Abstract
BackgroundElevated plasma levels of heparin-binding protein (HBP) are associated with risk of organ dysfunction and mortality in sepsis, but little is known about causality and mechanisms of action of HBP. The objective of the present study was to test the hypothesis that HBP is a key mediator of the increased endothelial permeability observed in sepsis and to test potential treatments that inhibit HBP-induced increases in permeability.MethodsAssociation between HBP at admission with clinical signs of increased permeability was investigated in 341 patients with septic shock. Mechanisms of action and potential treatment strategies were investigated in cultured human endothelial cells and in mice.ResultsFollowing adjustment for comorbidities and Acute Physiology and Chronic Health Evaluation (APACHE) II, plasma HBP concentrations were weakly associated with fluid overload during the first 4 days of septic shock and the degree of hypoxemia (PaO2/FiO2) as measures of increased systemic and lung permeability, respectively. In mice, intravenous injection of recombinant human HBP induced a lung injury similar to that observed after lipopolysaccharide injection. HBP increased permeability of vascular endothelial cell monolayers in vitro, and enzymatic removal of luminal cell surface glycosaminoglycans (GAGs) using heparinase III and chondroitinase ABC abolished this effect. Similarly, unfractionated heparins and low molecular weight heparins counteracted permeability increased by HBP in vitro. Intracellular, selective inhibition of protein kinase C (PKC) and Rho-kinase pathways reversed HBP-mediated permeability effects.ConclusionsHBP is a potential mediator of sepsis-induced acute lung injury through enhanced endothelial permeability. HBP increases permeability through an interaction with luminal GAGs and activation of the PKC and Rho-kinase pathways. Heparins are potential inhibitors of HBP-induced increases in permeability.Electronic supplementary materialThe online version of this article (doi:10.1186/s40635-016-0104-3) contains supplementary material, which is available to authorized users.
Highlights
Elevated plasma levels of heparin-binding protein (HBP) are associated with risk of organ dysfunction and mortality in sepsis, but little is known about causality and mechanisms of action of HBP
Our results show that increased plasma HBP concentration in human septic shock is associated with increased vascular leak as reflected indirectly by percent fluid overload and the severity of hypoxemia
The presence of heparan sulfate and chondroitin sulfate moieties on the endothelial cell surface is required for HBP-induced increased permeability as shown by enzymatic degradation of these compounds, which
Summary
Elevated plasma levels of heparin-binding protein (HBP) are associated with risk of organ dysfunction and mortality in sepsis, but little is known about causality and mechanisms of action of HBP. A key feature in the pathophysiology of adult respiratory distress syndrome (ARDS) and septic shock is increased microvascular permeability; the current understanding of the underlying mechanisms is limited [1]. It has been shown that HBP binds to cell surface proteoglycans, but the importance of this binding for permeability increases has not been investigated [3, 4]. Support for the importance of the permeabilityincreasing effect of HBP may be inferred from the observation that elevated plasma levels of HBP are associated with shock in septic patients [5,6,7]. While patients with severe ARDS have been shown to have higher HBP levels than those with less severe ARDS [8], it is unclear if increased levels of HBP merely reflect injury severity or if there is a causal relationship between HBP and ARDS
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