C1 inhibitor prevents Gram-negative bacterial lipopolysaccharide-induced vascular permeability.
Gram-negative bacterial endotoxemia may lead to the pathological increase of vascular permeability with systemic vascular collapse, a vascular leak syndrome, multiple organ failure (MOF), and/or shock. Previous studies demonstrated that C1 inhibitor (C1INH) protects mice from lipopolysaccharide (LPS)-induced lethal septic shock via a direct interaction with LPS. Here, we report that C1INH blocked the LPS-induced increase in transendothelial flux through an endothelial monolayer. In addition, LPS-mediated detachment of cultured endothelial cells was prevented with C1INH. C1INH also inhibited LPS-induced endothelial cell apoptosis as demonstrated by suppression of DNA fragmentation and annexin V expression. As illustrated by laser scanning confocal microscopy, C1INH completely blocked the binding of fluorescein isothiocyanate (FITC)-LPS to human umbilical vein endothelial cells (HUVECs). C1INH protected from localized LPS-induced increased plasma leakage in C57BL/6J mice and in C1INH-deficient mice. Local vascular permeability in response to LPS was increased to a greater extent in C1INH-deficient mice compared with wild-type littermate controls and was reversed by treatment with C1INH. Systemic administration of LPS to mice resulted in increased vascular permeability, which was reduced by C1INH. Therefore, these studies demonstrate that C1INH, in addition to its role in suppression of LPS-mediated macrophage activation, may play an important role in the prevention of LPS-mediated increased vascular permeability, endothelial cell injury, and multiple organ failure.
Liu
Dongxu
D
CBR Institute for Biomedical Research, Children's Hospital Boston, Harvard Medical School, 800 Huntington Ave, Boston, MA 02115, USA.
Zhang
Dong
D
Scafidi
Jennifer
J
Wu
Xiao
X
Cramer
Cort C
CC
Davis
Alvin E
AE
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D050718:Complement C1 Inhibitor Protein / Q000008:administration & dosage* / Q000235:genetics; D053938:DNA Fragmentation / Q000187:drug effects*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006090:Gram-Negative Bacteria; D006801:Humans; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D012772:Shock, Septic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D014471:Umbilical Veins / Q000378:metabolism / Q000473:pathology
D050718:Complement C1 Inhibitor Protein; D008070:Lipopolysaccharides