Role of neuropeptides in lung vascular permeability.

The inflammatory mediator thrombin proteolytically activates protease-activated receptor (PAR1) eliciting a transient, but reversible increase in vascular permeability. PAR1-induced dissociation of Gα subunit from heterotrimeric Gq and G12/G13 proteins is known to signal the increase in endothelial permeability. However, the role of released Gβγ is unknown. We now show that impairment of Gβγ function does not affect the permeability increase induced by PAR1, but prevents reannealing of adherens junctions (AJ), thereby persistently elevating endothelial permeability. We observed that in the naive endothelium Gβ1, the predominant Gβ isoform is sequestered by receptor for activated C kinase 1 (RACK1). Thrombin induced dissociation of Gβ1 from RACK1, resulting in Gβ1 interaction with Fyn and focal adhesion kinase (FAK) required for FAK activation. RACK1 depletion triggered Gβ1 activation of FAK and endothelial barrier recovery, whereas Fyn knockdown interrupted with Gβ1-induced barrier recovery indicating RACK1 negatively regulates Gβ1-Fyn signaling. Activated FAK associated with AJ and stimulated AJ reassembly in a Fyn-dependent manner. Fyn deletion prevented FAK activation and augmented lung vascular permeability increase induced by PAR1 agonist. Rescuing FAK activation in fyn−/− mice attenuated the rise in lung vascular permeability. Our results demonstrate that Gβ1-mediated Fyn activation integrates FAK with AJ, preventing persistent endothelial barrier leakiness.

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Leukocyte repletion reverses protective effect of neutropenia in thrombin-induced increase in lung vascular permeability

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1990.259.1.h149 ◽

1990 ◽

Vol 259 (1) ◽

pp. H149-H155 ◽

Cited By ~ 3

Author(s):

S. K. Lo ◽

R. R. Garcia-Szabo ◽

A. B. Malik

Keyword(s):

Vascular Permeability ◽

Lymph Flow ◽

Control Group ◽

Base Line ◽

Pulmonary Vascular Permeability ◽

Protein Clearance ◽

Pulmonary Hemodynamic ◽

Lung Lymph ◽

Lung Vascular Permeability

We examined the role of leukocytes in the pathogenesis of lung vascular injury induced by thrombin in awake sheep prepared with the lung lymph fistulas. Thrombin (80 U/kg) infusion in control sheep (n = 6) increased pulmonary arterial pressure (Ppa) twofold and pulmonary vascular resistance (PVR) three-fold for the 5-h experimental period. Thrombin also increased pulmonary vascular permeability to protein as assessed by decrease in the reflection coefficient (sigma) from 0.70 +/- 0.03 to 0.61 +/- 0.01. Thrombin caused similar initial pulmonary hemodynamic changes in sheep rendered neutropenic (n = 7; 2% neutrophil count of controls) by treatment with hydroxyurea; however, both Ppa and PVR returned toward base-line values within 120 min postthrombin challenge. The increases in pulmonary lymph flow and transvascular protein clearance also recovered rapidly beginning at 60 min after challenge with thrombin in neutropenic sheep. Neutropenia prevented the increase in lung vascular permeability as the sigma value of 0.71 +/- 0.02 was similar to the control value. Leukocytes isolated from control donor sheep were infused intra-arterially into recipient neutropenic sheep (n = 4) to assess the effects of neutrophil repletion on the pulmonary vascular responses. Thrombin (80 U/kg) challenge infused at 1-3 h after infusion of leukocytes increased lung lymph flow twofold and transvascular protein clearance fourfold and produced increases in Ppa and PVR comparable with the control group. The increases in these parameters were sustained for the 5-h experiment duration. The data indicate the essential pathogenetic role of neutrophils in mediating the thrombin-induced increase in lung vascular permeability.

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Role of Krev Interaction Trapped-1 in Prostacyclin-Induced Protection against Lung Vascular Permeability Induced by Excessive Mechanical Forces and Thrombin Receptor Activating Peptide 6

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/rcmb.2014-0376oc ◽

2015 ◽

Vol 53 (6) ◽

pp. 834-843 ◽

Cited By ~ 8

Author(s):

Angelo Meliton ◽

Fanyong Meng ◽

Yufeng Tian ◽

Alok A. Shah ◽

Anna A. Birukova ◽

...

Keyword(s):

Vascular Permeability ◽

Thrombin Receptor ◽

Mechanical Forces ◽

Lung Vascular Permeability

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Critical role of Cdc42 in mediating endothelial barrier protection in vivo

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.90241.2008 ◽

2008 ◽

Vol 295 (2) ◽

pp. L363-L369 ◽

Cited By ~ 24

Author(s):

Ramaswamy Ramchandran ◽

Dolly Mehta ◽

Stephen M. Vogel ◽

Muhammad K. Mirza ◽

Panos Kouklis ◽

...

Keyword(s):

Endothelial Cells ◽

Vascular Permeability ◽

Rho Gtpase ◽

Critical Role ◽

Endothelial Barrier ◽

Endothelial Monolayers ◽

Interendothelial Junctions ◽

Lung Vascular Permeability

Activation of the Rho GTPase Cdc42 has been shown in endothelial cell monolayers to prevent disassembly of interendothelial junctions and the increase in endothelial permeability. Here, we addressed the in vivo role of Cdc42 activity in mediating endothelial barrier protection in lungs by generating mice expressing the dominant active mutant V12Cdc42 protein in vascular endothelial cells targeted via the VE-cadherin promoter. These mice developed normally and exhibited constitutively active GTP-bound Cdc42. The increase in lung vascular permeability and gain in tissue water content in response to intraperitoneal lipopolysaccharide challenge (7 mg/kg) were markedly attenuated in the transgenic mice. To address the basis of the protective effect, we observed that expression of V12Cdc42 mutant in endothelial monolayers reduced the decrease in transendothelial electrical resistance, a measure of opening of interendothelial junctions, thus indicating that Cdc42 activity preserved junctional integrity. RhoA activity in V12Cdc42-expressing endothelial monolayers was reduced compared with untransfected cells, suggesting that activated Cdc42 functions by counteracting the canonical RhoA-mediated mechanism of endothelial hyperpermeability. Therefore, Cdc42 activity of microvessel endothelial cells is a critical determinant of junctional barrier restrictiveness and may represent a means of therapeutically modulating increased lung vascular permeability and edema formation.

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