title: Dexamethasone Suppressed LPS-Induced Matrix Metalloproteinase and Its Effect on Endothelial Glycocalyx Shedding.
abstract: The aim of this study is to determine the mechanism of sepsis-induced vascular hyperpermeability and the beneficial effect of glucocorticoid in protecting vascular endothelium. Male Sprague-Dawley rats were given either a bolus intraperitoneal injection of a nonlethal dose of LPS (Escherichia coli 055:B5, 10 mg/kg, Sigma) or vehicle (pyrogen-free water). Animals of treatment groups were also given either dexamethasone (4 mg/kg, 30 min prior to LPS injection) or the matrix metalloproteinases (MMPs) inhibitor doxycycline (4 mg/kg, 30 min after LPS injection). Both activities and protein levels of MMP-2 (p < 0.001) and MMP-9 (p < 0.001) were significantly upregulated in aortic homogenates from LPS-treated rats, associated with decreased ZO-1 (p < 0.001) and syndecan-1 (p = 0.011) protein contents. Both dexamethasone and doxycycline could significantly inhibit MMPs activity and reserve the expressions of ZO-1 and syndecan-1. The inhibition of MMPs by dexamethasone was significantly lower than that by doxycycline, while the rescue of syndecan-1 expression from LPS-induced endotoxemic rat thoracic aorta was significantly higher in the dexamethasone-treated compared to the doxycycline-treated (p = 0.03). In conclusion, activation of MMPs plays important role in regulating ZO-1 and syndecan-1 protein levels in LPS mediated endothelial perturbation. Both dexamethasone and doxycycline inhibit activation of MMPs that may contribute to the rescue of ZO-1 and syndecan-1 expression.
authors.affiliation: Department of Critical Care Medicine, Peking Union Medical College Hospital, Beijing 100730, China.
authors.forename: Na
authors.initials: N
authors.lastname: Cui
authors.affiliation: Department of Critical Care Medicine, Peking Union Medical College Hospital, Beijing 100730, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Critical Care Medicine, Peking Union Medical College Hospital, Beijing 100730, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Long
authors.affiliation: Department of Critical Care Medicine, Peking Union Medical College Hospital, Beijing 100730, China.
authors.forename: Longxiang
authors.initials: L
authors.lastname: Su
authors.affiliation: Department of Critical Care Medicine, Peking Union Medical College Hospital, Beijing 100730, China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Liu
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D003907:Dexamethasone / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D019276:Glycocalyx; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051381:Rats; D053668:Syndecan-1 / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D053668:Syndecan-1; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D003907:Dexamethasone; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9