Information de reference pour ce titreAccession Number: | 00003246-200304000-00024.
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Author: | Uchiba, Mitsuhiro MD; Okajima, Kenji MD; Kaun, Christoph BSc; Binder, Bernd R. MD; Wojta, Johann PhD
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Institution: | From the Department of Laboratory Medicine (MU, KO), Kumamoto University School of Medicine, Kumamoto, Japan; and the Institute of Vascular Biology and Thrombosis Research (CK, BRB, JW), University of Vienna, Vienna, Austria.
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Title: | |
Source: | Critical Care Medicine. 31(4):1147-1153, April 2003.
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Abstract: | Objective: Gabexate mesilate, a synthetic protease inhibitor, has been shown to reduce endotoxin-induced pulmonary vascular injury in an animal model of sepsis by inhibiting leukocyte activation. We examined whether gabexate mesilate inhibits tumor necrosis factor-[alpha]-induced expression of leukocyte adhesion molecules in cultured endothelial cells.
Design: Prospective, randomized, controlled study.
Setting: Research laboratory at a university medical center
Subjects: Cultured human umbilical vein endothelial cell (HUVECs).
Interventions: HUVECs were stimulated with tumor necrosis factor-[alpha] or lipopolysaccharide in the presence or absence of gabexate mesilate. Expression of E-selectin and intercellular adhesion molecule-1 was measured by cellular enzyme-linked immunosorbent assay. Messenger RNA levels of E-selectin and intercellular adhesion molecule-1 were determined by reverse transcription-polymerase chain reaction. DNA-binding activity of p65 in the nuclear extracts was evaluated by enzyme-linked immunosorbent assay. Nuclear translocation of nuclear factor-[kappa]B induced by tumor necrosis factor-[alpha] was evaluated by immunocytostaining and Western blot analysis. Degradation and phosphorylation of inhibitor of nuclear factor-[kappa]B (I[kappa]B) induced by tumor necrosis factor-[alpha] were evaluated by Western blot analysis.
Measurements and Main Results: Gabexate mesilate inhibited the tumor necrosis factor-[alpha]-induced increases in the endothelial expression of E-selectin and intercellular adhesion molecule-1 by inhibiting the transcription. Tumor necrosis factor-[alpha]-induced increase in DNA binding of p65 was inhibited by gabexate mesilate through inhibition of the nuclear translocation of p65. Gabexate mesilate inhibited the tumor necrosis factor-[alpha]-induced degradation of I[kappa]B[alpha], an inhibitor of nuclear factor-[kappa]B, by inhibiting phosphorylation of I[kappa]B[alpha] in HUVECs.
Conclusions: Gabexate mesilate inhibited the expression of leukocyte adhesion molecules by inhibiting the nuclear factor-[kappa]B-mediated transcription in HUVECs. Inhibition of nuclear factor-[kappa]B activation by gabexate mesilate could be explained by inhibition of degradation of I[kappa]B. Gabexate mesilate might reduce lipopolysaccharide-induced pulmonary vascular injury not only by inhibiting monocytic tumor necrosis factor-[alpha] production but by inhibiting the expression of endothelial leukocyte adhesion molecules.
(C) 2003 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins
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Author Keywords: | gabexate mesilate; disseminated intravascular coagulation; acute respiratory distress syndrome; E-selectin; intercellular adhesion molecule-1; nuclear factor-[kappa]B.
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Language: | English.
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Document Type: | LABORATORY INVESTIGATIONS.
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Journal Subset: | Clinical Medicine.
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ISSN: | 0090-3493
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NLM Journal Code: | dtf, 0355501
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DOI Number: | https://dx.doi.org/10.1097/01.CC...- ouverture dans une nouvelle fenêtre
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