endothelin-1 and Capillary-Leak-Syndrome

Idiopathic systemic capillary leak syndrome (SCLS) is a rare and potentially fatal vascular disorder characterized by reversible bouts of hypotension and edema resulting from fluid and solute escape into soft tissues. Although spikes in permeability-inducing factors have been linked to acute SCLS flares, whether or not they act on an inherently dysfunctional endothelium is unknown. To assess the contribution of endothelial-intrinsic mechanisms in SCLS, we derived blood-outgrowth endothelial cells (BOEC) from patients and healthy controls and examined gene expression patterns. Ednra, encoding Endothelin receptor A (ETA)-the target of Endothelin 1 (ET-1)-was significantly increased in SCLS BOEC compared to healthy controls. Although vasoconstriction mediated by ET-1 through ETA activation on vascular smooth muscle cells has been well characterized, the expression and function of ETA receptors in endothelial cells (ECs) has not been described. To determine the role of ETA and its ligand ET-1 in SCLS, if any, we examined ET-1 levels in SCLS sera and functional effects of endothelial ETA expression. ETA overexpression in EAhy926 endothelioma cells led to ET-1-induced hyper-permeability through canonical mechanisms. Serum ET-1 levels were elevated in acute SCLS sera compared to remission and healthy control sera, suggesting a possible role for ET-1 and ETA in SCLS pathogenesis. However, although ET-1 alone did not induce hyper-permeability of patient-derived BOEC, an SCLS-related mediator (CXCL10) increased Edrna quantities in BOEC, suggesting a link between SCLS and endothelial ETA expression. These results demonstrate that ET-1 triggers classical mechanisms of vascular barrier dysfunction in ECs through ETA. Further studies of the ET-1-ETA axis in SCLS and in more common plasma leakage syndromes including sepsis and filovirus infection would advance our understanding of vascular integrity mechanisms and potentially uncover new treatment strategies.

Topics: Calcium Signaling; Capillary Leak Syndrome; Case-Control Studies; Cell Line; Cell Membrane Permeability; Chemokine CXCL10; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Female; Gene Expression Regulation; Humans; Inflammation Mediators; Male; Middle Aged; Receptor, Endothelin A

Vascular leakage and oedema formation are key components in sepsis. In septic patients, plasma levels of the vasoconstrictive and pro-inflammatory peptide endothelin-1 (ET-1) correlate with mortality. During sepsis, neutrophils release heparin-binding protein (HBP) known to increase vascular permeability and to be a promising biomarker of human sepsis. As disruption of ET-signalling in endotoxemia attenuates formation of oedema, we hypothesized that this effect could be related to decreased levels of HBP. To investigate this, we studied the effects of ET-receptor antagonism on plasma HBP and oedema formation in a porcine model of sepsis. In addition, to further characterize a potential endothelin/HBP interaction, we investigated the effects of graded ET-receptor agonist infusions.. Sixteen anesthetized pigs were subjected to 5 h of endotoxemia and were randomized to receive either the ET-receptor antagonist tezosentan or vehicle after 2 h. Haemodynamics, gas-exchange and lung water were monitored. In separate experiments, plasma HBP was measured in eight non-endotoxemic animals exposed to graded infusion of ET-1 or sarafotoxin 6c.. Endotoxemia increased plasma ET-1, plasma HBP, and extravascular lung water. Tezosentan-treatment markedly attenuated plasma HBP and extravascular lung water, and these parameters correlated significantly. Tezosentan decreased pulmonary vascular resistance and increased respiratory compliance. In non-endotoxemic pigs graded ET-1 and sarafotoxin 6c infusions caused a dose-dependent increase in plasma HBP.. ET-receptor antagonism reduces porcine endotoxin-induced pulmonary oedema and plasma levels of the oedema-promoting protein HBP. Moreover, direct ET-receptor stimulation distinctively increases plasma HBP. Together, these results suggest a novel mechanism by which ET-1 contributes to formation of oedema during experimental sepsis.

Topics: Animals; Antimicrobial Cationic Peptides; Blood Proteins; Capillary Leak Syndrome; Carrier Proteins; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endotoxemia; Endotoxins; Extravascular Lung Water; Female; Hemodynamics; Inflammation; Infusions, Intravenous; Leukocyte Count; Male; Neutrophil Activation; Pulmonary Edema; Pyridines; Random Allocation; Receptor, Endothelin B; Sus scrofa; Swine; Tetrazoles; Viper Venoms

A consequence of ischemia/reperfusion (IR) is endothelial barrier dysfunction and intravascular volume loss. The purposes of our study are to explore the impact of: 1) cyclic guanosine monophosphate (cGMP) synthesis inhibition, 2) cyclic adenosine monophosphate (cAMP) synthesis inhibition, 3) treatment with endothelin-1, and 4) endothelin-1 (ET-1)-mediated cAMP changes on IR-induced fluid leak. We hypothesize that IR-mediated microvascular fluid leak results from increased cGMP activity and ET-1 decreases IR-induced fluid leak via cAMP.. A micro-cannulation technique was used to determine fluid leak or hydraulic permeability (Lp) in rat mesenteric venules. Lp was measured during IR and after treatment with 1) cGMP synthesis inhibitor (LY83583,10 micromol/L) 2) cAMP synthesis inhibitor (2',5'dideoxyadenosine,10 micromol/L), 3) ET-1 (80 pM), and 4) cAMP synthesis inhibitor plus ET-1 (n=6 in each group; Lp represented as mean+/-standard error of the mean; units 10-cm/sec/cmH2O).. IR resulted in an increase in Lp (Lp=7.07+/-0.20) sevenfold above baseline (1.05+/-0.31) (p

Topics: Animals; Capillary Leak Syndrome; Capillary Permeability; Cyclic AMP; Cyclic GMP; Endothelin-1; Female; Mesenteric Veins; Microcirculation; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Hypoxia increases pulmonary vascular leak, which is regulated in part by neutral endopeptidase (NEP). NEP is a cell-surface metalloprotease that degrades several vasoactive peptides, including endothelin-1 (ET-1) and atrial natriuretic peptide (ANP). We therefore hypothesized that NEP attenuates high altitude-induced pulmonary vascular leak. Wild-type and NEP null mice were exposed to a simulated high altitude (HA) of 6,728 m (22,000 ft; P(B) = 328 mmHg) or remained at the relatively low altitude (LA) of 1,500 m (4,920 ft; P(B) = 640 mmHg) for 24 h. Plasma ANP and ET-1 concentrations, right ventricular pressure (P(RV)), and indexes of lung injury were recorded. At HA, lung wet weight-to-body weight increased in all animals, but was greatest in the NEP wild-type mice. Vascular leak, as measured by Evans blue dye, increased only in the NEP wild-type mice at HA. P(RV) increased in both genotypes at HA. Plasma ANP concentrations increased at HA in both genotypes, but plasma ET-1 concentrations were elevated only in the NEP null mice at HA. Correlations between lung wet weight-to-body weight versus P(RV) (r = 0.56; p = 0.0136) and ANP versus P(RV) (r = -0.54; p = 0.02) were noted. We conclude that NEP null mice exposed to HA have a greater rise in ANP versus ET-1 plasma concentration, decreased pulmonary vascular pressure, and reduced high altitude-induced pulmonary vascular leak.

Topics: Altitude Sickness; Animals; Atrial Natriuretic Factor; Capillary Leak Syndrome; Capillary Permeability; Endothelin-1; Mice; Neprilysin

Endothelin-1 (ET-1) has been formerly demonstrated to have potent vasocontractile as well as bronchoconstrictor effects in vitro. This followup study was aimed to evaluate the possible changes in ET-1 levels in the plasma of asthmatic children, according to disease activity and severity.. Plasma ET-1 was estimated by enzyme-linked immunoadsorbent assay in 30 asthmatic patients (6 to 12 years old) during and after remission of an acute attack. Thirty age- and sex-matched healthy children were included as a control group.. Plasma ET-1 immunoreactivity was significantly increased in the asthmatic children during the attacks (17.2+/-6.9 pg/mL) in comparison to the levels during quiescence of symptoms (0.9+/-1.13 pg/mL). Further, both values were significantly higher than the control value (0.22+/-0.29 pg/mL). The severity of attacks as judged clinically and by peak expiratory flow rate measurement did not influence the plasma endothelin status; neither did the family history of atopy nor the absolute eosinophil count. However, serum total IgE levels could be positively correlated to the plasma endothelin concentrations measured after remission of the asthmatic attacks (P < 0.05).. Our findings reinforce the concept that ET-1 may be implicated in the pathogenesis of bronchoconstriction. This may encourage further studies on the value of ET-1 antagonism among alternative therapeutic modalities of childhood asthma.

Topics: Acute Disease; Asthma; Bronchial Spasm; Bronchoconstriction; Capillary Leak Syndrome; Case-Control Studies; Child; Convalescence; Endothelin-1; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Female; Fibronectins; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Male; Phospholipases A; Severity of Illness Index

Capillary leakage with fluid loss into the third space contributes to many of the early systemic complications in severe acute pancreatitis. There has been increasing interest in endothelin as one of the factors affecting capillary permeability.. To elucidate further the role of endothelin in the development of capillary leakage in acute pancreatitis by investigating the effect of exogenous endothelin administration and endothelin receptor blockade in sham operated animals and two models of acute pancreatitis.. Determination of capillary permeability in the pancreas and colonic mucosa by quantifying extravasation of fluorescein labelled dextran using a novel computer assisted video image analysis system.. Pancreatic and colonic capillary permeability increased stepwise from mild to severe acute pancreatitis. Endothelin increased pancreatic and colonic capillary permeability in healthy animals and animals with mild acute pancreatitis but had no additional adverse effect in severe acute pancreatitis. Endothelin receptor blockade decreased pancreatic capillary permeability in sham operated rats but had no effect on the colon. In mild and severe acute pancreatitis, endothelin receptor blockade stabilised increased capillary permeability in both the pancreas and colon.. Endothelin plays an important role in mediating capillary permeability in the pancreas. In severe pancreatitis, it increases capillary permeability even outside the pancreas, thereby contributing to capillary leakage. Endothelin receptor blockade significantly reduces capillary permeability in acute pancreatitis both in and outside the pancreas, suggesting a therapeutic approach to counteract capillary leakage in severe acute pancreatitis.

Topics: Animals; Capillary Leak Syndrome; Capillary Permeability; Endothelin Receptor Antagonists; Endothelin-1; Male; Pancreatitis; Rats; Rats, Sprague-Dawley; Receptors, Endothelin