Mediators released from LPS-challenged lungs induce inflammatory responses in liver vascular endothelial cells and neutrophilic leukocytes

2009 ◽  
Vol 297 (6) ◽  
pp. G1066-G1076 ◽  
Author(s):  
N. Markovic ◽  
L. A. McCaig ◽  
J. Stephen ◽  
S. Mizuguchi ◽  
R. A. W. Veldhuizen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Ros Production ◽  
Proinflammatory Mediators ◽  
Primary Mouse ◽  
Mouse Lungs

The systemic inflammatory response plays an important role in the progression of acute lung injury (ALI) to multiple organ dysfunction syndrome (MODS). However, the role of lung-derived inflammatory mediators in induction of the inflammatory response in remote organs is poorly understood. To address the above, we investigated the effects of lung inflammation on induction of inflammatory response(s) in the liver in vitro. Inflammation in mouse lungs was induced by intranasal administration of lipopolysaccharide (LPS; 1 mg/ml) followed by mechanical ventilation using the isolated perfused mouse lung method to obtain and characterize lung perfusate from the pulmonary circulation. LPS administration to mouse lungs resulted in an increased release of inflammation-relevant cytokines and chemokines into the perfusate (Luminex assay) compared with the saline-controls. Subsequently, primary mouse liver vascular endothelial cells (LVEC) or mouse polymorphonuclear leukocytes (PMN) in vitro were stimulated with the perfusate obtained from saline- or LPS-challenged lungs and assessed for various inflammation-relevant end points. The obtained results indicate that stimulation of LVEC with perfusate obtained from LPS-challenged lungs results in 1) reactive oxygen species (ROS) production; 2) activation of NF-κB; and 3) expression of E-selectin, ICAM-1, and VCAM-1 and a subsequent increase in PMN rolling and adhesion to LVEC. In addition, perfusate from LPS-challenged lung induced activation of PMN with respect to increased ROS production and upregulation of cell surface levels of adhesion molecules MAC-1 and VLA-4. Heat-inactivation of the perfusate obtained from LPS-challenged lungs was very effective in suppressing increased proadhesive phenotype (i.e., E-selectin and ICAM-1 expression) in LVEC, whereas targeted inhibition (immunoneutralization) of TNF-α and/or IL-6 in LPS-lung perfusate had no effect. Taken together, these findings indicate that multiple proinflammatory mediators (proteinaceous in nature) released from inflamed lungs act synergistically to induce systemic activation of circulating PMN and promote inflammatory responses in liver vascular endothelial cells.

scholarly journals Artesunate Exerts a Direct Effect on Endothelial Cell Activation and NF-κB Translocation in a Mechanism Independent of Plasmodium Killing

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Mariana C. Souza ◽  
Flávio Henrique Marcolino Paixão ◽  
Fausto K. Ferraris ◽  
Isabela Ribeiro ◽  
Maria das Graças M. O. Henriques
Keyword(s):  
Endothelial Cells ◽  
Inflammatory Response ◽  
Malaria Infection ◽  
Cell Activation ◽  
Nuclear Translocation ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Endothelial Cell Activation ◽  
Malaria Model

Artemisinin and its derivates are an important class of antimalarial drug and are described to possess immunomodulatory activities. Few studies have addressed the effect of artesunate in the murine malaria model or its effect on host immune response during malaria infection. Herein, we study the effect of artesunate treatment and describe an auxiliary mechanism of artesunate in modulating the inflammatory response during experimental malaria infection in mice. Treatment with artesunate did not reduce significantly the parasitemia within 12 h, however, reduced BBB breakdown and TNF-α mRNA expression in the brain tissue of artesunate-treated mice. Conversely, mefloquine treatment was not able to alter clinical features. Notably, artesunate pretreatment failed to modulate the expression of LFA-1 in splenocytes stimulated with parasitized red blood cells (pRBCs) in vitro; however, it abrogated the expression of ICAM-1 in pRBC-stimulated endothelial cells. Accordingly, a cytoadherence in vitro assay demonstrated that pRBCs did not adhere to artesunate-treated vascular endothelial cells. In addition, NF-κB nuclear translocation in endothelial cells stimulated with pRBCs was impaired by artesunate treatment. Our results suggest that artesunate is able to exert a protective effect against the P. berghei-induced inflammatory response by inhibiting NF-κB nuclear translocation and the subsequent expression of ICAM-1.

scholarly journals Mitophagy Protects the Retina Against Anti-Vascular Endothelial Growth Factor Therapy-Driven Hypoxia via Hypoxia-Inducible Factor-1α Signaling

2021 ◽  
Vol 9 ◽  
Author(s):  
Yimeng Sun ◽  
Feng Wen ◽  
Chun Yan ◽  
Lishi Su ◽  
Jiawen Luo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Müller Cells ◽  
Ros Generation ◽  
Hypoxic Cell ◽  
Vascular Endothelial ◽  
Ros Production ◽  
Muller Cells ◽  
Anti Vegf

Anti-VEGF drugs are first-line treatments for retinal neovascular diseases, but these anti-angiogenic agents may also aggravate retinal damage by inducing hypoxia. Mitophagy can protect against hypoxia by maintaining mitochondrial quality, thereby sustaining metabolic homeostasis and reducing reactive oxygen species (ROS) generation. Here we report that the anti-VEGF agent bevacizumab upregulated the hypoxic cell marker HIF-1α in photoreceptors, Müller cells, and vascular endothelial cells of oxygen-induced retinopathy (OIR) model mice, as well as in hypoxic cultured 661W photoreceptors, MIO-MI Müller cells, and human vascular endothelial cells. Bevacizumab also increased expression of mitophagy-related proteins, and mitophagosome formation both in vivo and in vitro, but did not influence cellular ROS production or apoptosis rate. The HIF-1α inhibitor LW6 blocked mitophagy, augmented ROS production, and triggered apoptosis. Induction of HIF-1α and mitophagy were associated with upregulation of BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3) and FUN14 domain containing 1 (FUNDC1), and overexpression of these proteins in culture reversed the effects of HIF-1α inhibition. These findings suggest that bevacizumab does induce retinal hypoxia, but that concomitant activation of the HIF-1α-BNIP3/FUNDC1 signaling pathway also induces mitophagy, which can mitigate the deleterious effects by reducing oxidative stress secondary. Promoting HIF-1α-BNIP3/FUNDC1-mediated mitophagy may enhance the safety of anti-VEGF therapy for retinal neovascular diseases and indicate new explanation and possible new target of the anti-VEGF therapy with suboptimal effect.

Ambient fine particulate matter induces inflammatory responses of vascular endothelial cells through activating TLR-mediated pathway

2019 ◽  
Vol 35 (10) ◽  
pp. 670-678 ◽  
Author(s):  
Yifei Le ◽  
Xiao Hu ◽  
Ji Zhu ◽  
Cui Wang ◽  
Zhen Yang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Particulate Matter ◽  
Inflammatory Responses ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Fine Particulate Matter ◽  
Inflammatory Factors ◽  
Vascular Endothelial ◽  
Fine Particulate

This study aims to investigate the role of Toll-like receptors (TLRs) on fine particulate matter (PM2.5)-induced inflammatory responses of vascular endothelial cells. Inflammatory factors and TLRs were examined in the aorta of mice after nonsurgical intratracheal instillation of PM2.5 as well as in the human umbilical vein endothelial cells (HUVECs) treated with PM2.5. In addition, the effects of TLR2 and TLR4 inhibitors in the secretion of interleukin 6 (IL-6) and IL-1β and the expression of TLRs were determined in the HUVECs. The results showed that PM2.5 could increase the expression of IL-1β, IL-6, TLR2, and TLR4 in vitro and in vivo. Anti-TLR2 IgG or TAK242, an inhibitor of TLR4, decreased the secretion of IL-1β and IL-6 by HUVECs and reduced the expression of corresponding TLRs. In conclusion, we demonstrate that both TLR2 and TLR4 are involved in PM2.5-induced inflammatory responses of vascular endothelial cells. Inhibition of TLR2 and TLR4 expression has the potential to prevent PM2.5-induced cardiovascular diseases.

scholarly journals Regulation of the inflammatory response of vascular endothelial cells by EPAC1

2012 ◽  
Vol 166 (2) ◽  
pp. 434-446 ◽  
Author(s):  
Euan Parnell ◽  
Brian O Smith ◽  
Timothy M Palmer ◽  
Anna Terrin ◽  
Manuela Zaccolo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Inflammatory Response ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial

scholarly journals Synthesis and physiological activity of heterodimers comprising different splice forms of vascular endothelial growth factor and placenta growth factor

1996 ◽  
Vol 316 (3) ◽  
pp. 703-707 ◽  
Author(s):  
Ralf BIRKENHÄGER ◽  
Bernard SCHNEPPE ◽  
Wolfgang RÖCKL ◽  
Jörg WILTING ◽  
Herbert A. WEICH ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Vascular Endothelial Cells ◽  
Physiological Activity ◽  
Expression System ◽  
Vascular Endothelial ◽  
Placenta Growth Factor ◽  
Splice Forms

Vascular endothilial growth factor (VEGF) and placenta growth factor (PIGF) are members of a dimeric-growth-factor family with angiogenic properties. VEGF is a highly potent and specific mitogen for endothelial cells, playing a vital role in angiogenesis in vivo. The role of PIGF is less clear. We expressed the monomeric splice forms VEGF-165, VEGF-121, PIGF-1 and PlGF-2 as unfused genes in Escherichia coli using the pCYTEXP expression system. In vitro dimerization experiments revealed that both homo- and hetero-dimers can be formed from these monomeric proteins. The dimers were tested for their ability to promote capillary growth in vivo and stimulate DNA synthesis in cultured human vascular endothelial cells. Heterodimers comprising different VEGF splice forms, or combinations of VEGF/PlGF splice forms, showed mitogenic activity. The results demonstrate that four different heterodimeric growth factors are likely to have as yet uncharacterized functions in vivo.

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