Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome)

The systemic capillary leak syndrome (SCLS) is a rare disorder characterized by transient episodes of hypotensive shock and anasarca thought to arise from reversible microvascular barrier dysfunction. Although the high prevalence of a monoclonal gammopathy of unknown significance in SCLS suggests a...

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Vydáno v:	Blood Ročník 119; číslo 18; s. 4321
Hlavní autoři:	Xie, Zhihui, Ghosh, Chandra C, Patel, Roshni, Iwaki, Shoko, Gaskins, Donna, Nelson, Celeste, Jones, Nina, Greipp, Philip R, Parikh, Samir M, Druey, Kirk M
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 03.05.2012
Témata:	Acute Disease Adherens Junctions - drug effects Adherens Junctions - ultrastructure Adult Aged Angiopoietin-2 - antagonists & inhibitors Angiopoietin-2 - blood Antibodies, Monoclonal, Humanized - pharmacology Apoptosis - drug effects Bevacizumab Capillary Leak Syndrome - blood Capillary Leak Syndrome - etiology Capillary Leak Syndrome - physiopathology Capillary Permeability Cells, Cultured - drug effects Chronic Disease Convalescence Cytoskeleton - ultrastructure Endothelial Cells - drug effects Endothelium, Vascular - physiopathology Female Humans Immunoglobulins, Intravenous - therapeutic use Male Middle Aged Paraproteinemias - blood Paraproteinemias - complications Recombinant Proteins - pharmacology Vascular Endothelial Growth Factor A - antagonists & inhibitors Vascular Endothelial Growth Factor A - blood Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor A - pharmacology
ISSN:	1528-0020, 1528-0020
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Shrnutí:	The systemic capillary leak syndrome (SCLS) is a rare disorder characterized by transient episodes of hypotensive shock and anasarca thought to arise from reversible microvascular barrier dysfunction. Although the high prevalence of a monoclonal gammopathy of unknown significance in SCLS suggests a pathogenic contribution of endogenous immunoglobulins, the mechanisms of vascular hyperpermeability remain obscure. Herein, we report clinical and molecular findings on 23 patients, the largest SCLS case series to date. Application of episodic SCLS sera, but neither the purified immunoglobulin fraction nor sera obtained from patients during remission, to human microvascular endothelial cells caused vascular endothelial cadherin internalization, disruption of interendothelial junctions, actin stress fiber formation, and increased permeability in complementary functional assays without inducing endothelial apoptosis. Intravenous immunoglobulin, one promising therapy for SCLS, mitigated the permeability effects of episodic sera. Consistent with the presence of endogenous, nonimmunoglobulin, circulating permeability factor(s) constrained to SCLS episodes, we found that vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2), were elevated in episodic SCLS sera but not in remission sera. Ab-based inhibition of Ang2 counteracted permeability induced by episodic SCLS sera. Comparable experiments with anti-VEGF Ab (bevacizumab) yielded less interpretable results, probably because of endothelial toxicity of VEGF withdrawal. Our results support a model of SCLS pathogenesis in which nonimmunoglobulin humoral factors such as VEGF and Ang2 contribute to transient endothelial contraction, suggesting a molecular mechanism for this highly lethal disorder.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1528-0020 1528-0020
DOI:	10.1182/blood-2011-08-375816