Inflammation without Vascular Leakage. Science Fiction No Longer?

Filewod, Niall; Lee, Warren L.

doi:10.1164/rccm.201905-1011cp

Cited by 29 publications

(31 citation statements)

References 38 publications

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“…Importantly, induction of inflammatory markers and cell counts in the broncho-alveolar lavage fluid were comparable in Arg −/− mice versus WT mice upon LPS exposure, corroborating previous reports that vascular leak and leukocyte extravasation are separately regulated processes [51,54]. These findings indicate that Arg inhibition can be harbored as treatment strategy to target vascular leakage, while leaving the immune response intact [55]. Finally, we also observed that Arg deficiency inhibited VEGF-induced vascular leak in the skin.…”

Section: Discussionsupporting

confidence: 90%

Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation

Amado-Azevedo¹,

Stalborch

Valent³

et al. 2021

Angiogenesis

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Endothelial barrier disruption and vascular leak importantly contribute to organ dysfunction and mortality during inflammatory conditions like sepsis and acute respiratory distress syndrome. We identified the kinase Arg/Abl2 as a mediator of endothelial barrier disruption, but the role of Arg in endothelial monolayer regulation and its relevance in vivo remain poorly understood. Here we show that depletion of Arg in endothelial cells results in the activation of both RhoA and Rac1, increased cell spreading and elongation, redistribution of integrin-dependent cell-matrix adhesions to the cell periphery, and improved adhesion to the extracellular matrix. We further show that Arg is activated in the endothelium during inflammation, both in murine lungs exposed to barrier-disruptive agents, and in pulmonary microvessels of septic patients. Importantly, Arg-depleted endothelial cells were less sensitive to barrier-disruptive agents. Despite the formation of F-actin stress fibers and myosin light chain phosphorylation, Arg depletion diminished adherens junction disruption and intercellular gap formation, by reducing the disassembly of cell-matrix adhesions and cell retraction. In vivo, genetic deletion of Arg diminished vascular leak in the skin and lungs, in the presence of a normal immune response. Together, our data indicate that Arg is a central and non-redundant regulator of endothelial barrier integrity, which contributes to cell retraction and gap formation by increasing the dynamics of adherens junctions and cell-matrix adhesions in a Rho GTPase-dependent fashion. Therapeutic inhibition of Arg may provide a suitable strategy for the treatment of a variety of clinical conditions characterized by vascular leak.

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Section: Discussionsupporting

confidence: 90%

Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation

Amado-Azevedo¹,

Stalborch

Valent³

et al. 2021

Angiogenesis

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“…Severe sepsis also leads to disruption of the endothelial glycoprotein layer, damage to the microvasculature, resulting in interstitial accumulation of uid and subsequently edema. Increased vascular permeability and tissue edema are likely to cause bacterial displacement, aggravating the in ammatory response and forming a vicious circle [25,26]. Therefore, albumin is associated with disease severity and the mortality rate [27].…”

Section: Discussionmentioning

confidence: 99%

The C-Reactive Protein to Albumin Ratio as a New Predictor for Bacterial Culture in Patients with Severe Sepsis and Septic Shock: A Single-Center Retrospective Analysis.

guo

Lin

et al. 2021

Preprint

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Background: Severe sepsis and septic shock with a high mortality rate are common critical illnesses in the emergency department. Early detection and intervention are a key to improve patient outcomes. The CAR is a fresh inflammation-based prognostic score and widely used in clinics. The primary aim of this study was to investigate the relationship between CAR and blood culture. Methods: 331 adult subjects admitted to the Emergency Intensive care unit via the emergency department from December 1, 2018 to June 30, 2020 were included in this analysis. The study population was divided into positive group and negative group according to the results of blood culture, ROC curves was used to assess the diagnostic performance of CAR, PCT and other risk factors for predicting blood culture, and Youden’s index derived cut-offs were calculated. Results: The patients were subdivided into the positive group and the negative group, 72 cases and 259 cases, respectively. The university analysis indicated that admission PCT, review of PCT, CAR, hepatobiliary system infection, urinary tract infection (relative to lung infection) was significantly corelated with the risk of bloodstream infection. Albumin was negatively correlated with the risk of bloodstream infection. A prediction value of CAR>5 was a significant marker in predicting bloodstream infection (sensitivity:50%; specificity: 71.43%; PPV32.73%; NPV83.71%; P<0.001). Admission PCT and reviewed PCT exhibited greater predictive significance compared with CRP or CAR. At a cut-off of 3.98 ng/ml, reviewed PCT offered the best accuracy in predicting bloodstream infection with the sensitivity, specificity, PPV, and NPV of 84.72%,54.83%, 34.08% and 92.76%; There was no difference in hospital stay and 28-day mortality between the two groups.Conclusion: A higher CAR is associated with increased incidence of bloodstream infection in patients with severe sepsis and septic shock.

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“…The clustering triggers Src-dependent phosphorylation of cortactin and also actin polymerisation [ 90 ]. Importantly, although loosening of the EC junctions is essential for effective paracellular migration [ 91 ], this is not associated with vascular leak [ 92 ]. VE-cadherin is a central mediator of endothelial barrier integrity [ 93 ].VE-cadherin phosphorylation at tyrosine residues 658 and 731 is associated with its internalisation, playing a key role in destabilising EC junctions and thus facilitating paracellular migration of leucocytes [ 94 ].…”

Section: Leucocyte Traffickingmentioning

confidence: 99%

The Tumour Vasculature as a Target to Modulate Leucocyte Trafficking

Zhao

Ting

Coleman

et al. 2021

Cancers

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The effectiveness of immunotherapy against solid tumours is dependent on the appropriate leucocyte subsets trafficking and accumulating in the tumour microenvironment (TME) with recruitment occurring at the endothelium. Such recruitment involves interactions between the leucocytes and the endothelial cells (ECs) of the vessel and occurs through a series of steps including leucocyte capture, their rolling, adhesion, and intraluminal crawling, and finally leucocyte transendothelial migration across the endothelium. The tumour vasculature can curb the trafficking of leucocytes through influencing each step of the leucocyte recruitment process, ultimately producing an immunoresistant microenvironment. Modulation of the tumour vasculature by strategies such as vascular normalisation have proven to be efficient in facilitating leucocyte trafficking into tumours and enhancing immunotherapy. In this review, we discuss the underlying mechanisms of abnormal tumour vasculature and its impact on leucocyte trafficking, and potential strategies for overcoming the tumour vascular abnormalities to boost immunotherapy via increasing leucocyte recruitment.

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Inflammation without Vascular Leakage. Science Fiction No Longer?

Abstract: Contributions: NCF wrote the first draft and drew the initial figures, edited subsequent drafts and approved the final version. WLL conceived of the original idea for the manuscript, edited and wrote subsequent drafts of the manuscript, edited the figures and approved the final version.

Cited by 29 publications

References 38 publications

Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation

Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation

The C-Reactive Protein to Albumin Ratio as a New Predictor for Bacterial Culture in Patients with Severe Sepsis and Septic Shock: A Single-Center Retrospective Analysis.

The Tumour Vasculature as a Target to Modulate Leucocyte Trafficking

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Inflammation without Vascular Leakage. Science Fiction No Longer?

Abstract: Contributions: NCF wrote the first draft and drew the initial figures, edited subsequent drafts and approved the final version. WLL conceived of the original idea for the manuscript, edited and wrote subsequent drafts of the manuscript, edited the figures and approved the final version.

Cited by 29 publications

References 38 publications

Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation

Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation

The C-Reactive Protein to Albumin Ratio as a New Predictor for Bacterial Culture&nbsp;in Patients with Severe Sepsis and Septic Shock: A Single-Center Retrospective Analysis.

The Tumour Vasculature as a Target to Modulate Leucocyte Trafficking

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The C-Reactive Protein to Albumin Ratio as a New Predictor for Bacterial Culture in Patients with Severe Sepsis and Septic Shock: A Single-Center Retrospective Analysis.