Cyclic AMP Blocks Bacterial Lipopolysaccharide-Induced Myosin Light Chain Phosphorylation in Endothelial Cells Through Inhibition of Rho/Rho Kinase Signaling

Essler, Markus; Staddon, James M.; Weber, Peter; Aepfelbacher, Martin

doi:10.4049/jimmunol.164.12.6543

Cited by 138 publications

(103 citation statements)

References 33 publications

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“…Neutrophil TEM can be regulated by Rho kinase that induces cytoskeleton reorganization in endothelial cells (Tasaka et al, 2005;Essler et al, 2000;Saito et al, 1998). The involvement of Rho kinase in LPS-induced neutrophil TEM was determined with the specific Rho kinase inhibitor Y27632.…”

Section: Rho Kinase Activation Is Required For Lps-induced Neutrophilmentioning

confidence: 99%

“…LPS, a cell wall component of Gram-negative bacteria recognized by cells through Toll like receptor 4 (TLR4), is a potent activator of neutrophil TEM (Wagner and Roth, 2000;Lu et al, 2008). Endothelial cells stimulated with LPS exhibit an increased expression of ICAM-1 and activation of Rho kinase (Basit et al, 2006;Essler et al, 2000) which have been shown to play a critical role in LPS-induced neutrophil recruitment in the lungs (Becker et al, 2001;Basit et al, 2006;Tasaka et al, 2005). In addition, LPS can also stimulate either endothelial cells or neutrophils to secrete interleukin 8 (IL-8), a chemokine that has a major role in leukocyte TEM.…”

Section: Introductionmentioning

confidence: 99%

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Endothelial P2Y2 receptor regulates LPS-induced neutrophil transendothelial migration in vitro

Kukulski

Yebdri

Bahrami

et al. 2010

Molecular Immunology

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Previous studies showed that P2 receptors are involved in neutrophil migration via stimulation of chemokine release and by facilitating chemoattractant gradient sensing. Here, we have investigated whether these receptors are involved in LPS-induced neutrophil transendothelial migration (TEM) using a Boyden chamber where neutrophils migrated through a layer of lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs). In line with a role of P2 receptors, neutrophil TEM was inhibited by the P2 receptor antagonists suramin and reactive blue 2 (RB-2) acting on the basolateral, but not luminal, HUVECs' P2 receptors. HUVECs express P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 and P2Y 11 . The involvement of P2Y 4 was unlikely as this receptor is insensitive to suramin while P2Y 1 , P2Y 6 and P2Y 11 were excluded with available selective antagonists, leaving P2Y 2 as the only candidate. Indeed, the P2Y 2 knockdown in HUVECs inhibited neutrophil TEM compared to control HUVECs transfected with scrambled siRNA. Moreover, UTP, a P2Y 2 ligand, markedly potentiated LPS-induced TEM. Interestingly, IL-8 and ICAM-1 had a modest effect on neutrophil TEM in this 3 h assay which was significantly diminished by the inhibition of Rho kinase in HUVECs with Y27632. In summary, endothelial P2Y 2 receptors control the early LPSinduced neutrophil TEM in vitro via Rho kinase activation.

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Section: Rho Kinase Activation Is Required For Lps-induced Neutrophilmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Endothelial P2Y2 receptor regulates LPS-induced neutrophil transendothelial migration in vitro

Kukulski

Yebdri

Bahrami

et al. 2010

Molecular Immunology

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“…In addition to modulating the Src PTKs, we postulate that TLR4 may be interacting through RhoA and Rac to modify actin cytoskeleton. Several studies have observed changes in the actin cytoskeleton in response to TLR ligands such as LPS (48,49), a role for RhoA downstream of LPS signaling (13,43) and Rac activation has been observed (51).…”

Section: -H Repmentioning

confidence: 99%

Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema

Zanotti

Casiraghi

Abano³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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like receptors (TLRs) of the innate immune system contribute to noninfectious inflammatory processes. We employed a murine model of hilar clamping (1 h) with reperfusion times between 15 min and 3 h in TLR4-sufficient (C3H/ OuJ) and TLR4-deficient (C3H/HeJ) anesthetized mice with additional studies in chimeric and myeloid differentiation factor 88 (MyD88)-and TLR4-deficient mice to determine the role of TLR4 in lung ischemia-reperfusion injury. Human pulmonary microvascular endothelial monolayers were subjected to simulated warm ischemia and reperfusion with and without CRX-526, a competitive TLR4 inhibitor. Functional TLR4 solely on pulmonary parenchymal cells, not bone marrow-derived cells, mediates early lung edema following ischemia-reperfusion independent of MyD88. Activation of MAPKs and NF-B was significantly blunted and/or delayed in lungs of TLR4-deficient mice as a consequence of ischemia-reperfusion injury, but edema development appeared to be independent of activation of these signaling pathways. Pretreatment with a competitive TLR4 inhibitor prevented edema in vivo and reduced actin cytoskeletal rearrangement and gap formation in pulmonary microvascular endothelial monolayers subjected to simulated warm ischemia and reperfusion. In addition to its well-accepted role to alter gene transcription, functioning TLR4 on pulmonary parenchymal cells plays a key role in very early and profound pulmonary edema in murine lung ischemiareperfusion injury. This may be due to a novel mechanism: regulation of endothelial cell cytoskeleton affecting microvascular endothelial cell permeability. microvascular permeability; endothelial cell; pulmonary edema ACUTE LUNG INJURY IS A FEATURE of sepsis, systemic inflammatory response, and adult respiratory distress syndrome. Noncardiogenic pulmonary edema and impaired gas exchange are consequences of acute lung injury, irrespective of etiology. The mechanisms causing pulmonary edema due to acute lung injury are not well-understood. Ischemia-reperfusion injury (IRI), a form of acute lung injury occurring immediately following lung transplantation, is a frequent complication causing morbidity and mortality (26). A greater understanding of lung IRI is likely relevant to many types of acute lung injury and thus may benefit not only lung transplant recipients, but also substantial numbers of other patients with lung injury. Such knowledge would also facilitate retrieval of lungs from nonheart-beating cadaver donors for transplant and/or may assist in the salvage of lungs not considered suitable for transplant, thereby reducing the critical shortage of transplantable lungs (8, 11).Reperfusion following an interval of ischemia results in an inflammatory response involving components of the innate immune system, including the complement and coagulation cascades. Both parenchymal and myeloid cells elaborate free radicals, nitric oxide, and pro-and anti-inflammatory cytokines (4, 5). Recently, there has been increasing awareness of the important contribution of the innate immune syst...

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“…In particular, RhoA is important in LPS-mediated regulation of interleukin-8 production (62). Furthermore, LPS induces RhoA/ ROCK-mediated myosin light chain phosphorylation (63,64), with inhibition of ROCK attenuating LPS-induced acute lung injury (65).…”

Section: Discussionmentioning

confidence: 99%

CD44 Regulates Hepatocyte Growth Factor-mediated Vascular Integrity

Singleton

Salgia

Moreno‐Vinasco

et al. 2007

Journal of Biological Chemistry

108

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The preservation of vascular endothelial cell (EC) barrier integrity is critical to normal vessel homeostasis, with barrier dysfunction being a feature of inflammation, tumor angiogenesis, atherosclerosis, and acute lung injury. Therefore, agents that preserve or restore vascular integrity have important therapeutic implications. In this study, we explored the regulation of hepatocyte growth factor (HGF)-mediated enhancement of EC barrier function via CD44 isoforms. We observed that HGF promoted c-Met association with CD44v10 and recruitment of c-Met into caveolin-enriched microdomains (CEM) containing CD44s (standard form). Treatment of EC with CD44v10-blocking antibodies inhibited HGF-mediated c-Met phosphorylation and c-Met recruitment to CEM. Silencing CD44 expression (small interfering RNA) attenuated HGF-induced recruitment of c-Met, Tiam1 (a Rac1 exchange factor), cortactin (an actin cytoskeletal regulator), and dynamin 2 (a vesicular regulator) to CEM as well as HGF-induced trans-EC electrical resistance. In addition, silencing Tiam1 or dynamin 2 reduced HGF-induced Rac1 activation, cortactin recruitment to CEM, and EC barrier regulation. We observed that both HGF-and high molecular weight hyaluronan (CD44 ligand)-mediated protection from lipopolysaccharide-induced pulmonary vascular hyperpermeability was significantly reduced in CD44 knock-out mice, thus validating these in vitro findings in an in vivo murine model of inflammatory lung injury. Taken together, these results suggest that CD44 is an important regulator of HGF/c-Met-mediated in vitro and in vivo barrier enhancement, a process with essential involvement of Tiam1, Rac1, dynamin 2, and cortactin.

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Cyclic AMP Blocks Bacterial Lipopolysaccharide-Induced Myosin Light Chain Phosphorylation in Endothelial Cells Through Inhibition of Rho/Rho Kinase Signaling

Cited by 138 publications

References 33 publications

Endothelial P2Y2 receptor regulates LPS-induced neutrophil transendothelial migration in vitro

Endothelial P2Y2 receptor regulates LPS-induced neutrophil transendothelial migration in vitro

Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema

CD44 Regulates Hepatocyte Growth Factor-mediated Vascular Integrity

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