The P38alpha and P38delta MAP kinases may be gene therapy targets in the future treatment of severe burns.
Microvascular barrier damage, induced by thermal injury, imposes life-threatening problems owing to the pathophysiological consequences of plasma loss and impaired perfusion that finally may lead to multiple organ failure. The aim of the present study was to define the signaling role of selected mitogen-activated protein kinases (MAPKs) in general vessel hyperpermeability caused by burns and to look for a potential gene therapy. Rearrangement of cytoskeletons and cell tight junctions were evaluated by phalloidin labeling of actin and immunocytochemical demonstration of the ZO-1 protein, whereas blood vessel permeability was evaluated by a fluorescence ratio technique. The p38 MAPK inhibitor SB203580 largely blocked burn serum-induced stress-fiber formation and tight-junction damage. Using the adenoviral approach to transfect dominant negative forms of p38 MAPKs, we found that p38alpha and p38delta had similar effects. The in vivo part of the study showed that transfection of these two constructs significantly lowered general venular hyperpermeability and enhanced the survival of burned animals. Because the p38 MAPK pathway seems to play a crucial role in burn-induced vascular hyperpermeability, general transfection with p38 MAP dominant negative constructs might become a new therapeutic method to block burn-induced plasma leakage.
Wang
Shuyun
S
Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong, Southern Medical University, Guangzhou, People's Republic of China.
Huang
Qiaobing
Q
Guo
Xiaohua
X
Brunk
Ulf T
UT
Han
Jiahuai
J
Zhao
Keseng
K
Zhao
Ming
M
D000199:Actins / Q000378:metabolism; D000818:Animals; D002056:Burns / Q000097:blood / Q000628:therapy*; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects; D048292:Mitogen-Activated Protein Kinase 13 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000627:therapeutic use; D019108:Tight Junctions / Q000187:drug effects
D000199:Actins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D048292:Mitogen-Activated Protein Kinase 13; D011493:Protein Kinase C; D048308:Mitogen-Activated Protein Kinase 14; C093642:SB 203580