiber formation) with ensuing cellular contraction and enhanced vessel permeability. Inhibition of p38 MAPK and extracellular signal-related kinase MAPK by their inhibitors SB203580 and PD98059, respectively, significantly reduces burn serum-induced EC stress-fiber formation, whereas SB203580 also inhibits burn serum-induced EC tight-junction damage and thereby general blood vessel hyperpermeability. The JNK MAPK inhibitor, SP600125, on the contrary, influences neither stress-fiber formation nor EC tight-junction damage. Extracellular signal-related kinase MAPK inhibition significantly decreases burn serum-induced Monocyte chemotactic protein-1 (MCP-1) release, whereas SB203580 and SP600125 have only limited such effects. Western blotting, real-time reverse transcriptase-polymerase chain reaction, and confocal laser scanning microscopy proved that SP600125 significantly inhibits burn serum-induced intercellular adhesion molecule 1 expression, whereas SB203580 depresses the expression of P selectin. In vivo studies, using the dominant negative adenoviral approach of MAPK kinase 3b and MAPK kinase 6b to block p38 MAPKs, and MKK4 and MKK7 to block JNK MAPKs, show that the latter MAPKs are involved in the regulation of P selectin and intercellular adhesion molecule 1 expression, respectively, following thermal injury. Taken together, the results suggest that several MAPKs play important, although different, roles in general EC alterations following burn injuries.
Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong, Southern Medical University, Guangzhou, P. R. China.
Wei
W
Wu
Qiaobing
Q
Huang
Fei
F
He
Mingjia
M
Xiao
Shiyu
S
Pang
Xiaohua
X
Guo
Ulf T
UT
Brunk
Kesen
K
Zhao
Ming
M
Zhao
D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002056:Burns / Q000503:physiopathology*; D018932:Chemokine CCL2 / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D019007:P-Selectin / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019108:Tight Junctions / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D000873:Anthracenes; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D005419:Flavonoids; D007093:Imidazoles; D019007:P-Selectin; D011725:Pyridines; D018799:Intercellular Adhesion Molecule-1; C432165:pyrazolanthrone; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one