Pulmonary Endothelium in Thromboembolism

2009 ◽  
pp. 471-483 ◽  
Author(s):  
Irene M. Lang
Keyword(s):  
Pulmonary Endothelium

scholarly journals Flow-dependent regulation of endothelial Tie2 by GATA3 in vivo

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Temitayo O. Idowu ◽  
Valerie Etzrodt ◽  
Thorben Pape ◽  
Joerg Heineke ◽  
Klaus Stahl ◽  
...  
Keyword(s):  
Gene Expression ◽  
Regulation Of Gene Expression ◽  
Experimental Models ◽  
Common Denominator ◽  
Dependent Manner ◽  
Pulmonary Endothelium ◽  
Delivery Platform ◽  
Transient Overexpression ◽  
Plasmid Delivery

Abstract Background Reduced endothelial Tie2 expression occurs in diverse experimental models of critical illness, and experimental Tie2 suppression is sufficient to increase spontaneous vascular permeability. Looking for a common denominator among different critical illnesses that could drive the same Tie2 suppressive (thereby leak inducing) phenotype, we identified “circulatory shock” as a shared feature and postulated a flow-dependency of Tie2 gene expression in a GATA3 dependent manner. Here, we analyzed if this mechanism of flow-regulation of gene expression exists in vivo in the absence of inflammation. Results To experimentally mimic a shock-like situation, we developed a murine model of clonidine-induced hypotension by targeting a reduced mean arterial pressure (MAP) of approximately 50% over 4 h. We found that hypotension-induced reduction of flow in the absence of confounding disease factors (i.e., inflammation, injury, among others) is sufficient to suppress GATA3 and Tie2 transcription. Conditional endothelial-specific GATA3 knockdown (B6-Gata3tm1-Jfz VE-Cadherin(PAC)-cerERT2) led to baseline Tie2 suppression inducing spontaneous vascular leak. On the contrary, the transient overexpression of GATA3 in the pulmonary endothelium (jet-PEI plasmid delivery platform) was sufficient to increase Tie2 at baseline and completely block its hypotension-induced acute drop. On the functional level, the Tie2 protection by GATA3 overexpression abrogated the development of pulmonary capillary leakage. Conclusions The data suggest that the GATA3–Tie2 signaling pathway might play a pivotal role in controlling vascular barrier function and that it is affected in diverse critical illnesses with shock as a consequence of a flow-regulated gene response. Targeting this novel mechanism might offer therapeutic opportunities to treat vascular leakage of diverse etiologies.

Signal transduction and regulation of lung endothelial cell permeability. Interaction between calcium and cAMP

1998 ◽  
Vol 275 (2) ◽  
pp. L203-L222 ◽  
Author(s):  
Timothy M. Moore ◽  
Paul M. Chetham ◽  
John J. Kelly ◽  
Troy Stevens
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Intracellular Signaling ◽  
Endothelial Permeability ◽  
Cell Permeability ◽  
Gap Formation ◽  
Pulmonary Endothelium ◽  
Intracellular Signals ◽  
Endothelial Cell Permeability ◽  
Cell Cell

Pulmonary endothelium forms a semiselective barrier that regulates fluid balance and leukocyte trafficking. During the course of lung inflammation, neurohumoral mediators and oxidants act on endothelial cells to induce intercellular gaps permissive for transudation of proteinaceous fluid from blood into the interstitium. Intracellular signals activated by neurohumoral mediators and oxidants that evoke intercellular gap formation are incompletely understood. Cytosolic Ca2+ concentration ([Ca2+]i) and cAMP are two signals that importantly dictate cell-cell apposition. Although increased [Ca2+]ipromotes disruption of the macrovascular endothelial cell barrier, increased cAMP enhances endothelial barrier function. Furthermore, during the course of inflammation, elevated endothelial cell [Ca2+]idecreases cAMP to facilitate intercellular gap formation. Given the significance of both [Ca2+]iand cAMP in mediating cell-cell apposition, this review addresses potential sites of cross talk between these two intracellular signaling pathways. Emerging data also indicate that endothelial cells derived from different vascular sites within the pulmonary circulation exhibit distinct sensitivities to permeability-inducing stimuli; that is, elevated [Ca2+]ipromotes macrovascular but not microvascular barrier disruption. Thus this review also considers the roles of [Ca2+]iand cAMP in mediating site-specific alterations in endothelial permeability.

Pathology and Pathobiology of Pulmonary Hypertension

2017 ◽  
Vol 38 (05) ◽  
pp. 571-584 ◽  
Author(s):  
Peter Dorfmüller ◽  
Christophe Guignabert
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Inflammation ◽  
Right Heart Catheterization ◽  
Point Of View ◽  
Heart Catheterization ◽  
Pulmonary Endothelium ◽  
Hemodynamic State ◽  
Pulmonary Arterial ◽  
Genetic And Environmental Factors ◽  
And Migration

Pulmonary hypertension (PH) is a hemodynamic state defined by a mean pulmonary artery pressure ≥ 25 mm Hg during resting right heart catheterization. PH can result from precapillary (arterial) or postcapillary (venous) pathophysiological mechanisms. Interestingly, recent PH pathology has shown that pulmonary arterial or pulmonary venous remodelling are rarely independent phenomena, but frequently occur in combined fashion in lungs from patients suffering from different forms of PH, including pulmonary arterial hypertension (PAH). In PAH, it is now becoming clear that aberrant signals present in vessel wall microenvironment, which is largely orchestrated by dysfunctional pulmonary endothelial cells, are key contributors of the pulmonary vascular remodeling process, fostering proliferation, and survival and migration of resident pulmonary vascular cells such as smooth muscle cells, myofibroblasts, and pericytes. In addition, both genetic and environmental factors are also critical in the development of pulmonary vascular inflammation and chronic impairment of the pulmonary endothelium. This article outlines the current understanding of this disease from the point of view of pathology and pathobiology.

Dissociation between alveolar transmigration of neutrophils and lung injury in hyperoxia

2006 ◽  
Vol 291 (5) ◽  
pp. L1050-L1058 ◽  
Author(s):  
Sandra Perkowski ◽  
Arnaud Scherpereel ◽  
Juan-Carlos Murciano ◽  
Evguenia Arguiri ◽  
Charalambos C. Solomides ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Lung Injury ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Wild Type ◽  
Pulmonary Endothelium ◽  
Pulmonary Uptake ◽  
Endothelial Surface ◽  
Platelet Endothelial Cell Adhesion ◽  
Cell Adhesion Molecule 1

The objective of this study was to quantitatively assess changes in cell adhesion molecule (CAM) expression on the pulmonary endothelial surface during hyperoxia and to assess the functional significance of those changes on cellular trafficking and development of oxygen-induced lung injury. Mice were placed in >95% O2 for 0–72 h, and pulmonary injury and neutrophil (PMN) sequestration were assessed. Specific pulmonary CAM expression was quantified with a dual-radiolabeled MAb technique. To test the role of CAMs in PMN trafficking during hyperoxia, blocking MAbs to murine P-selectin, ICAM-1, or platelet-endothelial cell adhesion molecule-1 (PECAM-1) were injected in wild-type mice. Mice genetically deficient in these CAMs and PMN-depleted mice were also evaluated. PMN sequestration occurred within 8 h of hyperoxia, although alveolar emigration occurred later (between 48 and 72 h), coincident with rapid escalation of the lung injury. Hyperoxia significantly increased pulmonary uptake of radiolabeled antibodies to P-selectin, ICAM-1, and PECAM-1, reflecting an increase in their level on pulmonary endothelium and possibly sequestered blood cells. Although both anti-PECAM-1 and anti-ICAM-1 antibodies suppressed PMN alveolar influx in wild-type mice, only mice genetically deficient in PECAM-1 showed PMN influx suppression. Neither CAM blockade, nor genetic deficiency, nor PMN depletion attenuated lung injury. We conclude that early pulmonary PMN retention during hyperoxia is not temporally associated with an increase in endothelial CAMs; however, subsequent PMN emigration into the alveolar space may be supported by PECAM-1 and ICAM-1. Blocking PMN recruitment did not prevent lung injury, supporting dissociation between PMN infiltration and lung injury during hyperoxia in mice.

Immunotargeting of catalase to lung endothelium via anti-angiotensin-converting enzyme antibodies attenuates ischemia-reperfusion injury of the lung in vivo

2007 ◽  
Vol 293 (1) ◽  
pp. L162-L169 ◽  
Author(s):  
Kai Nowak ◽  
Sandra Weih ◽  
Roman Metzger ◽  
Ronald F. Albrecht ◽  
Stefan Post ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Weight Ratio ◽  
Dry Weight ◽  
Serum Levels ◽  
Converting Enzyme ◽  
Pulmonary Endothelium ◽  
Preferential Expression

Limitation of reactive oxygen species-mediated ischemia-reperfusion (I/R) injury of the lung by vascular immunotargeting of antioxidative enzymes has the potential to become a promising modality for extension of the viability of banked transplantation tissue. The preferential expression of angiotensin-converting enzyme (ACE) in pulmonary capillaries makes it an ideal target for therapy directed toward the pulmonary endothelium. Conjugates of ACE monoclonal antibody (MAb) 9B9 with catalase (9B9-CAT) have been evaluated in vivo for limitation of lung I/R injury in rats. Ischemia of the right lung was induced for 60 min followed by 120 min of reperfusion. Sham-operated animals (sham, n = 6) were compared with ischemia-reperfused untreated animals (I/R, n = 6), I/R animals treated with biotinylated catalase (CAT, n = 6), and I/R rats treated with the conjugates (9B9-CAT, n = 6). The 9B9-CAT accumulation in the pulmonary endothelium of injured lungs was elucidated immunohistochemically. Arterial oxygenation during reperfusion was significantly higher in 9B9-CAT (221 ± 36 mmHg) and sham (215 ± 16 mmHg; P < 0.001 for both) compared with I/R (110 ± 10 mmHg) and CAT (114 ± 30 mmHg). Wet-dry weight ratio of I/R (6.78 ± 0.94%) and CAT (6.54 ± 0.87%) was significantly higher than of sham (4.85 ± 0.29%; P < 0.05), which did not differ from 9B9-CAT (5.58 ± 0.80%). The significantly lower degree of lung injury in 9B9-CAT-treated animals compared with I/R rats was also shown by decreased serum levels of endothelin-1 (sham, 18 ± 9 fmol/mg; I/R, 42 ± 12 fmol/mg; CAT, 36 ± 11 fmol/mg; 9B9-CAT, 26 ± 9 fmol/mg; P < 0.01) and mRNA for inducible nitric oxide synthase (iNOS) [iNOS-GAPDH ratio: sham, 0.15 ± 0.06 arbitrary units (a.u.); I/R, 0.33 ± 0.08 a.u.; CAT, 0.26 ± 0.05 a.u.; 9B9-CAT, 0.14 ± 0.04 a.u.; P < 0.001]. These results validate immunotargeting by anti-ACE conjugates as a prospective and specific strategy to augment antioxidative defenses of the pulmonary endothelium in vivo.

Pulmonary oxygen toxicity in awake dogs: metabolic and physiological effects

1984 ◽  
Vol 57 (5) ◽  
pp. 1480-1488 ◽  
Author(s):  
A. L. Harabin ◽  
L. D. Homer ◽  
M. E. Bradley
Keyword(s):  
Oxygen Toxicity ◽  
Plasma Renin ◽  
Hemodynamic Instability ◽  
Blood Gas ◽  
Metabolic Capacity ◽  
Pulmonary Endothelium ◽  
Physiological Variables ◽  
Terminal Response ◽  
Ace Activity

Because the pulmonary endothelium is sensitive to O2-induced damage, we studied in vivo angiotensin-converting enzyme (ACE) activity in the lungs of 14 catheterized unanesthetized dogs exposed either to air or continuous 100% O2 at 1 ATA. For 5 days, or until the dog died, we measured physiological variables and lung ACE activity. The metabolic data were analyzed with a model that accounted for the effect of changes in cardiac output. Nine dogs breathing O2 lived 88 +/- 21.8 (SD) h and except for blood O2 tensions were indistinguishible from controls until development of a terminal response lasting only a few hours. Hemodynamic instability preceded a precipitous terminal change in blood gas tensions which resulted in impairment of arterial oxygenation, hypercapnia, and acidosis. Plasma renin activity increased. The metabolic capacity of the pulmonary endothelium of O2-exposed animals decreased with time so that after 96 h it was 50% of the control. That of five control animals did not change with time. Thus changes in lung ACE activity preceded alterations in hemodynamics or gas exchange, and the contributions of each are discussed.

scholarly journals Injection of Staphylococcus aureus EDIN by the Bacillus anthracis Protective Antigen Machinery Induces Vascular Permeability

2009 ◽  
Vol 77 (9) ◽  
pp. 3596-3601 ◽  
Author(s):  
Monica Rolando ◽  
Patrick Munro ◽  
Caroline Stefani ◽  
Patrick Auberger ◽  
Gilles Flatau ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Vascular Permeability ◽  
Protective Antigen ◽  
Lethal Factor ◽  
Vascular Leakage ◽  
Host Cells ◽  
Mitogen Activated Protein Kinase ◽  
Systemic Injection ◽  
Pulmonary Endothelium ◽  
Endothelium Permeability

ABSTRACT Systemic injection of Bacillus anthracis lethal toxin (LT) produces vascular leakage and animal death. Recent studies suggest that LT triggers direct endothelial cell cytotoxicity that is responsible for the vascular leakage. LT is composed of heptamers of protective antigen (PA), which drives the endocytosis and translocation into host cells of the lethal factor (LF), a mitogen-activated protein kinase kinase protease. Here we investigated the consequences of injection of an endothelium-permeabilizing factor using LT as a “molecular syringe.” To this end, we generated the chimeric factor LE, corresponding to the PA-binding domain of LF (LF1-254) fused to EDIN exoenzyme. EDIN ADP ribosylates RhoA, leading to actin cable disruption and formation of transcellular tunnels in endothelial cells. We report that systemic injection of LET (LE plus PA) triggers a PA-dependent increase in the pulmonary endothelium permeability. We also report that native LT induces a progressive loss of endothelium barrier function. We established that there is a direct correlation between the extent of endothelium permeability induced by LT and the cytotoxic activity of LT. This suggests new ways to design therapeutic drugs against anthrax directed toward vascular permeability.

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