Inflammatory, metabolic, and genetic mechanisms of vascular calcification

PubMed Central

Demer, Linda L.; Tintut, Yin

2014-01-01

This review centers on updating the active research area of vascular calcification. This pathology underlies substantial cardiovascular morbidity and mortality, through adverse mechanical effects on vascular compliance, vasomotion, and, most likely, plaque stability. Biomineralization is a complex, regulated process occurring widely throughout nature. Decades ago, its presence in the vasculature was considered a mere curiosity and an unregulated, “dystrophic” process that does not involve biological mechanisms. While it remains controversial whether the process has any adaptive value or past evolutionary advantage, substantial advances have been made in understanding the biological mechanisms driving the process. Different types of calcific vasculopathy, such as inflammatory vs. metabolic, have parallel mechanisms in skeletal bone calcification, such as intramembranous and endochondral ossification. Recent work has identified important regulatory roles for inflammation, oxidized lipids, elastin, alkaline phosphatase, osteoprogenitor cells, matrix gamma-carboxyglutamic acid protein (MGP), transglutaminase, osteoclastic regulatory factors, phosphate regulatory hormones and receptors, apoptosis, prelamin A, autophagy, and microvesicles or microparticles similar to the matrix vesicles of skeletal bone. Recent work has uncovered fascinating interactions between MGP, vitamin K, warfarin and transport proteins. And, lastly, recent breakthroughs in inherited forms of calcific vasculopathy, have identified the genes responsible as well as an unexpected overlap of phenotypes. PMID:24665125

Nitro-oleic acid inhibits vascular endothelial inflammatory responses and the endothelial-mesenchymal transition.

PubMed

Ambrozova, Gabriela; Fidlerova, Tana; Verescakova, Hana; Koudelka, Adolf; Rudolph, Tanja K; Woodcock, Steven R; Freeman, Bruce A; Kubala, Lukas; Pekarova, Michaela

2016-11-01

Inflammatory-mediated pathological processes in the endothelium arise as a consequence of the dysregulation of vascular homeostasis. Of particular importance are mediators produced by stimulated monocytes/macrophages inducing activation of endothelial cells (ECs). This is manifested by excessive soluble pro-inflammatory mediator production and cell surface adhesion molecule expression. Nitro-fatty acids are endogenous products of metabolic and inflammatory reactions that display immuno-regulatory potential and may represent a novel therapeutic strategy to treat inflammatory diseases. The purpose of our study was to characterize the effects of nitro-oleic acid (OA-NO2) on inflammatory responses and the endothelial-mesenchymal transition (EndMT) in ECs that is a consequence of the altered healing phase of the immune response. The effect of OA-NO2 on inflammatory responses and EndMT was determined in murine macrophages and murine and human ECs using Western blotting, ELISA, immunostaining, and functional assays. OA-NO2 limited the activation of macrophages and ECs by reducing pro-inflammatory cytokine production and adhesion molecule expression through its modulation of STAT, MAPK and NF-κB-regulated signaling. OA-NO2 also decreased transforming growth factor-β-stimulated EndMT and pro-fibrotic phenotype of ECs. These effects are related to the downregulation of Smad2/3. The study shows the pleiotropic effect of OA-NO2 on regulating EC-macrophage interactions during the immune response and suggests a role for OA-NO2 in the regulation of vascular endothelial immune and fibrotic responses arising during chronic inflammation. These findings propose the OA-NO2 may be useful as a novel therapeutic agent for treatment of cardiovascular disorders associated with dysregulation of the endothelial immune response. Copyright © 2016 Elsevier B.V. All rights reserved.

The bone morphogenic protein inhibitor, noggin, reduces glycemia and vascular inflammation in db/db mice

PubMed Central

Koga, Mitsuhisa; Engberding, Niels; Dikalova, Anna E.; Chang, Kyung Hwa; Seidel-Rogol, Bonnie; Long, James S.; Lassègue, Bernard; Jo, Hanjoong

2013-01-01

Vascular diseases frequently accompany diabetes mellitus. Based on the current understanding of atherosclerosis as an inflammatory disorder of the vascular wall, it has been speculated that diabetes may accelerate atherosclerosis by inducing a proinflammatory milieu in the vasculature. ANG II and bone morphogenic proteins (BMPs) have been implicated in vascular inflammation. We evaluated the effect of angiotensin receptor blockade by valsartan and BMP inhibition by noggin on markers of vascular inflammation in a mouse model of diabetes. Noggin had no effect on blood pressure but decreased serum glucose levels, whereas valsartan significantly decreased blood pressure, but not serum glucose. Both inhibitors reduced reactive oxygen species production in the aorta. Additionally, noggin and valsartan diminish gene transcription and protein expression of various inflammatory molecules in the vascular wall. These observations indicate that although both inhibitors block superoxide production and have similar effects on inflammatory gene expression, glycemia and blood pressure may represent a secondary target differentially affected by noggin and valsartan. Our data clearly identify the BMP pathway as a potentially potent therapeutic target in diabetic inflammatory vascular disease. PMID:23812391

Synthetic E-selectin prevents postoperative vascular restenosis by inhibiting nuclear factor κB in rats

PubMed Central

Liu, Jiangang; Liu, Zhongjie; Hu, Xiaohui; Zhang, Yuan; Zhang, Shiming

2018-01-01

During the development of postoperative vascular restenosis, the aberrant proliferation of vascular smooth muscle cells (VSMCs) is a critical event resulting in intimal hyperplasia. Inflammatory responses involving the activation of nuclear factor (NF)-κB are among the major molecular processes underlying restenosis. The present study aimed to investigate the roles of NF-κB in VSMC proliferation and restenosis following vascular anastomosis, as well as to evaluate the potential of synthetic E-selectin to downregulate NF-κB and thus inhibit vascular hyperplasia. A total of 72 adult male Sprague-Dawley rats were randomly assigned to three groups: Control, operation and treatment groups. Rats in the operation and treatment groups received longitudinal incisions in the right carotid arteries, which were closed using interrupted sutures. Following vascular anastomosis, synthetic E-selectin (10 mg/kg), or an equal volume of saline, was immediately injected into the right femoral vein of rats in the treatment and operation groups, respectively. Following surgery, the mRNA and protein expression levels of NF-κB at the site of anastomosis, the levels of tumor necrosis factor-α and interleukin-6 in the serum, NF-κB binding activity, and the presence of proliferating cell nuclear antigen (PCNA)-positive cells were evaluated by western blotting, reverse transcription-quantitative polymerase chain reaction, ELISA, electrophoretic mobility shift assay and immunofluorescence staining. The present results demonstrated that following treatment with synthetic E-selectin, the levels of NF-κB and the inflammatory response, as well as the presence of PCNA-positive cells, were significantly reduced (P<0.01). In conclusion, the results of the present study suggested that synthetic E-selectin may exert anti-inflammatory and anti-restenotic effects following vascular anastomosis in vivo. PMID:29393453

Remembering Professor Benito Casu (1927-2016).

PubMed

Torri, Giangiacomo; Cassinelli, Giuseppe

2018-01-31

Heparin and related drugs have contributed in so many different ways to the drug discovery process, and have provided a platform to understand the pathophysiology of vascular and inflammatory diseases for nearly 100 years.

Diabetic macular edema, retinopathy and age-related macular degeneration as inflammatory conditions

PubMed Central

2016-01-01

Diabetic macular edema (DME) and diabetic retinopathy (DR) are complications affecting about 25% of all patients with long-standing type 1 and type 2 diabetes mellitus and are a major cause of significant decrease in vision and quality of life. Age-related macular degeneration (AMD) is not uncommon, and diabetes mellitus affects the incidence and progression of AMD through altering hemodynamics, increasing oxidative stress, accumulating advanced glycation end products, etc. Recent studies suggest that DME, DR and AMD are inflammatory conditions characterized by a breakdown of the blood-retinal barrier, inflammatory processes and an increase in vascular permeability. Key factors that seem to have a dominant role in DME, DR and AMD are angiotensin II, prostaglandins and the vascular endothelial growth factor and a deficiency of anti-inflammatory bioactive lipids. The imbalance between pro- and anti-inflammatory eicosanoids and enhanced production of pro-angiogenic factors may initiate the onset and progression of DME, DR and AMD. This implies that bioactive lipids that possess anti-inflammatory actions and suppress the production of angiogenic factors could be employed in the prevention and management of DME, DR and AMD. PMID:27695506

Like a slippery fish, a little slime is a good thing: the glycocalyx revealed.

PubMed

Biddle, Chuck

2013-12-01

The glycocalyx is a dynamic network of multiple membrane-bound complexes lining the vascular endothelium. Its role in maintaining vascular homeostasis includes regulating vascular permeability as well as a range of vital functions, such as mechanotransduction, hemostasis, modulation of inflammatory processes, and serving as an antiatherogenic. Revisionist thinking about the Starling principle is discussed in terms of the major influence of the glycocalyx on capillary and tissue fluid homeostasis. The clinical and pathophysiologic threats to the glycocalyx are reviewed as well as strategies to maintain its integrity.

Oxidative and inflammatory signals in obesity-associated vascular abnormalities.

PubMed

Reho, John J; Rahmouni, Kamal

2017-07-15

Obesity is associated with increased cardiovascular morbidity and mortality in part due to vascular abnormalities such as endothelial dysfunction and arterial stiffening. The hypertension and other health complications that arise from these vascular defects increase the risk of heart diseases and stroke. Prooxidant and proinflammatory signaling pathways as well as adipocyte-derived factors have emerged as critical mediators of obesity-associated vascular abnormalities. Designing treatments aimed specifically at improving the vascular dysfunction caused by obesity may provide an effective therapeutic approach to prevent the cardiovascular sequelae associated with excessive adiposity. In this review, we discuss the recent evidence supporting the role of oxidative stress and cytokines and inflammatory signals within the vasculature as well as the impact of the surrounding perivascular adipose tissue (PVAT) on the regulation of vascular function and arterial stiffening in obesity. In particular, we focus on the highly plastic nature of the vasculature in response to altered oxidant and inflammatory signaling and highlight how weight management can be an effective therapeutic approach to reduce the oxidative stress and inflammatory signaling and improve vascular function. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Inflammasomes link vascular disease with neuroinflammation and brain disorders

PubMed Central

Lénárt, Nikolett; Brough, David

2016-01-01

The role of inflammation in neurological disorders is increasingly recognised. Inflammatory processes are associated with the aetiology and clinical progression of migraine, psychiatric conditions, epilepsy, cerebrovascular diseases, dementia and neurodegeneration, such as seen in Alzheimer’s or Parkinson’s disease. Both central and systemic inflammatory actions have been linked with the development of brain diseases, suggesting that complex neuro-immune interactions could contribute to pathological changes in the brain across multiple temporal and spatial scales. However, the mechanisms through which inflammation impacts on neurological disease are improperly defined. To develop effective therapeutic approaches, it is imperative to understand how detrimental inflammatory processes could be blocked selectively, or controlled for prolonged periods, without compromising essential immune defence mechanisms. Increasing evidence indicates that common risk factors for brain disorders, such as atherosclerosis, diabetes, hypertension, obesity or infection involve the activation of NLRP3, NLRP1, NLRC4 or AIM2 inflammasomes, which are also associated with various neurological diseases. This review focuses on the mechanisms whereby inflammasomes, which integrate diverse inflammatory signals in response to pathogen-driven stimuli, tissue injury or metabolic alterations in multiple cell types and different organs of the body, could functionally link vascular- and neurological diseases and hence represent a promising therapeutic target. PMID:27486046

Nitric oxide-donating atorvastatin attenuates neutrophil recruitment during vascular inflammation independent of changes in plasma cholesterol.

PubMed

Baetta, Roberta; Granata, Agnese; Miglietta, Daniela; Oliva, Francesca; Arnaboldi, Lorenzo; Bonomo, Alessandra; Ferri, Nicola; Ongini, Ennio; Bellosta, Stefano; Corsini, Alberto

2013-06-01

Polymorphonuclear neutrophils, the first leukocytes to infiltrate the inflamed tissue, can make important contributions to vascular inflammatory processes driving the development of atherosclerosis. We herein investigated the effects of atorvastatin and NCX 6560 (a nitric oxide (NO)-donating atorvastatin derivative that has completed a successful phase 1b study) on neutrophilic inflammation in carotid arteries of normocholesterolemic rabbits subjected to perivascular collar placement. Atorvastatin or NCX 6560 were administered orally (5 mg/kg/day or equimolar dose) to New Zealand White rabbits for 6 days, followed by collar implantation 1 h after the last dose. Twenty-four hours later carotids were harvested for neutrophil quantification by immunostaining. Treatment with NCX 6560 was associated with a lower neutrophil infiltration (-39.5 %), while atorvastatin did not affect neutrophil content. The result was independent of effects on plasma cholesterol or differences in atorvastatin bioavailability, which suggests an important role of NO-related mechanisms in mediating this effect. Consistent with these in vivo findings, in vitro studies showed that NCX 6560, as compared to atorvastatin, had greater inhibitory activity on processes involved in neutrophil recruitment, such as migration in response to IL-8 and IL-8 release by endothelial cells and by neutrophils themselves. Pretreatment with NCX 6560, but not with atorvastatin, reduced the ability of neutrophil supernatants to promote monocyte chemotaxis, a well-known pro-inflammatory activity of neutrophils. Experimental data suggest a potential role of NO-releasing statins in the control of the vascular inflammatory process mediated by polymorphonuclear neutrophils.

Anti-oxidative and anti-inflammatory vasoprotective effects of caloric restriction in aging: role of circulating factors and SIRT1

PubMed Central

Csiszar, Anna; Labinskyy, Nazar; Jimenez, Rosario; Pinto, John T.; Ballabh, Praveen; Losonczy, Gyorgy; Pearson, Kevin J.; de Cabo, Rafael; Ungvari, Zoltan

2009-01-01

Endothelial-dysfunction, oxidative stress and inflammation are associated with vascular aging and promote the development of cardiovascular-disease. Caloric restriction (CR) mitigates conditions associated with aging, but its effects on vascular dysfunction during aging remain poorly defined. To determine whether CR exerts vasoprotective effects in aging, aortas of ad libitum (AL) fed young and aged and CR-aged F344 rats were compared. Aging in AL-rats was associated with impaired acetylcholine-induced relaxation, vascular oxidative stress and increased NF-κB-activity. Lifelong CR significantly improved endothelial function, attenuated vascular ROS production, inhibited NF-κB activity and down-regulated inflammatory genes. To elucidate the role of circulating factors in mediation of the vasoprotective effects of CR, we determined whether sera obtained from CR-animals can confer anti-oxidant and anti-inflammatory effects in cultured coronary-arterial endothelial cells (CAECs), mimicking the effects of CR. In CAECs cultured in the presence of AL-serum TNFα elicited oxidative-stress, NF-κB-activation and inflammatory gene expression. By contrast, treatment of CAECs with CR-serum attenuated TNFα-induced ROS generation and prevented NF-κB-activation and induction of inflammatory genes. siRNA-knockdown of SIRT1 mitigated the anti-oxidant and anti-inflammatory effects of CR-serum. CR exerts anti-oxidant and anti-inflammatory vascular effects, which are likely mediated by circulating factors, in part, via a SIRT1-dependent pathway. PMID:19549533

Cellular Model of Atherogenesis Based on Pluripotent Vascular Wall Pericytes.

PubMed

Ivanova, Ekaterina A; Orekhov, Alexander N

2016-01-01

Pericytes are pluripotent cells that can be found in the vascular wall of both microvessels and large arteries and veins. They have distinct morphology with long branching processes and form numerous contacts with each other and with endothelial cells, organizing the vascular wall cells into a three-dimensional network. Accumulating evidence demonstrates that pericytes may play a key role in the pathogenesis of vascular disorders, including atherosclerosis. Macrovascular pericytes are able to accumulate lipids and contribute to growth and vascularization of the atherosclerotic plaque. Moreover, they participate in the local inflammatory process and thrombosis, which can lead to fatal consequences. At the same time, pericytes can represent a useful model for studying the atherosclerotic process and for the development of novel therapeutic approaches. In particular, they are suitable for testing various substances' potential for decreasing lipid accumulation induced by the incubation of cells with atherogenic low-density lipoprotein. In this review we will discuss the application of cellular models for studying atherosclerosis and provide several examples of successful application of these models to drug research.

Vascular signaling abnormalities in Alzheimer disease.

PubMed

Grammas, Paula; Sanchez, Alma; Tripathy, Debjani; Luo, Ester; Martinez, Joseph

2011-08-01

Our laboratory has documented that brain microvessels derived from patients with Alzheimer disease (AD) express or release a myriad of factors that have been implicated in vascular activation and angiogenesis. In addition, we have documented that signaling cascades associated with vascular activation and angiogenesis are upregulated in AD-derived brain microvessels. These results are consistent with emerging data suggesting that factors and processes characteristic of vascular activation and angiogenesis are found in the AD brain. Despite increases in proangiogenic factors and signals in the AD brain, however, evidence for increased vascularity in AD is lacking. Cerebral hypoperfusion/hypoxia, a potent stimulus for vascular activation and angiogenesis, triggers hypometabolic, cognitive, and degenerative changes in the brain. In our working model, hypoxia stimulates the angiogenic process; yet, there is no new vessel growth. Therefore, there are no feedback signals to shut off vascular activation, and endothelial cells become irreversibly activated. This activation results in release of a large number of proteases, inflammatory proteins, and other gene products with biologic activity that can injure or kill neurons. Pathologic activation of brain vasculature may contribute noxious mediators that lead to neuronal injury and disease processes in AD brains. This concept is supported by preliminary experiments in our laboratory, which show that pharmacologic blockade of vascular activation improves cognitive function in an animal model of AD. Thus, "vascular activation" could be a novel, unexplored therapeutic target in AD.

Metalloproteinases and atherothrombosis: MMP-10 mediates vascular remodeling promoted by inflammatory stimuli.

PubMed

Rodriguez, Jose A; Orbe, Josune; Martinez de Lizarrondo, Sara; Calvayrac, Olivier; Rodriguez, Cristina; Martinez-Gonzalez, Jose; Paramo, Jose A

2008-01-01

Atherosclerosis is the common pathophysiological substrate of ischemic vascular diseases and their thrombotic complications. The unbalance between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) has been hypothesized to be involved in the growth, destabilization, and eventual rupture of atherosclerotic lesions. Different MMPs have been assigned relevant roles in the pathology of vascular diseases and MMP-10 (stromelysin-2) has been involved in vascular development and atherogenesis. This article examines the pathophysiological role of MMPs, particularly MMP-10, in the onset and progression of vascular diseases and their regulation by pro-inflammatory stimuli. MMP-10 over-expression has been shown to compromise vascular integrity and it has been associated with aortic aneurysms. MMP-10 is induced by C-reactive protein in endothelial cells, and it is over-expressed in atherosclerotic lesions. Additionally, higher MMP-10 serum levels are associated with inflammatory markers, increased carotid intima-media thickness and the presence of atherosclerotic plaques. We have cloned the promoter region of the MMP-10 gene and studied the effect of inflammatory stimuli on MMP-10 transcriptional regulation, providing evidences further supporting the involvement of MMP-10 in the pathophysiology of atherothrombosis.

eNOS uncoupling in cardiovascular diseases--the role of oxidative stress and inflammation.

PubMed

Karbach, Susanne; Wenzel, Philip; Waisman, Ari; Munzel, Thomas; Daiber, Andreas

2014-01-01

Many cardiovascular diseases and drug-induced complications are associated with - or even based on - an imbalance between the formation of reactive oxygen and nitrogen species (RONS) and antioxidant enzymes catalyzing the break-down of these harmful oxidants. According to the "kindling radical" hypothesis, the formation of RONS may trigger in certain conditions the activation of additional sources of RONS. According to recent reports, vascular dysfunction in general and cardiovascular complications such as hypertension, atherosclerosis and coronary artery diseases may be connected to inflammatory processes. The present review is focusing on the uncoupling of endothelial nitric oxide synthase (eNOS) by different mechanisms involving so-called "redox switches". The oxidative depletion of tetrahydrobiopterin (BH4), oxidative disruption of the dimeric eNOS complex, S-glutathionylation and adverse phosphorylation as well as RONS-triggered increases in levels of asymmetric dimethylarginine (ADMA) will be discussed. But also new concepts of eNOS uncoupling and state of the art detection of this process will be described. Another part of this review article will address pharmaceutical interventions preventing or reversing eNOS uncoupling and thereby normalize vascular function in a given disease setting. We finally turn our attention to the inflammatory mechanisms that are also involved in the development of endothelial dysfunction and cardiovascular disease. Inflammatory cell and cytokine profiles as well as their interactions, which are among the kindling mechanisms for the development of vascular dysfunction will be discussed on the basis of the current literature.

Vascular dysfunction and fibrosis in stroke-prone spontaneously hypertensive rats: The aldosterone-mineralocorticoid receptor-Nox1 axis.

PubMed

Harvey, Adam P; Montezano, Augusto C; Hood, Katie Y; Lopes, Rheure A; Rios, Francisco; Ceravolo, Graziela; Graham, Delyth; Touyz, Rhian M

2017-06-15

We questioned whether aldosterone and oxidative stress play a role in vascular damage in severe hypertension and investigated the role of Nox1 in this process. We studied mesenteric arteries, aortas and vascular smooth muscle cells (VSMC) from WKY and SHRSP rats. Vascular effects of eplerenone or canrenoic acid (CA) (mineralocorticoid receptor (MR) blockers), ML171 (Nox1 inhibitor) and EHT1864 (Rac1/2 inhibitor) were assessed. Nox1-knockout mice were also studied. Vessels and VSMCs were probed for Noxs, reactive oxygen species (ROS) and pro-fibrotic/inflammatory signaling. Blood pressure and plasma levels of aldosterone and galectin-3 were increased in SHRSP versus WKY. Acetylcholine-induced vasorelaxation was decreased (61% vs 115%) and phenylephrine-induced contraction increased in SHRSP versus WKY (E max 132.8% vs 96.9%, p<0.05). Eplerenone, ML171 and EHT1864 attenuated hypercontractility in SHRSP. Vascular expression of collagen, fibronectin, TGFβ, MCP-1, RANTES, MMP2, MMP9 and p66Shc was increased in SHRSP versus WKY. These changes were associated with increased ROS generation, 3-nitrotyrosine expression and Nox1 upregulation. Activation of vascular p66Shc and increased expression of Nox1 and collagen I were prevented by CA in SHRSP. Nox1 expression was increased in aldosterone-stimulated WKY VSMCs, an effect that was amplified in SHRSP VSMCs (5.2vs9.9 fold-increase). ML171 prevented aldosterone-induced VSMC Nox1-ROS production. Aldosterone increased vascular expression of fibronectin and PAI-1 in wild-type mice but not in Nox1-knockout mice. Our findings suggest that aldosterone, which is increased in SHRSP, induces vascular damage through MR-Nox1-p66Shc-mediated processes that modulate pro-fibrotic and pro-inflammatory signaling pathways. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The Renin-Angiotensin-Aldosterone System in Vascular Inflammation and Remodeling

PubMed Central

Pacurari, Maricica; Kafoury, Ramzi; Tchounwou, Paul B.; Ndebele, Kenneth

2014-01-01

The RAAS through its physiological effectors plays a key role in promoting and maintaining inflammation. Inflammation is an important mechanism in the development and progression of CVD such as hypertension and atherosclerosis. In addition to its main role in regulating blood pressure and its role in hypertension, RAAS has proinflammatory and profibrotic effects at cellular and molecular levels. Blocking RAAS provides beneficial effects for the treatment of cardiovascular and renal diseases. Evidence shows that inhibition of RAAS positively influences vascular remodeling thus improving CVD outcomes. The beneficial vascular effects of RAAS inhibition are likely due to decreasing vascular inflammation, oxidative stress, endothelial dysfunction, and positive effects on regeneration of endothelial progenitor cells. Inflammatory factors such as ICAM-1, VCAM-1, TNFα, IL-6, and CRP have key roles in mediating vascular inflammation and blocking RAAS negatively modulates the levels of these inflammatory molecules. Some of these inflammatory markers are clinically associated with CVD events. More studies are required to establish long-term effects of RAAS inhibition on vascular inflammation, vascular cells regeneration, and CVD clinical outcomes. This review presents important information on RAAS's role on vascular inflammation, vascular cells responses to RAAS, and inhibition of RAAS signaling in the context of vascular inflammation, vascular remodeling, and vascular inflammation-associated CVD. Nevertheless, the review also equates the need to rethink and rediscover new RAAS inhibitors. PMID:24804145

Anti-inflammatory effect of low-level laser and light-emitting diode in zymosan-induced arthritis.

PubMed

de Morais, Núbia Cristina Rodrigues; Barbosa, Ana Maria; Vale, Mariana Lima; Villaverde, Antonio Balbin; de Lima, Carlos José; Cogo, José Carlos; Zamuner, Stella Regina

2010-04-01

The aim of this work was to investigate the effect of low-level laser therapy (LLLT) and light-emitting diode (LED) on formation of edema, increase in vascular permeability, and articular joint hyperalgesia in zymosan-induced arthritis. It has been suggested that low-level laser and LED irradiation can modulate inflammatory processes. Arthritis was induced in male Wistar rats (250-280 g) by intra-articular injection of zymosan (1 mg in 50 microL of a sterile saline solution) into one rear knee joint. Animals were irradiated immediately, 1 h, and 2 h after zymosan administration with a semiconductor laser (685 nm and 830 nm) and an LED at 628 nm, with the same dose (2.5 J/cm(2)) for laser and LED. In the positive control group, animals were injected with the anti-inflammatory drug dexamethasone 1 h prior to the zymosan administration. Edema was measured by the wet/dry weight difference of the articular tissue, the increase in vascular permeability was assessed by the extravasation of Evans blue dye, and joint hyperalgesia was measured using the rat knee-joint articular incapacitation test. Irradiation with 685 nm and 830 nm laser wavelengths significantly inhibited edema formation, vascular permeability, and hyperalgesia. Laser irradiation, averaged over the two wavelengths, reduced the vascular permeability by 24%, edema formation by 23%, and articular incapacitation by 59%. Treatment with LED (628 nm), with the same fluence as the laser, had no effect in zymosan-induced arthritis. LLLT reduces inflammatory signs more effectively than LED irradiation with similar irradiation times (100 sec), average outputs (20 mW), and energy doses (2 J) in an animal model of zymosan-induced arthritis. The anti-inflammatory effects of LLLT appear to be a class effect, which is not wavelength specific in the red and infrared parts of the optical spectrum.

Polymer-Based Therapeutics: Nanoassemblies and Nanoparticles for Management of Atherosclerosis

PubMed Central

Lewis, Daniel R.; Kamisoglu, Kubra; York, Adam; Moghe, Prabhas V.

2012-01-01

Coronary arterial disease, one of the leading causes of adult mortality, is triggered by atherosclerosis. A disease with complex etiology, atherosclerosis results from the progressive long-term combination of atherogenesis, the accumulation of modified lipoproteins within blood vessel walls, along with vascular and systemic inflammatory processes. The management of atherosclerosis is challenged by the localized flare-up of several multipronged signaling interactions between activated monocytes, atherogenic macrophages and inflamed or dysfunctional endothelial cells. A new generation of approaches is now emerging founded on multifocal, targeted therapies that seek to reverse or ameliorate the athero-inflammatory cascade within the vascular intima. This article reviews the various classes and primary examples of bioactive configurations of nanoscale assemblies. Of specific interest are polymer-based or polymer-lipid micellar assemblies designed as multimodal receptor-targeted blockers or drug carriers whose activity can be tuned by variations in polymer hydrophobicity, charge, and architecture. Also reviewed are emerging reports on multifunctional nanoassemblies and nanoparticles for improved circulation and enhanced targeting to athero-inflammatory lesions and atherosclerotic plaques. PMID:21523920

Synchrotron microbeam irradiation induces neutrophil infiltration, thrombocyte attachment and selective vascular damage in vivo.

PubMed

Brönnimann, Daniel; Bouchet, Audrey; Schneider, Christoph; Potez, Marine; Serduc, Raphaël; Bräuer-Krisch, Elke; Graber, Werner; von Gunten, Stephan; Laissue, Jean Albert; Djonov, Valentin

2016-09-19

Our goal was the visualizing the vascular damage and acute inflammatory response to micro- and minibeam irradiation in vivo. Microbeam (MRT) and minibeam radiation therapies (MBRT) are tumor treatment approaches of potential clinical relevance, both consisting of parallel X-ray beams and allowing the delivery of thousands of Grays within tumors. We compared the effects of microbeams (25-100 μm wide) and minibeams (200-800 μm wide) on vasculature, inflammation and surrounding tissue changes during zebrafish caudal fin regeneration in vivo. Microbeam irradiation triggered an acute inflammatory response restricted to the regenerating tissue. Six hours post irradiation (6 hpi), it was infiltrated by neutrophils and fli1a(+) thrombocytes adhered to the cell wall locally in the beam path. The mature tissue was not affected by microbeam irradiation. In contrast, minibeam irradiation efficiently damaged the immature tissue at 6 hpi and damaged both the mature and immature tissue at 48 hpi. We demonstrate that vascular damage, inflammatory processes and cellular toxicity depend on the beam width and the stage of tissue maturation. Minibeam irradiation did not differentiate between mature and immature tissue. In contrast, all irradiation-induced effects of the microbeams were restricted to the rapidly growing immature tissue, indicating that microbeam irradiation could be a promising tumor treatment tool.

VLA-4 antagonists: potent inhibitors of lymphocyte migration.

PubMed

Yang, Ginger X; Hagmann, William K

2003-05-01

Circulating lymphocytes normally migrate through extravascular spaces in relatively low numbers as important members of the immunosurveillance process. That is until signals are received by endothelial cells that there is an underlying infection or inflammatory condition. These vascular surface cells in turn overexpress and present ligands to circulating lymphocyte adhesion molecules. Upon encountering this higher density of ligands, lymphocytes, which had been leisurely rolling along the vascular surface, now become more firmly attached, change shape, and migrate through tight junctions to the sites of infection or inflammation. If the initiating events are not resolved and the condition becomes chronic, there can be a sustained extravasation of lymphocytes that can exacerbate the inflammatory condition, which in turn will continue to recruit more inflammatory cells resulting in unwanted tissue destruction. It is for the attenuation of this cycle of sustained inflammatory cell recruitment that very late activating antigen-4 (VLA-4) antagonists are being developed. Most lymphocytes, except neutrophils, express VLA-4 on their surface and they interact with endothelial vascular cell adhesion molecule-1 (VCAM-1). It is this interaction that VLA-4 antagonists are intended to disrupt, thus, putting an end to the cycle of chronic inflammation, which is the hallmark of many diseases. This review will provide an update of VLA-4 antagonists that have appeared since early 2001 and will discuss some of the issues, both positive and negative, that may be encountered in their development. Copyright 2003 Wiley Periodicals, Inc.

Platelets as Cellular Effectors of Inflammation in Vascular Diseases

PubMed Central

Rondina, Matthew T.; Weyrich, Andrew S.; Zimmerman, Guy A.

2013-01-01

Platelets are chief effector cells in hemostasis. In addition, they are multifaceted inflammatory cells with functions that span the continuum from innate immune responses to adaptive immunity. Activated platelets have key “thromboinflammatory” activities in a variety of vascular disorders and vasculopathies. Recently-identified inflammatory and immune activities provide insights into the biology of these versatile blood cells that are directly relevant to human vascular diseases. PMID:23704217

Strychnine inhibits inflammatory angiogenesis in mice via down regulation of VEGF, TNF-α and TGF-β.

PubMed

Saraswati, Sarita; Agarwal, S S

2013-05-01

Strychnine is known to possess anti-inflammatory and antitumour activity, but its roles in tumour angiogenesis, the key step involved in tumour growth and metastasis, and the involved molecular mechanism are still unknown. We aimed to investigate the effects of strychnine on key components of inflammatory angiogenesis in the murine cannulated sponge implant angiogenesis model. Polyester-polyurethane sponges, used as a framework for fibrovascular tissue growth, were implanted in Swiss albino mice and strychnine (0.25, and 0.5 mg/kg/day) was given through installed cannulas for 9 days. The implants collected at day 9 postimplantation were processed for the assessment of haemoglobin (Hb), myeloperoxidase (MPO), N-acetylglucosaminidase (NAG) and collagen used as indexes for angiogenesis, neutrophil and macrophage accumulation and extracellular matrix deposition, respectively. Relevant inflammatory, angiogenic and fibrogenic cytokines were also determined. Strychnine treatment attenuated the main components of the fibrovascular tissue, wet weight, vascularization (Hb content), macrophage recruitment (NAG activity), collagen deposition and the levels of vascular endothelial growth factor (VEGF), tumour necrosis factor (TNF)-α and transforming growth factor (TGF-β). A regulatory function of strychnine on multiple parameters of main components of inflammatory angiogenesis has been revealed giving insight into the potential therapeutic underlying the actions of strychnine. Copyright © 2013 Elsevier Inc. All rights reserved.

Monocyte Chemoattractant Protein-1 in the choroid plexus: a potential link between vascular pro-inflammatory mediators and the CNS during peripheral tissue inflammation

PubMed Central

Mitchell, K.; Yang, H.-Y. T.; Berk, J. D.; Tran, J. H.; Iadarola, M. J.

2009-01-01

During peripheral tissue inflammation, inflammatory processes in the CNS can be initiated by blood-borne pro-inflammatory mediators. The choroid plexus, the site of CSF production, is a highly specialized interface between the vascular system and CNS, and thus, this structure may be an important element in communication between the vascular compartment and the CNS during peripheral tissue inflammation. We investigated the potential participation of the choroid plexus in this process during peripheral tissue inflammation by examining expression of the SCYA2 gene which codes for monocyte chemoattractant protein-1 (MCP-1). MCP-1 protein was previously reported to be induced in a variety of cells during peripheral tissue inflammation. In the basal state, SCYA2 is highly expressed in the choroid plexus as compared to other CNS tissues. During hind paw inflammation, SCYA2 expression was significantly elevated in choroid plexus, whereas it remained unchanged in a variety of brain regions. The SCYA2-expressing cells were strongly associated with the choroid plexus as vascular depletion of blood cells by whole-body saline flush did not significantly alter SCYA2 expression in the choroid plexus. In situ hybridization suggested that the SCYA2-expressing cells were localized to the choroid plexus stroma. To elucidate potential molecular mechanisms of SCYA2 increase, we examined genes in the NF-κβ signaling cascade including TNF-α, IL-1β and IκBα in choroid tissue. Given that we also detected increased levels of MCP-1 protein by ELISA, we sought to identify potential downstream targets of MCP-1 and observed altered expression levels of mRNAs encoding tight junction proteins TJP2 and claudin 5. Finally, we detected a substantial up-regulation of the transcript encoding E-selectin, a molecule which could participate in leukocyte recruitment to the choroid plexus along with MCP-1. Together, these results suggest that profound changes occur in the choroid plexus during peripheral tissue inflammation, likely initiated by blood-borne inflammatory mediators, which may modify events in CNS. PMID:19032979

Vascular and Inflammatory Factors in the Pathophysiology of Blast-Induced Brain Injury

PubMed Central

Elder, Gregory A.; Gama Sosa, Miguel A.; De Gasperi, Rita; Stone, James Radford; Dickstein, Dara L.; Haghighi, Fatemeh; Hof, Patrick R.; Ahlers, Stephen T.

2015-01-01

Blast-related traumatic brain injury (TBI) has received much recent attention because of its frequency in the conflicts in Iraq and Afghanistan. This renewed interest has led to a rapid expansion of clinical and animal studies related to blast. In humans, high-level blast exposure is associated with a prominent hemorrhagic component. In animal models, blast exerts a variety of effects on the nervous system including vascular and inflammatory effects that can be seen with even low-level blast exposures which produce minimal or no neuronal pathology. Acutely, blast exposure in animals causes prominent vasospasm and decreased cerebral blood flow along with blood-brain barrier breakdown and increased vascular permeability. Besides direct effects on the central nervous system, evidence supports a role for a thoracically mediated effect of blast; whereby, pressure waves transmitted through the systemic circulation damage the brain. Chronically, a vascular pathology has been observed that is associated with alterations of the vascular extracellular matrix. Sustained microglial and astroglial reactions occur after blast exposure. Markers of a central and peripheral inflammatory response are found for sustained periods after blast injury and include elevation of inflammatory cytokines and other inflammatory mediators. At low levels of blast exposure, a microvascular pathology has been observed in the presence of an otherwise normal brain parenchyma, suggesting that the vasculature may be selectively vulnerable to blast injury. Chronic immune activation in brain following vascular injury may lead to neurobehavioral changes in the absence of direct neuronal pathology. Strategies aimed at preventing or reversing vascular damage or modulating the immune response may improve the chronic neuropsychiatric symptoms associated with blast-related TBI. PMID:25852632

Pathogenesis of vascular leak in dengue virus infection.

PubMed

Malavige, Gathsaurie Neelika; Ogg, Graham S

2017-07-01

Endothelial dysfunction leading to vascular leak is the hallmark of severe dengue. Vascular leak typically becomes clinically evident 3-6 days after the onset of illness, which is known as the critical phase. This critical phase follows the period of peak viraemia, and lasts for 24-48 hr and usually shows rapid and complete reversal, suggesting that it is likely to occur as a result of inflammatory mediators, rather than infection of the endothelium. Cytokines such as tumour necrosis factor-α, which are known to be elevated in the critical phase of dengue, are likely to be contributing factors. Dengue NS1, a soluble viral protein, has also been shown to disrupt the endothelial glycocalyx and thus contribute to vascular leak, although there appears to be a discordance between the timing of NS1 antigenaemia and occurrence of vascular leak. In addition, many inflammatory lipid mediators are elevated in acute dengue viral infection such as platelet activating factor (PAF) and leukotrienes. Furthermore, many other inflammatory mediators such as vascular endothelial growth factor and angiopoietin-2 have been shown to be elevated in patients with dengue haemorrhagic fever, exerting their action in part by inducing the activity of phospholipases, which have diverse inflammatory effects including generation of PAF. Platelets have also been shown to significantly contribute to endothelial dysfunction by production of interleukin-1β through activation of the NLRP3 inflammasome and also by inducing production of inflammatory cytokines by monocytes. Drugs that block down-stream immunological mediator pathways such as PAF may also be beneficial in the treatment of severe disease. © 2017 John Wiley & Sons Ltd.

Suppression of complement regulatory protein C1 inhibitor in vascular endothelial activation by inhibiting vascular cell adhesion molecule-1 action

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Haimou; Qin, Gangjian; Liang, Gang

Increased expression of adhesion molecules by activated endothelium is a critical feature of vascular inflammation associated with the several diseases such as endotoxin shock and sepsis/septic shock. Our data demonstrated complement regulatory protein C1 inhibitor (C1INH) prevents endothelial cell injury. We hypothesized that C1INH has the ability of an anti-endothelial activation associated with suppression of expression of adhesion molecule(s). C1INH blocked leukocyte adhesion to endothelial cell monolayer in both static assay and flow conditions. In inflammatory condition, C1INH reduced vascular cell adhesion molecule (VCAM-1) expression associated with its cytoplasmic mRNA destabilization and nuclear transcription level. Studies exploring the underlying mechanismmore » of C1INH-mediated suppression in VCAM-1 expression were related to reduction of NF-{kappa}B activation and nuclear translocation in an I{kappa}B{alpha}-dependent manner. The inhibitory effects were associated with reduction of inhibitor I{kappa}B kinase activity and stabilization of the NF-{kappa}B inhibitor I{kappa}B. These findings indicate a novel role for C1INH in inhibition of vascular endothelial activation. These observations could provide the basis for new therapeutic application of C1INH to target inflammatory processes in different pathologic situations.« less

Diabetes mellitus: The linkage between oxidative stress, inflammation, hypercoagulability and vascular complications.

PubMed

Domingueti, Caroline Pereira; Dusse, Luci Maria Sant'Ana; Carvalho, Maria das Graças; de Sousa, Lirlândia Pires; Gomes, Karina Braga; Fernandes, Ana Paula

2016-01-01

Vascular complications are the leading cause of morbidity and mortality among patients with type 1 and type 2 diabetes mellitus. These vascular abnormalities result of a chronic hyperglycemic state, which leads to an increase in oxidative stress and inflammatory responses. This review addresses the relationships among endothelial dysfunction, hypercoagulability and inflammation and their biomarkers in the development of vascular complications in type 1 and type 2 diabetes. Inflammation, endothelial dysfunction, and hypercoagulability are correlated to each other, playing an important role in the development of vascular complications in diabetic patients. Moreover, it has been observed that several endothelial, inflammatory and pro-coagulant biomarkers, such as VWF, IL-6, TNF-α, D-dimer and PAI-1, are increased in diabetic patients who have microvascular and macrovascular complications, including nephropathy or cardiovascular disease. It is promising the clinical and laboratory use of endothelial, inflammatory and pro-coagulant biomarkers for predicting the risk of cardiovascular and renal complications in diabetic patients and for monitoring these patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Dengue virus NS1 cytokine-independent vascular leak is dependent on endothelial glycocalyx components

PubMed Central

Beatty, P. Robert

2017-01-01

Dengue virus (DENV) is the most prevalent, medically important mosquito-borne virus. Disease ranges from uncomplicated dengue to life-threatening disease, characterized by endothelial dysfunction and vascular leakage. Previously, we demonstrated that DENV nonstructural protein 1 (NS1) induces endothelial hyperpermeability in a systemic mouse model and human pulmonary endothelial cells, where NS1 disrupts the endothelial glycocalyx-like layer. NS1 also triggers release of inflammatory cytokines from PBMCs via TLR4. Here, we examined the relative contributions of inflammatory mediators and endothelial cell-intrinsic pathways. In vivo, we demonstrated that DENV NS1 but not the closely-related West Nile virus NS1 triggers localized vascular leak in the dorsal dermis of wild-type C57BL/6 mice. In vitro, we showed that human dermal endothelial cells exposed to DENV NS1 do not produce inflammatory cytokines (TNF-α, IL-6, IL-8) and that blocking these cytokines does not affect DENV NS1-induced endothelial hyperpermeability. Further, we demonstrated that DENV NS1 induces vascular leak in TLR4- or TNF-α receptor-deficient mice at similar levels to wild-type animals. Finally, we blocked DENV NS1-induced vascular leak in vivo using inhibitors targeting molecules involved in glycocalyx disruption. Taken together, these data indicate that DENV NS1-induced endothelial cell-intrinsic vascular leak is independent of inflammatory cytokines but dependent on endothelial glycocalyx components. PMID:29121099

A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Shuai; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208; Lv, Jiaju

2012-03-30

Highlights: Black-Right-Pointing-Pointer Cyld deficiency suppresses pro-inflammatory phenotypic switch of VSMCs. Black-Right-Pointing-Pointer Cyld deficiency inhibits MAPK rather than NF-kB activity in inflamed VSMCs. Black-Right-Pointing-Pointer CYLD is up-regulated in the coronary artery with neointimal hyperplasia. -- Abstract: CYLD, a deubiquitinating enzyme (DUB), is a critical regulator of diverse cellular processes, ranging from proliferation and differentiation to inflammatory responses, via regulating multiple key signaling cascades such as nuclear factor kappa B (NF-{kappa}B) pathway. CYLD has been shown to inhibit vascular lesion formation presumably through suppressing NF-{kappa}B activity in vascular cells. However, herein we report a novel role of CYLD in mediating pro-inflammatory responsesmore » in vascular smooth muscle cells (VSMCs) via a mechanism independent of NF-{kappa}B activity. Adenoviral knockdown of Cyld inhibited basal and the tumor necrosis factor alpha (TNF{alpha})-induced mRNA expression of pro-inflammatory cytokines including monocyte chemotactic protein-1 (Mcp-1), intercellular adhesion molecule (Icam-1) and interleukin-6 (Il-6) in rat adult aortic SMCs (RASMCs). The CYLD deficiency led to increases in the basal NF-{kappa}B transcriptional activity in RASMCs; however, did not affect the TNF{alpha}-induced NF-{kappa}B activity. Intriguingly, the TNF{alpha}-induced I{kappa}B phosphorylation was enhanced in the CYLD deficient RASMCs. While knocking down of Cyld decreased slightly the basal expression levels of I{kappa}B{alpha} and I{kappa}B{beta} proteins, it did not alter the kinetics of TNF{alpha}-induced I{kappa}B protein degradation in RASMCs. These results indicate that CYLD suppresses the basal NF-{kappa}B activity and TNF{alpha}-induced I{kappa}B kinase activation without affecting TNF{alpha}-induced NF-{kappa}B activity in VSMCs. In addition, knocking down of Cyld suppressed TNF{alpha}-induced activation of mitogen activated protein kinases (MAPKs) including extracellular signal-activated kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 in RASMCs. TNF{alpha}-induced RASMC migration and monocyte adhesion to RASMCs were inhibited by the Cyld knockdown. Finally, immunochemical staining revealed a dramatic augment of CYLD expression in the injured coronary artery with neointimal hyperplasia. Taken together, our results uncover an unexpected role of CYLD in promoting inflammatory responses in VSMCs via a mechanism involving MAPK activation but independent of NF-{kappa}B activity, contributing to the pathogenesis of vascular disease.« less

H2S dependent and independent anti-inflammatory activity of zofenoprilat in cells of the vascular wall.

PubMed

Monti, Martina; Terzuoli, Erika; Ziche, Marina; Morbidelli, Lucia

2016-11-01

Cardiovascular diseases as atherosclerosis are associated to an inflammatory state of the vessel wall which is accompanied by endothelial dysfunction, and adherence and activation of circulating inflammatory cells. Hydrogen sulfide, a novel cardiovascular protective gaseous mediator, has been reported to exert anti-inflammatory activity. We have recently demonstrated that the SH containing ACE inhibitor zofenoprilat, the active metabolite of zofenopril, controls the angiogenic features of vascular endothelium through H 2 S enzymatic production by cystathionine gamma lyase (CSE). Based on H 2 S donor/generator property of zofenoprilat, the objective of this study was to evaluate whether zofenoprilat exerts anti-inflammatory activity in vascular cells through its ability to increase H 2 S availability. Here we found that zofenoprilat, in a CSE/H 2 S-mediated manner, abolished all the inflammatory features induced by interlukin-1beta (IL-1β) in human umbilical vein endothelial cells (HUVEC), especially the NF-κB/cyclooxygenase-2 (COX-2)/prostanoid biochemical pathway. The pre-incubation with zofenoprilat/CSE dependent H 2 S prevented IL-1β induced paracellular hyperpermeability through the control of expression and localization of cell-cell junctional markers ZO-1 and VE-cadherin. Moreover, zofenoprilat/CSE dependent H 2 S reduced the expression of the endothelial markers CD40 and CD31, involved in the recruitment of circulating mononuclear cells and platelets. Interestingly, this anti-inflammatory activity was also confirmed in vascular smooth muscle cells and fibroblasts as zofenoprilat reduced, in both cell lines, proliferation, migration and COX-2 expression induced by IL-1β, but independently from the SH moiety and H 2 S availability. These in vitro data document the anti-inflammatory activity of zofenoprilat on vascular cells, reinforcing the cardiovascular protective effect of this multitasking drug. Copyright © 2016 Elsevier Ltd. All rights reserved.

Spatially localized recruitment of anti-inflammatory monocytes by SDF-1α-releasing hydrogels enhances microvascular network remodeling.

PubMed

Krieger, J R; Ogle, M E; McFaline-Figueroa, J; Segar, C E; Temenoff, J S; Botchwey, E A

2016-01-01

Tissue repair processes are characterized by the biphasic recruitment of distinct subpopulations of blood monocytes, including classical ("inflammatory") monocytes (IMs, Ly6C(hi)Gr1(+)CX3CR1(lo)) and non-classical anti-inflammatory monocytes (AMs, Ly6C(lo)Gr1(-)CX3CR1(hi)). Drug-eluting biomaterial implants can be used to tune the endogenous repair process by the preferential recruitment of pro-regenerative cells. To enhance recruitment of AMs during inflammatory injury, a novel N-desulfated heparin-containing poly(ethylene glycol) diacrylate (PEG-DA) hydrogel was engineered to deliver exogenous stromal derived factor-1α (SDF-1α), utilizing the natural capacity of heparin to sequester and release growth factors. SDF-1α released from the hydrogels maintained its bioactivity and stimulated chemotaxis of bone marrow cells in vitro. Intravital microscopy and flow cytometry demonstrated that SDF-1α hydrogels implanted in a murine dorsal skinfold window chamber promoted spatially-localized recruitment of AMs relative to unloaded internal control hydrogels. SDF-1α delivery stimulated arteriolar remodeling that was correlated with AM enrichment in the injury niche. SDF-1α, but not unloaded control hydrogels, supported sustained arteriogenesis and microvascular network growth through 7 days. The recruitment of AMs correlated with parameters of vascular remodeling suggesting that tuning the innate immune response by biomaterial SDF-1α release is a promising strategy for promoting vascular remodeling in a spatially controlled manner. Copyright © 2015 Elsevier Ltd. All rights reserved.

Guinea-pig interpubic joint (symphysis pubica) relaxation at parturition: Underlying cellular processes that resemble an inflammatory response

PubMed Central

Rodríguez, Horacio A; Ortega, Hugo H; Ramos, Jorge G; Muñoz-de-Toro, Mónica; Luque, Enrique H

2003-01-01

Background At term, cervical ripening in coordination with uterine contractions becomes a prerequisite for a normal vaginal delivery. Currently, cervical ripening is considered to occur independently from uterine contractions. Many evidences suggest that cervical ripening resembles an inflammatory process. Comparatively little attention has been paid to the increased flexibility of the pelvic symphysis that occurs in many species to enable safe delivery. The aim of this study was to investigate whether the guinea-pig interpubic joint relaxation process observed during late pregnancy and parturition resembles an inflammatory process. Methods Samples of pubic symphysis were taken from pregnant guinea-pigs sacrificed along gestation, parturition and postpartum. Serial sections of paraffin-embedded tissues were used to measure the interpubic distance on digitalized images, stained with Giemsa to quantify leukocyte infiltration and to describe the vascular area changes, or studied by the picrosirius-polarization method to evaluate collagen remodeling. P4 and E2 serum levels were measured by a sequential immunometric assay. Results Data showed that the pubic relaxation is associated with an increase in collagen remodeling. In addition, a positive correlation between E2 serum levels and the increase in the interpubic distance was found. On the other hand, a leukocyte infiltration in the interpubic tissue around parturition was described, with the presence of almost all inflammatory cells types. At the same time, histological images show an increase in vascular area (angiogenesis). Eosinophils reached their highest level immediately before parturition; whereas for the neutrophilic and mononuclear infiltration higher values were recorded one day after parturition. Correlation analysis showed that eosinophils and mononuclear cells were positively correlated with E2 levels, but only eosinophilic infiltration was associated with collagen remodeling. Additionally, we observed typical histological images of dissolution of the connective tissue matrix around eosinophils. Conclusion The present study shows that a timely regulated influx of infiltrating leukocytes is associated with an extensive collagen remodeling process that allows the pubic separation for a normal delivery in guinea-pig. Thus, the findings in this study support the hypothesis that the guinea-pig pubic symphyseal relaxation at parturition resembles an inflammatory process. PMID:14633278

Cobalt chloride attenuates hypobaric hypoxia induced vascular leakage in rat brain: Molecular mechanisms of action of cobalt chloride

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kalpana, S.; Dhananjay, S.; Anju, B.

2008-09-15

This study reports the efficacy of cobalt preconditioning in preventing hypobaric hypoxia induced vascular leakage (an indicator of cerebral edema) using male Sprague-Dawley rats as model system. Exposure of animals to hypobaric hypoxia led to a significant increase in vascular leakage, reactive oxygen species (ROS), nitric oxide (NO), and vascular endothelial growth factor (VEGF) levels. There was a marked increase in Nuclear Factor {kappa}B (NF{kappa}B) DNA binding activity and levels of pro-inflammatory cytokines such as Monocyte chemoattractant protein (MCP-1), Interferon-{gamma} (IFN-{gamma}), Interleukin-1 (IL-1), and Tumor Necrosis Factor-{alpha} (TNF-{alpha}) and cell adhesion molecules such as Vascular Cell Adhesion Molecule-1 (VCAM-1), andmore » P-selectin. Chemical preconditioning by cobalt for 7 days (12.5 mg Co/kg b.w., oral) significantly attenuated cerebral vascular leakage and the expression of inflammatory mediators induced by hypoxia. Administration of NF{kappa}B inhibitor, curcumin (50 mg/kg b.w.; i.p.) appreciably inhibited hypoxia induced vascular leakage indicating the involvement of NF{kappa}B in causing vascular leakage. Interestingly, cobalt when administered at 12.5 mg Co/kg b.w. (i.p.), 1 h before hypoxia could not prevent the vascular leakage indicating that cobalt per se did not have an effect on NF{kappa}B. The lower levels of NF{kappa}B observed in the brains of cobalt administered animals might be due to higher levels of antioxidant and anti-inflammatory proteins (hemeoxygenase-1 and metallothionein). To conclude cobalt preconditioning inhibited hypobaric hypoxia induced cerebral vascular leakage by lowering NF{kappa}B DNA binding activity and its regulated pro-inflammatory mediators. This is contemplated to be mediated by cobalt induced reduction in ROS/NO and increase in HO-1 and MT.« less

Inhibition of p110δ PI3K prevents inflammatory response and restenosis after artery injury

PubMed Central

Rinaldi, Barbara; Oliviero, Maria Antonietta; Donniacuo, Maria; Monti, Maria Gaia; Boscaino, Amedeo; Marino, Irene; Friedman, Lori; Rossi, Francesco; Vanhaesebroeck, Bart; Migliaccio, Antimo

2017-01-01

Inflammatory cells play key roles in restenosis upon vascular surgical procedures such as bypass grafts, angioplasty and stent deployment but the molecular mechanisms by which these cells affect restenosis remain unclear. The p110δ isoform of phosphoinositide 3-kinase (PI3K) is mainly expressed in white blood cells. Here, we have investigated whether p110δ PI3K is involved in the pathogenesis of restenosis in a mouse model of carotid injury, which mimics the damage following arterial grafts. We used mice in which p110δ kinase activity has been disabled by a knockin (KI) point mutation in its ATP-binding site (p110δD910A/D910A PI3K mice). Wild-type (WT) and p110δD910A/D910A mice were subjected to longitudinal carotid injury. At 14 and 30 days after carotid injury, mice with inactive p110δ showed strongly decreased infiltration of inflammatory cells (including T lymphocytes and macrophages) and vascular smooth muscle cells (VSMCs), compared with WT mice. Likewise, PI-3065, a p110δ-selective PI3K inhibitor, almost completely prevented restenosis after artery injury. Our data showed that p110δ PI3K plays a main role in promoting neointimal thickening and inflammatory processes during vascular stenosis, with its inhibition providing significant reduction in restenosis following carotid injury. p110δ-selective inhibitors, recently approved for the treatment of human B-cell malignancies, therefore, present a new therapeutic opportunity to prevent the restenosis upon artery injury. PMID:28851839

Dengue Virus Infection Differentially Regulates Endothelial Barrier Function over Time through Type I Interferon Effects

PubMed Central

Liu, Ping; Woda, Marcia; Ennis, Francis A.; Libraty, Daniel H.

2013-01-01

Background The morbidity and mortality resulting from dengue hemorrhagic fever (DHF) are largely caused by endothelial barrier dysfunction and a unique vascular leakage syndrome. The mechanisms that lead to the location and timing of vascular leakage in DHF are poorly understood. We hypothesized that direct viral effects on endothelial responsiveness to inflammatory and angiogenesis mediators can explain the DHF vascular leakage syndrome. Methods We used an in vitro model of human endothelium to study the combined effects of dengue virus (DENV) type 2 (DENV2) infection and inflammatory mediators on paracellular macromolecule permeability over time. Results Over the initial 72 h after infection, DENV2 suppressed tumor necrosis factor (TNF)–α–mediated hyperpermeability in human umbilical vein endothelial cell (HUVEC) monolayers. This suppressive effect was mediated by type I interferon (IFN). By 1 week, TNF-α stimulation of DENV2-infected HUVECs synergistically increased cell cycling, angiogenic changes, and macromolecule permeability. This late effect could be prevented by the addition of exogenous type I IFN. Conclusions DENV infection of primary human endothelial cells differentially modulates TNF-α–driven angiogenesis and hyperpermeability over time. Type I IFN plays a central role in this process. Our findings suggest a rational model for the DHF vascular leakage syndrome. PMID:19530939

Effects of inhalational anaesthetics in experimental allergic asthma.

PubMed

Burburan, S M; Silva, J D; Abreu, S C; Samary, C S; Guimarães, I H L; Xisto, D G; Morales, M M; Rocco, P R M

2014-06-01

We evaluated whether isoflurane, halothane and sevoflurane attenuate the inflammatory response and improve lung morphofunction in experimental asthma. Fifty-six BALB/c mice were sensitised and challenged with ovalbumin and anaesthetised with isoflurane, halothane, sevoflurane or pentobarbital sodium for one hour. Lung mechanics and histology were evaluated. Gene expression of pro-inflammatory (tumour necrosis factor-α), pro-fibrogenic (transforming growth factor-β) and pro-angiogenic (vascular endothelial growth factor) mediators, as well as oxidative process modulators, were analysed. These modulators included nuclear factor erythroid-2 related factor 2, sirtuin, catalase and glutathione peroxidase. Isoflurane, halothane and sevoflurane reduced airway resistance, static lung elastance and atelectasis when compared with pentobarbital sodium. Sevoflurane minimised bronchoconstriction and cell infiltration, and decreased tumour necrosis factor-α, transforming growth factor-β, vascular endothelial growth factor, sirtuin, catalase and glutathione peroxidase, while increasing nuclear factor erythroid-2-related factor 2 expression. Sevoflurane down-regulated inflammatory, fibrogenic and angiogenic mediators, and modulated oxidant-antioxidant imbalance, improving lung function in this model of asthma. © 2014 The Association of Anaesthetists of Great Britain and Ireland.

Synchrotron microbeam irradiation induces neutrophil infiltration, thrombocyte attachment and selective vascular damage in vivo

PubMed Central

Brönnimann, Daniel; Bouchet, Audrey; Schneider, Christoph; Potez, Marine; Serduc, Raphaël; Bräuer-Krisch, Elke; Graber, Werner; von Gunten, Stephan; Laissue, Jean Albert; Djonov, Valentin

2016-01-01

Our goal was the visualizing the vascular damage and acute inflammatory response to micro- and minibeam irradiation in vivo. Microbeam (MRT) and minibeam radiation therapies (MBRT) are tumor treatment approaches of potential clinical relevance, both consisting of parallel X-ray beams and allowing the delivery of thousands of Grays within tumors. We compared the effects of microbeams (25–100 μm wide) and minibeams (200–800 μm wide) on vasculature, inflammation and surrounding tissue changes during zebrafish caudal fin regeneration in vivo. Microbeam irradiation triggered an acute inflammatory response restricted to the regenerating tissue. Six hours post irradiation (6 hpi), it was infiltrated by neutrophils and fli1a+ thrombocytes adhered to the cell wall locally in the beam path. The mature tissue was not affected by microbeam irradiation. In contrast, minibeam irradiation efficiently damaged the immature tissue at 6 hpi and damaged both the mature and immature tissue at 48 hpi. We demonstrate that vascular damage, inflammatory processes and cellular toxicity depend on the beam width and the stage of tissue maturation. Minibeam irradiation did not differentiate between mature and immature tissue. In contrast, all irradiation-induced effects of the microbeams were restricted to the rapidly growing immature tissue, indicating that microbeam irradiation could be a promising tumor treatment tool. PMID:27640676

Anti-inflammatory evaluation of the methanolic extract of Taraxacum officinale in LPS-stimulated human umbilical vein endothelial cells.

PubMed

Jeon, Daun; Kim, Seok Joong; Kim, Hong Seok

2017-11-29

Atherosclerosis is a chronic vascular inflammatory disease. Since even low-level endotoxemia constitutes a powerful and independent risk factor for the development of atherosclerosis, it is important to find therapies directed against the vascular effects of endotoxin to prevent atherosclerosis. Taraxacum officinale (TO) is used for medicinal purposes because of its choleretic, diuretic, antioxidative, anti-inflammatory, and anti-carcinogenic properties, but its anti-inflammatory effect on endothelial cells has not been established. We evaluated the anti-inflammatory activity of TO filtered methanol extracts in LPS-stimulated human umbilical vein endothelial cells (HUVECs) by monocyte adhesion and western blot assays. HUVECs were pretreated with 100 μg/ml TO for 1 h and then incubated with 1 μg/ml LPS for 24 h. The mRNA and protein expression levels of the targets (pro-inflammatory cytokines and adhesion molecules) were analyzed by real-time PCR and western blot assays. We also preformed HPLC analysis to identify the components of the TO methanol extract. The TO filtered methanol extracts dramatically inhibited LPS-induced endothelial cell-monocyte interactions by reducing vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1, and pro-inflammatory cytokine expression. TO suppressed the LPS-induced nuclear translocation of NF-κB, whereas it did not affect MAPK activation. Our findings demonstrated that methanol extracts of TO could attenuate LPS-induced endothelial cell activation by inhibiting the NF-κB pathway. These results indicate the potential clinical benefits and applications of TO for the prevention of vascular inflammation and atherosclerosis.

Autologous Bone Marrow Mesenchymal Stem Cells Improve the Quality and Stability of Vascularized Flap Surgery of Irradiated Skin in Pigs.

PubMed

Linard, Christine; Brachet, Michel; Strup-Perrot, Carine; L'homme, Bruno; Busson, Elodie; Squiban, Claire; Holler, Valerie; Bonneau, Michel; Lataillade, Jean-Jacques; Bey, Eric; Benderitter, Marc

2018-05-18

Cutaneous radiation syndrome has severe long-term health consequences. Because it causes an unpredictable course of inflammatory waves, conventional surgical treatment is ineffective and often leads to a fibronecrotic process. Data about the long-term stability of healed wounds, with neither inflammation nor resumption of fibrosis, are lacking. In this study, we investigated the effect of injections of local autologous bone marrow-derived mesenchymal stromal cells (BM-MSCs), combined with plastic surgery for skin necrosis, in a large-animal model. Three months after irradiation overexposure to the rump, minipigs were divided into three groups: one group treated by simple excision of the necrotic tissue, the second by vascularized-flap surgery, and the third by vascularized-flap surgery and local autologous BM-MSC injections. Three additional injections of the BM-MSCs were performed weekly for 3 weeks. The quality of cutaneous wound healing was examined 1 year post-treatment. The necrotic tissue excision induced a pathologic scar characterized by myofibroblasts, excessive collagen-1 deposits, and inadequate vascular density. The vascularized-flap surgery alone was accompanied by inadequate production of extracellular matrix (ECM) proteins (decorin, fibronectin); the low col1/col3 ratio, associated with persistent inflammatory nodules, and the loss of vascularization both attested to continued immaturity of the ECM. BM-MSC therapy combined with vascularized-flap surgery provided mature wound healing characterized by a col1/col3 ratio and decorin and fibronectin expression that were all similar to that of nonirradiated skin, with no inflammation, and vascular stability. In this preclinical model, vascularized flap surgery successfully and lastingly remodeled irradiated skin only when combined with BM-MSC therapy. Stem Cells Translational Medicine 2018. © 2018 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Txnip ablation reduces vascular smooth muscle cell inflammation and ameliorates atherosclerosis in apolipoprotein E knockout mice.

PubMed

Byon, Chang Hyun; Han, Tieyan; Wu, Judy; Hui, Simon T

2015-08-01

Inflammation of vascular smooth muscle cells (VSMC) is intimately linked to atherosclerosis and other vascular inflammatory disease. Thioredoxin interacting protein (Txnip) is a key regulator of cellular sulfhydryl redox and a mediator of inflammasome activation. The goals of the present study were to examine the impact of Txnip ablation on inflammatory response to oxidative stress in VSMC and to determine the effect of Txnip ablation on atherosclerosis in vivo. Using cultured VSMC, we showed that ablation of Txnip reduced cellular oxidative stress and increased protection from oxidative stress when challenged with oxidized phospholipids and hydrogen peroxide. Correspondingly, expression of inflammatory markers and adhesion molecules were diminished in both VSMC and macrophages from Txnip knockout mice. The blunted inflammatory response was associated with a decrease in NF-ĸB nuclear translocation. Loss of Txnip in VSMC also led to a dramatic reduction in macrophage adhesion to VSMC. In vivo data from Txnip-ApoE double knockout mice showed that Txnip ablation led to 49% reduction in atherosclerotic lesion in the aortic root and 71% reduction in the abdominal aorta, compared to control ApoE knockout mice. Our data show that Txnip plays an important role in oxidative inflammatory response and atherosclerotic lesion development in mice. The atheroprotective effect of Txnip ablation implicates that modulation of Txnip expression may serve as a potential target for intervention of atherosclerosis and inflammatory vascular disease. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

First Insights into Human Fingertip Regeneration by Echo-Doppler Imaging and Wound Microenvironment Assessment.

PubMed

Jafari, Paris; Muller, Camillo; Grognuz, Anthony; Applegate, Lee Ann; Raffoul, Wassim; di Summa, Pietro G; Durand, Sébastien

2017-05-13

Fingertip response to trauma represents a fascinating example of tissue regeneration. Regeneration derives from proliferative mesenchymal cells (blastema) that subsequently differentiate into soft and skeletal tissues. Clinically, conservative treatment of the amputated fingertip under occlusive dressing can shift the response to tissue loss from a wound repair process towards regeneration. When analyzing by Immunoassay the wound exudate from occlusive dressings, the concentrations of brain-derived neurotrophic factor (BDNF) and leukemia inhibitory factor (LIF) were higher in fingertip exudates than in burn wounds (used as controls for wound repair versus regeneration). Vascular endothelial growth factor A (VEGF-A) and platelet-derived growth factor (PDGF) were highly expressed in both samples in comparable levels. In our study, pro-inflammatory cytokines were relatively higher expressed in regenerative fingertips than in the burn wound exudates while chemokines were present in lower levels. Functional, vascular and mechanical properties of the regenerated fingertips were analyzed three months after trauma and the data were compared to the corresponding fingertip on the collateral uninjured side. While sensory recovery and morphology (pulp thickness and texture) were similar to uninjured sides, mechanical parameters (elasticity, vascularization) were increased in the regenerated fingertips. Further studies should be done to clarify the importance of inflammatory cells, immunity and growth factors in determining the outcome of the regenerative process and its influence on the clinical outcome.

First Insights into Human Fingertip Regeneration by Echo-Doppler Imaging and Wound Microenvironment Assessment

PubMed Central

Jafari, Paris; Muller, Camillo; Grognuz, Anthony; Applegate, Lee Ann; Raffoul, Wassim; di Summa, Pietro G.; Durand, Sébastien

2017-01-01

Fingertip response to trauma represents a fascinating example of tissue regeneration. Regeneration derives from proliferative mesenchymal cells (blastema) that subsequently differentiate into soft and skeletal tissues. Clinically, conservative treatment of the amputated fingertip under occlusive dressing can shift the response to tissue loss from a wound repair process towards regeneration. When analyzing by Immunoassay the wound exudate from occlusive dressings, the concentrations of brain-derived neurotrophic factor (BDNF) and leukemia inhibitory factor (LIF) were higher in fingertip exudates than in burn wounds (used as controls for wound repair versus regeneration). Vascular endothelial growth factor A (VEGF-A) and platelet-derived growth factor (PDGF) were highly expressed in both samples in comparable levels. In our study, pro-inflammatory cytokines were relatively higher expressed in regenerative fingertips than in the burn wound exudates while chemokines were present in lower levels. Functional, vascular and mechanical properties of the regenerated fingertips were analyzed three months after trauma and the data were compared to the corresponding fingertip on the collateral uninjured side. While sensory recovery and morphology (pulp thickness and texture) were similar to uninjured sides, mechanical parameters (elasticity, vascularization) were increased in the regenerated fingertips. Further studies should be done to clarify the importance of inflammatory cells, immunity and growth factors in determining the outcome of the regenerative process and its influence on the clinical outcome. PMID:28505080

Immunological and inflammatory mapping of vascularized composite allograft rejection processes in a rat model

PubMed Central

Friedman, Or; Carmel, Narin; Sela, Meirav; Abu Jabal, Ameen; Inbal, Amir; Ben Hamou, Moshe; Krelin, Yakov; Gur, Eyal

2017-01-01

Background Hand and face vascularized composite allotransplantation (VCA) is an evolving and challenging field with great opportunities. During VCA, massive surgical damage is inflicted on both donor and recipient tissues, which may contribute to the high VCA rejection rates. To segregate between the damage-induced and rejection phase of post-VCA responses, we compared responses occurring up to 5 days following syngeneic versus allogeneic vascularized groin flap transplantations, culminating in transplant acceptance or rejection, respectively. Methods The immune response elicited upon transplantation of a syngeneic versus allogeneic vascularized groin flap was compared at Post-operative days 2 or 5 by histology, immunohistochemistry and by broad-scope gene and protein analyses using quantitative real-time PCR and Multiplex respectively. Results Immune cell infiltration began at the donor-recipient interface and paralleled expression of a large group of wound healing-associated genes in both allografts and syngrafts. By day 5 post-transplantation, cell infiltration spread over the entire allograft but remained confined to the wound site in the syngraft. This shift correlated with upregulation of IL-18, INFg, CXCL9, 10 and 11, CCL2, CCL5, CX3CL1 and IL-10 in the allograft only, suggesting their role in the induction of the anti-alloantigen adaptive immune response. Conclusions High resemblance between the cues governing VCA and solid organ rejection was observed. Despite this high resemblance we describe also, for the first time, a damage induced inflammatory component in VCA rejection as immune cell infiltration into the graft initiated at the surgical damage site spreading to the entire allograft only at late stage rejection. We speculate that the highly inflammatory setting created by the unique surgical damage during VCA may enhance acute allograft rejection. PMID:28746417

Imaging of cerebrovascular pathology in animal models of Alzheimer's disease

PubMed Central

Klohs, Jan; Rudin, Markus; Shimshek, Derya R.; Beckmann, Nicolau

2014-01-01

In Alzheimer's disease (AD), vascular pathology may interact with neurodegeneration and thus aggravate cognitive decline. As the relationship between these two processes is poorly understood, research has been increasingly focused on understanding the link between cerebrovascular alterations and AD. This has at last been spurred by the engineering of transgenic animals, which display pathological features of AD and develop cerebral amyloid angiopathy to various degrees. Transgenic models are versatile for investigating the role of amyloid deposition and vascular dysfunction, and for evaluating novel therapeutic concepts. In addition, research has benefited from the development of novel imaging techniques, which are capable of characterizing vascular pathology in vivo. They provide vascular structural read-outs and have the ability to assess the functional consequences of vascular dysfunction as well as to visualize and monitor the molecular processes underlying these pathological alterations. This article focusses on recent in vivo small animal imaging studies addressing vascular aspects related to AD. With the technical advances of imaging modalities such as magnetic resonance, nuclear and microscopic imaging, molecular, functional and structural information related to vascular pathology can now be visualized in vivo in small rodents. Imaging vascular and parenchymal amyloid-β (Aβ) deposition as well as Aβ transport pathways have been shown to be useful to characterize their dynamics and to elucidate their role in the development of cerebral amyloid angiopathy and AD. Structural and functional imaging read-outs have been employed to describe the deleterious affects of Aβ on vessel morphology, hemodynamics and vascular integrity. More recent imaging studies have also addressed how inflammatory processes partake in the pathogenesis of the disease. Moreover, imaging can be pivotal in the search for novel therapies targeting the vasculature. PMID:24659966

[Recurrent vascular access trombosis associated with the prothrombin mutation G20210A in a adult patient in haemodialysis].

PubMed

Quintana, L F; Coll, E; Monteagudo, I; Collado, S; López-Pedret, J; Cases, A

2005-01-01

Vascular access-related complications are a frequent cause of morbidity in haemodialysis patients and generate high costs. We present the case of an adult patient with end-stage renal disease and recurrent vascular access thrombosis associated with the prothrombin mutation G20210A and renal graft intolerance. The clinical expression of this heterozygous gene mutation may have been favoured by inflammatory state, frequent in dialysis patients. In this patient, the inflammatory response associated with the renal graft intolerance would have favored the development of recurrent vascular access thrombosis in a adult heterozygous for prothrombin mutation G20210A. In the case of early dysfunction of haemodialysis vascular access and after ruling out technical problems, it is convenient to carry out a screening for thrombophilia.

Vascular, inflammatory, and metabolic factors associated with cognition in aging persons with chronic epilepsy.

PubMed

Hermann, Bruce P; Sager, Mark A; Koscik, Rebecca L; Young, Kate; Nakamura, Keith

2017-11-01

We examined cognition in aging persons with chronic epilepsy; characterized targeted vascular, inflammatory, and metabolic risk factors associated with abnormal cognitive aging in the general population; and examined associations between cognition and vascular, inflammatory, and metabolic health. Participants included 40 persons with chronic localization-related epilepsy and 152 controls, aged 54.6 and 55.3, respectively. Participants underwent neuropsychological assessment, clinical examination, and fasting blood evaluation for quantification of vascular status (systolic and diastolic blood pressure, obesity/body mass index [BMI], total and high-density lipoprotein [HDL] cholesterol level, and homocysteine), inflammatory markers (high sensitivity C-reactive protein [hs-CRP], and interleukin-6 [IL-6]), and metabolic status (insulin resistance [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)], glucose). Epilepsy participants exhibited impairment across all cognitive factor scores (all p's < 0.0001); abnormalities in BMI (p = 0.049), hs-CRP (p = 0.046), HOMA-IR (p = 0.0040), and fasting glucose (p = 0.03), with significant relationships between higher HOMA-IR with poorer Immediate Memory (p = 0.03) and Visuospatial Ability (0.03); elevated hs-CRP with poorer Visuospatial (p = 0.035) and Verbal Ability (p = 0.06); elevated BMI with poorer Speed/Flexibility (p = 0.04), Visuospatial (p = 0.001) and Verbal Ability (p = 0.02); and lower HDL with poorer Verbal Learning/Delayed Memory (p = 0.01), Speed/Flexibility (p = 0.043), and Working Memory (p = 0.008). Aging persons with chronic epilepsy exhibit multiple abnormalities in metabolic, inflammatory, and vascular health that are associated with poorer cognitive function. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Induced migration of endothelial cells into 3D scaffolds by chemoattractants secreted by pro-inflammatory macrophages in situ.

PubMed

Li, Xuguang; Dai, Yuankun; Shen, Tao; Gao, Changyou

2017-06-01

Cell migration in scaffolds plays a crucial role in tissue regeneration, which can better mimic cell behaviors in vivo . In this study, a novel model has been proposed on controlling 3D cell migration in porous collagen-chitosan scaffolds with various pore structures under the stimulation of inflammatory cells to mimic the angiogenesis process. Endothelial cells (ECs) cultured atop the scaffolds in the Transwell molds which were placed into a well of a 24-well culture plate were promoted to migrate into the scaffolds by chemoattractants such as vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) secreted by the pro-inflammatory macrophages incubated in the well culture plate. The phenotype of macrophages was mediated by 50 ng/ml interferon-gamma (IFN-γ) and different concentrations of lipopolysaccharide (LPS, 150-300 ng/ml). The cell migration depth had a positive correlation with LPS concentration, and thereby the TNF-α concentration. The ECs migrated easier to a deeper zone of the scaffolds prepared at - 10ºC (187 μm in pore diameter) than that at - 20ºC (108 μm in pore diameter) as well. The method provides a useful strategy to study the 3D cell migration, and is helpful to reveal the vascularization process during wound healing in the long run.

Induced migration of endothelial cells into 3D scaffolds by chemoattractants secreted by pro-inflammatory macrophages in situ

PubMed Central

Li, Xuguang; Dai, Yuankun; Shen, Tao

2017-01-01

Abstract Cell migration in scaffolds plays a crucial role in tissue regeneration, which can better mimic cell behaviors in vivo. In this study, a novel model has been proposed on controlling 3D cell migration in porous collagen-chitosan scaffolds with various pore structures under the stimulation of inflammatory cells to mimic the angiogenesis process. Endothelial cells (ECs) cultured atop the scaffolds in the Transwell molds which were placed into a well of a 24-well culture plate were promoted to migrate into the scaffolds by chemoattractants such as vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) secreted by the pro-inflammatory macrophages incubated in the well culture plate. The phenotype of macrophages was mediated by 50 ng/ml interferon-gamma (IFN-γ) and different concentrations of lipopolysaccharide (LPS, 150–300 ng/ml). The cell migration depth had a positive correlation with LPS concentration, and thereby the TNF-α concentration. The ECs migrated easier to a deeper zone of the scaffolds prepared at − 10ºC (187 μm in pore diameter) than that at − 20ºC (108 μm in pore diameter) as well. The method provides a useful strategy to study the 3D cell migration, and is helpful to reveal the vascularization process during wound healing in the long run. PMID:28596912

Protective Effects of N-Acetyl Cysteine against Diesel Exhaust Particles-Induced Intracellular ROS Generates Pro-Inflammatory Cytokines to Mediate the Vascular Permeability of Capillary-Like Endothelial Tubes

PubMed Central

Tseng, Chia-Yi; Chang, Jing-Fen; Wang, Jhih-Syuan; Chang, Yu-Jung; Gordon, Marion K.; Chao, Ming-Wei

2015-01-01

Exposure to diesel exhaust particles (DEP) is associated with pulmonary and cardiovascular diseases. Previous studies using in vitro endothelial tubes as a simplified model of capillaries have found that DEP-induced ROS increase vascular permeability with rearrangement or internalization of adherens junctional VE-cadherin away from the plasma membrane. This allows DEPs to penetrate into the cell and capillary lumen. In addition, pro-inflammatory cytokines are up-regulated and mediate vascular permeability in response to DEP. However, the mechanisms through which these DEP-induced pro-inflammatory cytokines increase vascular permeability remain unknown. Hence, we examined the ability of DEP to induce permeability of human umbilical vein endothelial cell tube cells to investigate these mechanisms. Furthermore, supplementation with NAC reduces ROS production following exposure to DEP. HUVEC tube cells contributed to a pro-inflammatory response to DEP-induced intracellular ROS generation. Endothelial oxidative stress induced the release of TNF-α and IL-6 from tube cells, subsequently stimulating the secretion of VEGF-A independent of HO-1. Our data suggests that DEP-induced intracellular ROS and release of the pro-inflammatory cytokines TNF- α and IL-6, which would contribute to VEGF-A secretion and disrupt cell-cell borders and increase vasculature permeability. Addition of NAC suppresses DEP-induced ROS efficiently and reduces subsequent damages by increasing endogenous glutathione. PMID:26148005

Distinct myeloid cell subsets promote meningeal remodeling and vascular repair after mild traumatic brain injury.

PubMed

Russo, Matthew V; Latour, Lawrence L; McGavern, Dorian B

2018-05-01

Mild traumatic brain injury (mTBI) can cause meningeal vascular injury and cell death that spreads into the brain parenchyma and triggers local inflammation and recruitment of peripheral immune cells. The factors that dictate meningeal recovery after mTBI are unknown at present. Here we demonstrated that most patients who had experienced mTBI resolved meningeal vascular damage within 2-3 weeks, although injury persisted for months in a subset of patients. To understand the recovery process, we studied a mouse model of mTBI and found extensive meningeal remodeling that was temporally reliant on infiltrating myeloid cells with divergent functions. Inflammatory myelomonocytic cells scavenged dead cells in the lesion core, whereas wound-healing macrophages proliferated along the lesion perimeter and promoted angiogenesis through the clearance of fibrin and production of the matrix metalloproteinase MMP-2. Notably, a secondary injury experienced during the acute inflammatory phase aborted this repair program and enhanced inflammation, but a secondary injury experienced during the wound-healing phase did not. Our findings demonstrate that meningeal vasculature can undergo regeneration after mTBI that is dependent on distinct myeloid cell subsets.

Characterization of the Phospholipid Platelet-Activating Factor As a Mediator of Inflammation in Chickens

PubMed Central

Garrido, Damien; Chanteloup, Nathalie K.; Trotereau, Angélina; Lion, Adrien; Bailleul, Geoffrey; Esnault, Evelyne; Trapp, Sascha; Quéré, Pascale; Schouler, Catherine; Guabiraba, Rodrigo

2017-01-01

Lipid mediators are known to play important roles in the onset and resolution phases of the inflammatory response in mammals. The phospholipid platelet-activating factor (PAF) is a pro-inflammatory lipid mediator which participates in vascular- and innate immunity-associated processes by increasing vascular permeability, by facilitating leukocyte adhesion to the endothelium, and by contributing to phagocyte activation. PAF exerts its function upon binding to its specific receptor, PAF receptor (PAFR), which is abundantly expressed in leukocytes and endothelial cells (ECs). In chickens, lipid mediators and their functions are still poorly characterized, and the role of PAF as an inflammatory mediator has not yet been investigated. In the present study we demonstrate that primary chicken macrophages express PAFR and lysophosphatidylcholine acyltransferase 2 (LPCAT2), the latter being essential to PAF biosynthesis during inflammation. Also, exogenous PAF treatment induces intracellular calcium increase, reactive oxygen species release, and increased phagocytosis by primary chicken macrophages in a PAFR-dependent manner. We also show that PAF contributes to the Escherichia coli lipopolysaccharide (LPS)-induced pro-inflammatory response and boosts the macrophage response to E. coli LPS via phosphatidylinositol 3-kinase/Akt- and calmodulin kinase II-mediated intracellular signaling pathways. Exogenous PAF treatment also increases avian pathogenic E. coli intracellular killing by chicken macrophages, and PAFR and LPCAT2 are upregulated in chicken lungs and liver during experimental pulmonary colibacillosis. Finally, exogenous PAF treatment increases cell permeability and upregulates the expression of genes coding for proteins involved in leukocyte adhesion to the endothelium in primary chicken endothelial cells (chAEC). In addition to these vascular phenomena, PAF boosts the chAEC inflammatory response to bacteria-associated molecular patterns in a PAFR-dependent manner. In conclusion, we identified PAF as an inflammation amplifier in chicken macrophages and ECs, which suggests that PAF could play important roles in the endothelium-innate immunity interface in birds during major bacterial infectious diseases such as colibacillosis. PMID:29326957

Anti-inflammatory and antiedematogenic activity of the Ocimum basilicum essential oil and its main compound estragole: In vivo mouse models.

PubMed

Rodrigues, Lindaiane Bezerra; Oliveira Brito Pereira Bezerra Martins, Anita; Cesário, Francisco Rafael Alves Santana; Ferreira E Castro, Fyama; de Albuquerque, Thaís Rodrigues; Martins Fernandes, Maria Neyze; Fernandes da Silva, Bruno Anderson; Quintans Júnior, Lucindo José; da Costa, José Galberto Martins; Melo Coutinho, Henrique Douglas; Barbosa, Roseli; Alencar de Menezes, Irwin Rose

2016-09-25

The genus Ocimum are used in cooking, however, their essential oils are utilized in traditional medicine as aromatherapy. The present study was carried out to investigate the chemical composition and systemic anti-inflammatory activity of the Ocimum basilicum essential oil (EOOB) and its major component estragole, as well as its possible mechanisms of action. The Ocimum basilicum essential oil was obtained by hydrodistillation and analyzed by GC-MS. The anti-inflammatory action was verified using acute and chronic in vivo tests as paw edema, peritonitis, and vascular permeability and granulomatous inflammation model. The anti-inflammatory mechanism of action was analyzed by the participation of histamine and arachidonic acid pathways. The chemical profile analysis identified fourteen components present in the essential oil, within them: estragole (60.96%). The in vivo test results show that treatment with EOOB (100 and 50 mg/kg) and estragole (60 and 30 mg/kg) significantly reduced paw edema induced by carrageenan and dextran. The smallest doses of EOOB (50 mg/kg) and estragole (30 mg/kg) showed efficacy in the reduction of paw edema induced by histamine and arachidonic acid, vascular permeability inhibition and leukocyte emigration in the peritoneal fluid. Theses doses were capable of reducing the chronic inflammatory process. The results observed between the EOOB and estragole demonstrate efficacy in anti-inflammatory activity, however, the essential oil is more efficacious in the acute and chronic anti-inflammatory action. This study confirms the therapeutic potential of this plant and reinforces the validity of its use in popular medicine. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Inflammatory Mediators and Angiogenic Factors in Choroidal Neovascularization: Pathogenetic Interactions and Therapeutic Implications

PubMed Central

Campa, Claudio; Costagliola, Ciro; Incorvaia, Carlo; Sheridan, Carl; Semeraro, Francesco; De Nadai, Katia; Sebastiani, Adolfo; Parmeggiani, Francesco

2010-01-01

Choroidal neovascularization (CNV) is a common and severe complication in heterogeneous diseases affecting the posterior segment of the eye, the most frequent being represented by age-related macular degeneration. Although the term may suggest just a vascular pathological condition, CNV is more properly definable as an aberrant tissue invasion of endothelial and inflammatory cells, in which both angiogenesis and inflammation are involved. Experimental and clinical evidences show that vascular endothelial growth factor is a key signal in promoting angiogenesis. However, many other molecules, distinctive of the inflammatory response, act as neovascular activators in CNV. These include fibroblast growth factor, transforming growth factor, tumor necrosis factor, interleukins, and complement. This paper reviews the role of inflammatory mediators and angiogenic factors in the development of CNV, proposing pathogenetic assumptions of mutual interaction. As an extension of this concept, new therapeutic approaches geared to have an effect on both the vascular and the extravascular components of CNV are discussed. PMID:20871825

Role of the nicotinic acetylcholine receptor α3 subtype in vascular inflammation.

PubMed

Yang, Cui; Li, Zhengtao; Yan, Saimei; He, Yonghui; Dai, Rong; Leung, George Pek-Heng; Pan, Shitian; Yang, Jinyan; Yan, Rong; Du, Guanhua

2016-11-01

Vascular inflammation is a major factor contributing to the development of vascular diseases. The aim of this study was to investigate the role of the nicotinic acetylcholine receptor α3 subtype (α3-nAChR) in vascular inflammation. Vascular inflammation was studied in apolipoprotein E knockout (ApoE -/- ) mice fed a high-fat diet. Inflammatory markers were measured in mouse aortic endothelial cells (MAECs) and macrophages after α3-nAChRs were antagonized pharmacologically, or after the gene of α3-nAChRs was silenced. Treatment with α-conotoxin MII (MII; an α3-nAChR antagonist) increased the number of inflammatory cells infiltrating the aortic walls and further impaired the endothelium-dependent vasodilatations in the aorta of ApoE -/- mice. MII also increased the plasma levels of inflammatory cytokines. Furthermore, the infiltration of classical activated macrophages into the arterial wall of ApoE -/- mice was markedly elevated by MII but that of alternative activated macrophages was reduced. In MAECs, the lipopolysaccharide-stimulated secretion of adhesion molecules and inflammatory cytokines was enhanced by MII, or by silencing the gene of α3-nAChRs. This effect was reversed by inhibitors of the PI3K-Akt-IκKα/β-IκBα-NFκB pathways. In macrophages, the classical activation was enhanced, but the alternative activation was reduced when the gene of α3-nACh receptors was silenced. These effects were prevented by inhibitors of the IκKα/β-IκBα-NFκB and JAK2-STAT6-PPARγ pathways respectively. α3-nAChRs play a pivotal role in regulating the inflammatory responses in endothelial cells and macrophages. The mechanisms involve the modulations of multiple cell signalling pathways. © 2016 The British Pharmacological Society.

Endogenous hydrogen sulfide is involved in the pathogenesis of atherosclerosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qiao, Wang; Chaoshu, Tang; Key Laboratory of Molecular Cardiovascular Medicine, Ministry of Education

2010-05-28

Atherosclerosis is a chronic, complex, and progressive pathological process in large and medium sized arteries. The exact mechanism of this process remains unclear. Hydrogen sulfide (H{sub 2}S), a novel gasotransmitter, was confirmed as playing a major role in the pathogenesis of many cardiovascular diseases. It plays a role in vascular smooth muscle cell (VSMC) proliferation and apoptosis, participates in the progress of hyperhomocysteinemia (HHCY), inhibits atherogenic modification of LDL, interferes with vascular calcification, intervenes with platelet function, and there are interactions between H{sub 2}S and inflammatory processes. The role of H{sub 2}S in atherosclerotic pathogenesis highlights the mysteries of atherosclerosismore » and inspires the search for innovative therapeutic strategies. Here, we review the studies to date that have considered the role of H{sub 2}S in atherosclerosis.« less

Altered gene expression in rat mesenteric tissue following in vivo exposure to a phosphodiesterase 4 inhibitor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dagues, Nicolas; Pawlowski, Valerie; Guigon, Ghislaine

Vascular injury is a relatively common finding during the pre-clinical toxicity testing of drugs. The mechanisms of the injury are poorly understood and in turn, sensitive and specific biomarkers for pre-clinical and clinical monitoring do not exist. The present study was undertaken to investigate the molecular mechanisms of drug-induced vascular injury in mesenteric tissue of rats treated with the selective phosphodiesterase 4 (PDE4) inhibitor CI-1044. In a time-course study, male Sprague Dawley rats were given daily doses of 40 or 80 mg/kg for 1, 2 or 3 successive days and were euthanized the following day. Gene expression profiles in mesentericmore » tissue were determined using Affymetrix RG{sub U}34A microarrays and fibrinogen and cytokine measurements were performed in blood samples. Hierarchical clustering analysis produced a clear pattern separation of the animals with inflammation, animal with inflammation and necrosis and animals without any lesion. Genes associated with inflammation, procoagulation, extracellular matrix remodeling were up-regulated. An altered expression of genes involved in vascular tone regulation, lipid and glucose metabolism was also observed. Selected genes expression changes were confirmed by TaqMan real-time RT-PCR. The inflammatory process was also detected in the bloodstream at the protein level since fibrinogen, IL6 and IL1{beta} concentrations were increased in treated animals. Overall, the present study reveals several molecular changes supporting the hypothesis by which PDE4 inhibitor-induced vascular lesions in rats are triggered by an inflammatory mechanism and/or a vascular tone dysregulation.« less

Suppressive effects of lysozyme on polyphosphate-mediated vascular inflammatory responses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chung, Jiwoo; Ku, Sae-Kwang; Lee, Suyeon

Lysozyme, found in relatively high concentration in blood, saliva, tears, and milk, protects us from the ever-present danger of bacterial infection. Previous studies have reported proinflammatory responses of endothelial cells to the release of polyphosphate(PolyP). In this study, we examined the anti-inflammatory responses and mechanisms of lysozyme and its effects on PolyP-induced septic activities in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behavior of human neutrophils, and vascular permeability were determined in PolyP-activated HUVECs and mice. Lysozyme suppressed the PolyP-mediated vascular barrier permeability, upregulation of inflammatory biomarkers, adhesion/migration of leukocytes, and activation and/ormore » production of nuclear factor-κB, tumor necrosis factor-α, and interleukin-6. Furthermore, lysozyme demonstrated protective effects on PolyP-mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of lysozyme on various systemic inflammatory diseases, such as sepsis or septic shock. -- Highlights: •PolyP is shown to be an important mediator of vascular inflammation. •Lysozyme inhibited PolyP-mediated hyperpermeability. •Lysozyme inhibited PolyP-mediated septic response. •Lysozyme reduced PolyP-induced septic mortality.« less

Thalidomide Ameliorates Inflammation and Vascular Injury but Aggravates Tubular Damage in the Irradiated Mouse Kidney

DOE Office of Scientific and Technical Information (OSTI.GOV)

Scharpfenecker, Marion, E-mail: m.scharpfenecker@nki.nl; Floot, Ben; Russell, Nicola S.

Purpose: The late side effects of kidney irradiation include vascular damage and fibrosis, which are promoted by an irradiation-induced inflammatory response. We therefore treated kidney-irradiated mice with the anti-inflammatory and angiogenesis-modulating drug thalidomide in an attempt to prevent the development of late normal tissue damage and radiation nephropathy in the mouse kidney. Methods and Materials: Kidneys of C57Bl/6 mice were irradiated with a single dose of 14 Gy. Starting from week 16 after irradiation, the mice were fed with thalidomide-containing chow (100 mg/kg body weight/day). Gene expression and kidney histology were analyzed at 40 weeks and blood samples at 10, 20, 30, andmore » 40 weeks after irradiation. Results: Thalidomide improved the vascular structure and vessel perfusion after irradiation, associated with a normalization of pericyte coverage. The drug also reduced infiltration of inflammatory cells but could not suppress the development of fibrosis. Irradiation-induced changes in hematocrit and blood urea nitrogen levels were not rescued by thalidomide. Moreover, thalidomide worsened tubular damage after irradiation and also negatively affected basal tubular function. Conclusions: Thalidomide improved the inflammatory and vascular side effects of kidney irradiation but could not reverse tubular toxicity, which probably prevented preservation of kidney function.« less

IN VIVO ANTI-INFLAMMATORY EFFECTS OF TARAXASTEROL AGAINST ANIMAL MODELS

PubMed Central

Wang, Ying; Li, Guan-Hao; Liu, Xin-Yu; Xu, Lu; Wang, Sha-Sha; Zhang, Xue-Mei

2017-01-01

Background: Traditional Chinese medicine Taraxacum officinale has been widely used to treat various inflammatory diseases. Taraxasterol is one of the main active components isolated from Taraxacum officinale. Recently, we have demonstrated that taraxasterol has the in vitro anti-inflammatory effects. This study aims to determine the in vivo anti-inflammatory effects of taraxasterol against animal models. Materials and Methods: Anti-inflammatory effects were assessed in four animal models by using dimethylbenzene-induced mouse ear edema, carrageenan-induced rat paw edema, acetic acid-induced mouse vascular permeability and cotton pellet-induced rat granuloma tests. Results: Our results demonstrated that taraxasterol dose-dependently attenuated dimethylbenzene-induced mouse ear edema and carrageenan-induced rat paw edema, decreased acetic acid-induced mouse vascular permeability and inhibited cotton pellet-induced rat granuloma formation. Conclusion: Our finding indicates that taraxasterol has obvious in vivo anti-inflammatory effects against animal models. It will provide experimental evidences for the traditional use of Taraxacum officinale and taraxasterol in inflammatory diseases. PMID:28480383

Deletion of metallothionein exacerbates intermittent hypoxia-induced oxidative and inflammatory injury in aorta.

PubMed

Zhou, Shanshan; Wang, Yonggang; Tan, Yi; Cai, Xiaohong; Cai, Lu; Cai, Jun; Zheng, Yang

2014-01-01

The present study was to explore the effect of metallothionein (MT) on intermittent hypoxia (IH) induced aortic pathogenic changes. Markers of oxidative damages, inflammation, and vascular remodeling were observed by immunohistochemical staining after 3 days and 1, 3, and 8 weeks after IH exposures. Endogenous MT was induced after 3 days of IH but was significantly decreased after 8 weeks of IH. Compared with the wild-type mice, MT knock-out mice exhibited earlier and more severe pathogenic changes of oxidative damages, inflammatory responses, and cellular apoptosis, as indicated by the significant accumulation of collagen, increased levels of connective tissue growth factor, transforming growth factor β1, tumor necrosis factor-alpha, vascular cell adhesion molecule 1,3-nitrotyrosine, and 4-hydroxy-2-nonenal in the aorta. These findings suggested that chronic IH may lead to aortic damages characterized by oxidative stress and inflammation, and MT may play a pivotal role in the above pathogenesis process.

Role of Platelet-Derived Microvesicles As Crosstalk Mediators in Atherothrombosis and Future Pharmacology Targets: A Link between Inflammation, Atherosclerosis, and Thrombosis

PubMed Central

Badimon, Lina; Suades, Rosa; Fuentes, Eduardo; Palomo, Iván; Padró, Teresa

2016-01-01

Reports in the last decade have suggested that the role of platelets in atherosclerosis and its thrombotic complications may be mediated, in part, by local secretion of platelet-derived microvesicles (pMVs), small cell blebs released during the platelet activation process. MVs are the most abundant cell-derived microvesicle subtype in the circulation. High concentrations of circulating MVs have been reported in patients with atherosclerosis, acute vascular syndromes, and/or diabetes mellitus, suggesting a potential correlation between the quantity of microvesicles and the clinical severity of the atherosclerotic disease. pMVs are considered to be biomarkers of disease but new information indicates that pMVs are also involved in signaling functions. pMVs evoke or promote haemostatic and inflammatory responses, neovascularization, cell survival, and apoptosis, processes involved in the pathophysiology of cardiovascular disease. This review is focused on the complex cross-talk between platelet-derived microvesicles, inflammatory cells and vascular elements and their relevance in the development of the atherosclerotic disease and its clinical outcomes, providing an updated state-of-the art of pMV involvement in atherothrombosis and pMV potential use as therapeutic agent influencing cardiovascular biomedicine in the future. PMID:27630570

Modulation of Endothelial Glycocalyx Structure under Inflammatory Conditions

PubMed Central

Kolářová, Hana; Ambrůzová, Barbora; Švihálková Šindlerová, Lenka; Klinke, Anna; Kubala, Lukáš

2014-01-01

The glycocalyx of the endothelium is an intravascular compartment that creates a barrier between circulating blood and the vessel wall. The glycocalyx is suggested to play an important role in numerous physiological processes including the regulation of vascular permeability, the prevention of the margination of blood cells to the vessel wall, and the transmission of shear stress. Various theoretical models and experimental approaches provide data about changes to the structure and functions of the glycocalyx under various types of inflammatory conditions. These alterations are suggested to promote inflammatory processes in vessels and contribute to the pathogenesis of number of diseases. In this review we summarize current knowledge about the modulation of the glycocalyx under inflammatory conditions and the consequences for the course of inflammation in vessels. The structure and functions of endothelial glycocalyx are briefly discussed in the context of methodological approaches regarding the determination of endothelial glycocalyx and the uncertainty and challenges involved in glycocalyx structure determination. In addition, the modulation of glycocalyx structure under inflammatory conditions and the possible consequences for pathogenesis of selected diseases and medical conditions (in particular, diabetes, atherosclerosis, ischemia/reperfusion, and sepsis) are summarized. Finally, therapeutic strategies to ameliorate glycocalyx dysfunction suggested by various authors are discussed. PMID:24803742

Injuries to the vascular endothelium: vascular wall and endothelial dysfunction.

PubMed

Fisher, Mark

2008-01-01

Vascular endothelial injury has multiple elements, and this article focuses on ischemia-related processes that have particular relevance to ischemic stroke. Distinctions between necrotic and apoptotic cell death provide a basic science context in which to better understand the significance of classical core and penumbra concepts of acute stroke, with apoptotic processes particularly prominent in the penumbra. The mitochondria are understood to serve as a reservoir of proteins that mediate apoptosis. Oxidative stress pathways generating reactive oxygen species (ROS) are prominent in endothelial injury, both ischemic and nonischemic, with prominent roles of enzyme- and nonenzymemediated pathways; mitochondria once again have a critical role, particularly in the nonenzymatic pathways generating ROS. Inflammation also contributes to vascular endothelial injury, and endothelial cells have the capacity to rapidly increase expression of inflammatory mediators following ischemic challenge; this leads to enhanced leukocyte-endothelial interactions mediated by selectins and adhesion molecules. Preconditioning consists of a minor version of an injurious event, which in turn may protect vascular endothelium from injury following a more substantial event. Presence of the blood-brain barrier creates unique responses to endothelial injury, with permeability changes due to impairment of endothelial-matrix interactions compounding altered vasomotor tone and tissue perfusion mediated by nitric oxide. Pharmacological protection against vascular endothelial injury can be provided by several of the phosphodiesterases (cilostazol and dipyridamole), along with statins. Optimal clinical responses for protection of brain vascular endothelium may use preconditioning as a model, and will likely require combined protection against apoptosis, ROS, and inflammation.

Labial salivary gland biopsy assessment in rheumatoid vasculitis.

PubMed

Flipo, R M; Janin, A; Hachulla, E; Houvenagel, E; Foulet, A; Cardon, T; Desbonnet, A; Grardel, B; Duquesnoy, B; Delcambre, B

1994-10-01

To assess the vascular involvement in labial salivary gland (LSG) from patients with rheumatoid vasculitis (RV). Forty seven patients with rheumatoid arthritis (RA) took part in a prospective study. Among them, 12 had proven RV. LSG biopsy was performed after local anaesthesia. Histological appearance of inflammatory vascular damage was observed in all but one patient with proven RV (92%). Inflammatory vascular involvement was also identified in LSG biopsy of seven patients with RA (20%) and only one patient in the control group (8%). A second specimen of LSG was studied after a mean treatment period of six months and failed to show any feature of inflammatory vascular involvement in three of the five cases that were analysed. The study emphasises the high incidence of immunopathological features of microvascular damage in patients with RV. LSG biopsy is minimally invasive and may be a potential useful tool for the diagnosis of RV especially when skin lesions are absent or impossible to biopsy. The assessment of the predictive value of positive LSG biopsy in RA requires a long term prospective study.

Labial salivary gland biopsy assessment in rheumatoid vasculitis.

PubMed Central

Flipo, R M; Janin, A; Hachulla, E; Houvenagel, E; Foulet, A; Cardon, T; Desbonnet, A; Grardel, B; Duquesnoy, B; Delcambre, B

1994-01-01

OBJECTIVES--To assess the vascular involvement in labial salivary gland (LSG) from patients with rheumatoid vasculitis (RV). METHODS--Forty seven patients with rheumatoid arthritis (RA) took part in a prospective study. Among them, 12 had proven RV. LSG biopsy was performed after local anaesthesia. RESULTS--Histological appearance of inflammatory vascular damage was observed in all but one patient with proven RV (92%). Inflammatory vascular involvement was also identified in LSG biopsy of seven patients with RA (20%) and only one patient in the control group (8%). A second specimen of LSG was studied after a mean treatment period of six months and failed to show any feature of inflammatory vascular involvement in three of the five cases that were analysed. CONCLUSIONS--The study emphasises the high incidence of immunopathological features of microvascular damage in patients with RV. LSG biopsy is minimally invasive and may be a potential useful tool for the diagnosis of RV especially when skin lesions are absent or impossible to biopsy. The assessment of the predictive value of positive LSG biopsy in RA requires a long term prospective study. Images PMID:7979576

Diet, inflammation and prediabetes-impact of quality of diet.

PubMed

Uusitupa, Matti; Schwab, Ursula

2013-10-01

Low grade inflammation has been linked to risk of type 2 diabetes and atherosclerotic vascular diseases. Obesity and, in particular, abdominal obesity increase the risk of diabetes and atherosclerotic vascular diseases. One of the mechanisms could be low grade inflammation and vascular endothelial dysfunction. Permanent weight reduction is the first line of treatment both for obese individuals at increased risk of diabetes and for newly onset type 2 diabetes. Weight reduction lowers the level of several inflammatory factors in the body while increasing the level of adiponectin. Besides weight reduction the quality of diet and physical activity also modifies low grade inflammation. Based on the literature survey and our own studies in humans, it is possible to have dietary patterns that reduce inflammatory stress in the body and improves vascular endothelial dysfunction. There is strong evidence to suggest that IL-1 Ra is a very sensitive marker of low grade inflammation in obesity and related phenotypes; however, its level is markedly lowered by weight reduction and by choosing foods that have been shown to reduce inflammatory stress in the body. Copyright © 2013. Published by Elsevier Inc.

Macrophage Migration Inhibitory Factor-Induced Autophagy Contributes to Thrombin-Triggered Endothelial Hyperpermeability in Sepsis.

PubMed

Chao, Chiao-Hsuan; Chen, Hong-Ru; Chuang, Yung-Chun; Yeh, Trai-Ming

2018-07-01

Vascular leakage contributes to the high morbidity and mortality associated with sepsis. Exposure of the endothelium to inflammatory mediators, such as thrombin and cytokines, during sepsis leads to hyperpermeability. We recently observed that autophagy, a cellular process for protein turnover, is involved in macrophage migration inhibitory factor (MIF)-induced endothelial hyperpermeability. Even though it is known that thrombin induces endothelial cells to secrete MIF and to increase vascular permeability, the possible role of autophagy in this process is unknown. In this study, we proposed and tested the hypothesis that MIF-induced autophagy plays an important role in thrombin-induced endothelial hyperpermeability. We evaluated the effects of thrombin on endothelial permeability, autophagy induction, and MIF secretion in vitro using the human microvascular endothelial cell line-1 and human umbilical vein endothelial cells. Several mechanisms/read outs of endothelial permeability and autophagy formation were examined. We observed that blocking autophagy attenuated thrombin-induced endothelial hyperpermeability. Furthermore, thrombin-induced MIF secretion was involved in this process because MIF inhibition reduced thrombin-induced autophagy and hyperpermeability. Finally, we showed that blocking MIF or autophagy effectively alleviated vascular leakage and mortality in endotoxemic mice. Thus, MIF-induced autophagy may represent a common mechanism causing vascular leakage in sepsis.

Downregulation of the glucocorticoid-induced leucine zipper (GILZ) promotes vascular inflammation.

PubMed

Hahn, Rebecca T; Hoppstädter, Jessica; Hirschfelder, Kerstin; Hachenthal, Nina; Diesel, Britta; Kessler, Sonja M; Huwer, Hanno; Kiemer, Alexandra K

2014-06-01

Glucocorticoid-induced leucine zipper (GILZ) represents an anti-inflammatory mediator, whose downregulation has been described in various inflammatory processes. Aim of our study was to decipher the regulation of GILZ in vascular inflammation. Degenerated aortocoronary saphenous vein bypass grafts (n = 15), which exhibited inflammatory cell activation as determined by enhanced monocyte chemoattractrant protein 1 (MCP-1, CCL2) and Toll-like receptor 2 (TLR2) expression, showed significantly diminished GILZ protein and mRNA levels compared to healthy veins (n = 23). GILZ was also downregulated in human umbilical vein endothelial cells (HUVEC) and macrophages upon treatment with the inflammatory cytokine TNF-α in a tristetraprolin (ZFP36, TTP)- and p38 MAPK-dependent manner. To assess the functional implications of decreased GILZ expression, we determined NF-κB activation after GILZ knockdown by siRNA and found that NF-κB activity and inflammatory gene expression were significantly enhanced. Importantly, ZFP36 is induced in TNF-α-activated HUVEC as well as in degenerated vein bypasses. When atheroprotective laminar shear stress was employed, GILZ levels in HUVEC increased on mRNA and protein level. Laminar flow also counteracted TNF-α-induced ZFP36 expression and GILZ downregulation. MAP kinase phosphatase 1 (MKP-1, DUSP1), a negative regulator of ZFP36 expression, was distinctly upregulated under laminar shear stress conditions and downregulated in degenerated vein bypasses. Our data show a diminished expression of the anti-inflammatory mediator GILZ in the inflamed vasculature and indicate that GILZ downregulation requires the mRNA binding protein ZFP36. We suggest that reduced GILZ levels play a role in cardiovascular disease. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Mechanisms underlying caloric restriction and life span regulation: implications for vascular aging

PubMed Central

Ungvari, Zoltan; Parrado-Fernandez, Cristina; Csiszar, Anna; de Cabo, Rafael

2008-01-01

This review focuses on the emerging evidence that attenuation of the production of reactive oxygen species (ROS) and inhibition of inflammatory pathways play a central role in the anti-aging cardiovascular effects of caloric restriction (CR). Particular emphasis is placed on the potential role of the plasma membrane redox system in CR-induced pathways responsible for sensing oxidative stress and increasing cellular oxidative stress resistance. We propose that CR increases bioavailability of NO, decreases vascular ROS generation, activates the Nrf2/ARE pathway inducing ROS detoxification systems, exerts anti-inflammatory effects and, thereby, suppresses initiation/progression of vascular disease that accompany aging. PMID:18340017

Weight loss and vascular inflammatory markers in overweight women with and without polycystic ovary syndrome.

PubMed

Moran, Lisa J; Noakes, Manny; Wittert, Gary A; Clifton, Peter M; Norman, Robert J

2012-11-01

Polycystic ovary syndrome (PCOS) is associated with increased cardiovascular disease risk. The effect of weight loss on the vascular inflammatory markers plasminogen activator inhibitor-1 (PAI-1), asymmetric dimethylarginine (ADMA), soluble vascular cell adhesion molecule-1 (sVCAM-1) and intracellular adhesion molecule-1 (sICAM-1) is unknown. Overweight women with (n=14) and without (n=13) PCOS of comparable age and body mass index undertook an 8-week weight-loss programme. Women with PCOS had elevated PAI-1, sVCAM-1 and sICAM-1 before and after weight loss compared with the controls. For all women, sVCAM-1 (P=0.026) and sICAM-1 (P=0.04) decreased with weight loss. Women with PCOS have elevated inflammatory markers, which are partially reduced by weight loss. Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Mononuclear cells in the corneal response to endotoxin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Howes, E.L.; Cruse, V.K.; Kwok, M.T.

A severe keratitis can be produced after the direct injection of bacterial endotoxin, or lipopolysaccharide (LPS), in rabbits. Corneal inflammation can progress to scarring and vascularization within a 2 to 3 week period. Pretreatment with systemic adrenal corticosteroids (triamcinolone) prevents this response. Limbal cellular and vascular events were studied during the first 20 hr after injection of LPS in treated and nontreated rabbits. Perivascular limbal inflammatory cells were counted and limbal vascular permeability was assessed by extravasation of 131I-albumin and 125I-fibrinogen in the cornea. Corticosteroids decreased but did not prevent the early protein extravasation and profoundly altered the inflammatory cellmore » population around blood vessels at the limbus. Mononuclear cells, particularly mononuclear phagocytes, were sharply reduced. It is proposed that these cell types play an important role in the perpetuation and amplification of the inflammatory response in this reaction.« less

The Decay of Stem Cell Nourishment at the Niche

PubMed Central

de Mora, Jaime Font

2013-01-01

Abstract One of the main features of human aging is the loss of adult stem cell homeostasis. Organs that are very dependent on adult stem cells show increased susceptibility to aging, particularly organs that present a vascular stem cell niche. Reduced regenerative capacity in tissues correlates with reduced stem cell function, which parallels a loss of microvascular density (rarefraction) and plasticity. Moreover, the age-related loss of microvascular plasticity and rarefaction has significance beyond metabolic support for tissues because stem cell niches are regulated co-ordinately with the vascular cells. In addition, microvascular rarefaction is related to increased inflammatory signals that may negatively regulate the stem cell population. Thus, the processes of microvascular rarefaction, adult stem cell dysfunction, and inflammation underlie the cycle of physiological decline that we call aging. Observations from new mouse models and humans are discussed here to support the vascular aging theory. We develop a novel theory to explain the complexity of aging in mammals and perhaps in other organisms. The connection between vascular endothelial tissue and organismal aging provides a potential evolutionary conserved mechanism that is an ideal target for the development of therapies to prevent or delay age-related processes in humans. PMID:23937078

Chlamydia pneumoniae Infection in Atherosclerotic Lesion Development through Oxidative Stress: A Brief Overview

PubMed Central

Di Pietro, Marisa; Filardo, Simone; De Santis, Fiorenzo; Sessa, Rosa

2013-01-01

Chlamydia pneumoniae, an obligate intracellular pathogen, is known as a leading cause of respiratory tract infections and, in the last two decades, has been widely associated with atherosclerosis by seroepidemiological studies, and direct detection of the microorganism within atheroma. C. pneumoniae is presumed to play a role in atherosclerosis for its ability to disseminate via peripheral blood mononuclear cells, to replicate and persist within vascular cells, and for its pro-inflammatory and angiogenic effects. Once inside the vascular tissue, C. pneumoniae infection has been shown to induce the production of reactive oxygen species in all the cells involved in atherosclerotic process such as macrophages, platelets, endothelial cells, and vascular smooth muscle cells, leading to oxidative stress. The aim of this review is to summarize the data linking C. pneumoniae-induced oxidative stress to atherosclerotic lesion development. PMID:23877837

Maternal choline supplementation during murine pregnancy modulates placental markers of inflammation, apoptosis and vascularization in a fetal sex-dependent manner.

PubMed

Kwan, Sze Ting Cecilia; King, Julia H; Yan, Jian; Jiang, Xinyin; Wei, Emily; Fomin, Vladislav G; Roberson, Mark S; Caudill, Marie A

2017-05-01

Normal placental vascular development is influenced by inflammatory, angiogenic and apoptotic processes, which may be modulated by choline through its role in membrane biosynthesis, cellular signaling and gene expression regulation. The current study examined the effect of maternal choline supplementation (MCS) on placental inflammatory, angiogenic and apoptotic processes during murine pregnancy. Pregnant dams were randomized to receive 1, 2 or 4 times (X) the normal choline content of rodent diets, and tissues were harvested on embryonic day (E) 10.5, 12.5, 15.5 or 18.5 for gene expression, protein abundance and immunohistochemical analyses. The choline-induced changes in the inflammatory and angiogenic markers were a function of fetal sex. Specifically, 4X (versus 1X) choline reduced the transcript (P ≤ 0.05) and protein (P ≤ 0.06) expression of TNF-a and IL-1β in the male placentas at E10.5 and E18.5, respectively. In the female placentas, 4X (versus 1X) choline modulated the transcript expression of Il1b in a biphasic pattern with reduced Il1b at E12.5 (P = 0.045) and E18.5 (P = 0.067) but increased Il1b at E15.5 (P = 0.031). MCS also induced an upregulation of Vegfa expression in the female placentas at E15.5 (P = 0.034; 4X versus 2X) and E18.5 (P = 0.026; 4X versus 1X). MCS decreased (P = 0.011; 4X versus 1X) placental apoptosis at E10.5. Additionally, the luminal area of the maternal spiral arteries was larger (P ≤ 0.05; 4X versus 1X) in response to extra choline throughout gestation. MCS during murine pregnancy has fetal sex-specific effects on placental inflammation and angiogenesis, with possible consequences on placental vascular development. Copyright © 2017 Elsevier Ltd. All rights reserved.

[EBOLA HEMORRHAGIC FEVER; ETIOLOGY, EPIDEMIOLOGY, PATHOGENESIS, AND CLINICAL SYMPTOMS].

PubMed

Zhdanov, K W; Zakharenko, S M; Kovalenko, A N; Semenov, A V; Fusin, A Ya

2015-01-01

The data on the prevalence of disease caused by Ebola virus, biological features of its pathogen, character of the epidemiological process, pathogenesis and clinical symptoms are presented. The disease is characterized by suppression of protective immunological mechanisms and systemic inflammatory reaction accounting for the lesions of vascular endothelium, hemostatic and immune systems. It eventually leads to polyorgan insufficiency and severe shock. Lethality amounts to 50%.

The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activator dh404 protects against diabetes-induced endothelial dysfunction.

PubMed

Sharma, Arpeeta; Rizky, Luddwi; Stefanovic, Nada; Tate, Mitchel; Ritchie, Rebecca H; Ward, Keith W; de Haan, Judy B

2017-03-03

Vascular dysfunction is a pivotal event in the development of diabetes-associated vascular disease. Increased inflammation and oxidative stress are major contributors to vascular dysfunction. Nrf2, a master regulator of several anti-oxidant genes and a suppressor of inflammatory NF-κB, has potential as a target to combat oxidative stress and inflammation. The aim of this study was to investigate the effects of a novel Nrf2 activator, the bardoxolone methyl derivative dh404, on endothelial function in vitro and in vivo. dh404 at 3 mg/kg was administered to male Akita mice, an established diabetic mouse model of insulin insufficiency and hyperglycemia, from 6 weeks of age. At 26 weeks of age, vascular reactivity was assessed by wire myography, pro-inflammatory expression was assessed in the aortas by qRT-PCR and immunohistochemistry, and systemic and vascular oxidative stress measurements were determined. Additionally, studies in human aortic endothelial cells (HAECs) derived from normal and diabetic patients in the presence or absence of dh404 included assessment of pro-inflammatory genes by qRT-PCR and western blotting. Oxidative stress was assessed by three methods; L-012, DCFDA and amplex red. Static adhesion assays were performed to determine the leukocyte-endothelial interaction in the presence or absence of dh404. Dh404 significantly attenuated endothelial dysfunction in diabetic Akita mice characterized by reduced contraction in response to phenylephrine and the downregulation of inflammatory genes (VCAM-1, ICAM-1, p65, IL-1β) and pro-oxidant genes (Nox1 and Nox2). Furthermore, reduced systemic and vascular oxidative stress levels were observed in diabetic Akita mice. dh404 exhibited cytoprotective effects in diabetic HAECs in vitro, reflected by significant upregulation of Nrf2-responsive genes, NAD(P)H quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1), reduction of oxidative stress markers (O 2 ·- and H 2 O 2 ), inhibition of inflammatory genes (VCAM-1 and the p65 subunit of NF-κB) and attenuation of leukocyte-endothelial interactions (P < 0.05 for all in vitro and in vivo parameters; one or two-way ANOVA as appropriate with post hoc testing). These studies demonstrate that upregulation of Nrf2 by dh404 represents a novel therapeutic strategy to limit diabetes-associated vascular injury.

Pleiotropic benefit of monomeric and oligomeric flavanols on vascular health--a randomized controlled clinical pilot study.

PubMed

Weseler, Antje R; Ruijters, Erik J B; Drittij-Reijnders, Marie-José; Reesink, Koen D; Haenen, Guido R M M; Bast, Aalt

2011-01-01

Cardiovascular diseases are expanding to a major social-economic burden in the Western World and undermine man's deep desire for healthy ageing. Epidemiological studies suggest that flavanol-rich foods (e.g. grapes, wine, chocolate) sustain cardiovascular health. For an evidenced-based application, however, sound clinical data on their efficacy are strongly demanded. In a double-blind, randomized, placebo-controlled intervention study we supplemented 28 male smokers with 200 mg per day of monomeric and oligomeric flavanols (MOF) from grape seeds. At baseline, after 4 and 8 weeks we measured macro- and microvascular function and a cluster of systemic biomarkers for major pathological processes occurring in the vasculature: disturbances in lipid metabolism and cellular redox balance, and activation of inflammatory cells and platelets. In the MOF group serum total cholesterol and LDL decreased significantly (P ≤ 0.05) by 5% (n = 11) and 7% (n = 9), respectively in volunteers with elevated baseline levels. Additionally, after 8 weeks the ratio of glutathione to glutathione disulphide in erythrocytes rose from baseline by 22% (n = 15, P<0.05) in MOF supplemented subjects. We also observed that MOF supplementation exerts anti-inflammatory effects in blood towards ex vivo added bacterial endotoxin and significantly reduces expression of inflammatory genes in leukocytes. Conversely, alterations in macro- and microvascular function, platelet aggregation, plasma levels of nitric oxide surrogates, endothelin-1, C-reactive protein, fibrinogen, prostaglandin F2alpha, plasma antioxidant capacity and gene expression levels of antioxidant defense enzymes did not reach statistical significance after 8 weeks MOF supplementation. However, integrating all measured effects into a global, so-called vascular health index revealed a significant improvement of overall vascular health by MOF compared to placebo (P ≤ 0.05). Our integrative multi-biomarker approach unveiled the pleiotropic vascular health benefit of an 8 weeks supplementation with 200 mg/d MOF in humans. ClinicalTrials.gov NCT00742287.

Effect of lidocaine- and prilocaine-based topical anesthetics on the inflammatory exudates in subcutaneous tissue of rats.

PubMed

Pochapski, Márcia Thaís; Neto, José Laufer; Jassen, Jocélia Lago; Farago, Paulo Vitor; Santos, Fábio André

2012-01-01

The aim of this present study was to evaluate the irritative potential of 2 topical anesthetics used in intrapocket anesthesia for periodontal scaling/root planing when applied in subcutaneous tissue of rats. Sixty animals were divided into 4 groups: group 1, saline solution (control); group 2, poloxamer gel (thermosetting vehicle); group 3, lidocaine and prilocaine poloxamer thermosetting gel; group 4: EMLA, a lidocaine and prilocaine dermatological cream. Injections of 2% Evans blue were administrated intravenously into the lateral caudal vein. In order to analyze vascular permeability, the tested substances were injected intradermally. The rats were sacrificed 3, 6, and 9 hours after injection of the substances. The dorsal skin was dissected and removed. The vascular permeability was evaluated by the measurement of area of dye extravasation and the dye was subsequently extracted after immersion in formamide. Statistical analyses were made by ANOVA with Bonferroni's post hoc test and Pearson correlation. The 2 methods to analyze the exudative phase of the inflammatory process showed statistically significant difference among the groups and periods of evaluation (P < .05). Both methods had a significant correlation (P < .0001). Under the tested conditions, the anesthetic agents showed mild initial inflammatory response when implanted in subcutaneous connective tissue.

Effect of Lidocaine- and Prilocaine-Based Topical Anesthetics on the Inflammatory Exudates in Subcutaneous Tissue of Rats

PubMed Central

Pochapski, Márcia Thaís; Neto, José Laufer; Jassen, Jocélia Lago; Farago, Paulo Vitor; Santos, Fábio André

2012-01-01

The aim of this present study was to evaluate the irritative potential of 2 topical anesthetics used in intrapocket anesthesia for periodontal scaling/root planing when applied in subcutaneous tissue of rats. Sixty animals were divided into 4 groups: group 1, saline solution (control); group 2, poloxamer gel (thermosetting vehicle); group 3, lidocaine and prilocaine poloxamer thermosetting gel; group 4: EMLA, a lidocaine and prilocaine dermatological cream. Injections of 2% Evans blue were administrated intravenously into the lateral caudal vein. In order to analyze vascular permeability, the tested substances were injected intradermally. The rats were sacrificed 3, 6, and 9 hours after injection of the substances. The dorsal skin was dissected and removed. The vascular permeability was evaluated by the measurement of area of dye extravasation and the dye was subsequently extracted after immersion in formamide. Statistical analyses were made by ANOVA with Bonferroni's post hoc test and Pearson correlation. The 2 methods to analyze the exudative phase of the inflammatory process showed statistically significant difference among the groups and periods of evaluation (P < .05). Both methods had a significant correlation (P < .0001). Under the tested conditions, the anesthetic agents showed mild initial inflammatory response when implanted in subcutaneous connective tissue. PMID:22822991

Attenuation of Lipopolysaccharide-Induced Lung Vascular Stiffening by Lipoxin Reduces Lung Inflammation

PubMed Central

Meng, Fanyong; Mambetsariev, Isa; Tian, Yufeng; Beckham, Yvonne; Meliton, Angelo; Leff, Alan; Gardel, Margaret L.; Allen, Michael J.; Birukov, Konstantin G.

2015-01-01

Reversible changes in lung microstructure accompany lung inflammation, although alterations in tissue micromechanics and their impact on inflammation remain unknown. This study investigated changes in extracellular matrix (ECM) remodeling and tissue stiffness in a model of LPS-induced inflammation and examined the role of lipoxin analog 15-epi-lipoxin A4 (eLXA4) in the reduction of stiffness-dependent exacerbation of the inflammatory process. Atomic force microscopy measurements of live lung slices were used to directly measure local tissue stiffness changes induced by intratracheal injection of LPS. Effects of LPS on ECM properties and inflammatory response were evaluated in an animal model of LPS-induced lung injury, live lung tissue slices, and pulmonary endothelial cell (EC) culture. In vivo, LPS increased perivascular stiffness in lung slices monitored by atomic force microscopy and stimulated expression of ECM proteins fibronectin, collagen I, and ECM crosslinker enzyme, lysyl oxidase. Increased stiffness and ECM remodeling escalated LPS-induced VCAM1 and ICAM1 expression and IL-8 production by lung ECs. Stiffness-dependent exacerbation of inflammatory signaling was confirmed in pulmonary ECs grown on substrates with high and low stiffness. eLXA4 inhibited LPS-increased stiffness in lung cross sections, attenuated stiffness-dependent enhancement of EC inflammatory activation, and restored lung compliance in vivo. This study shows that increased local vascular stiffness exacerbates lung inflammation. Attenuation of local stiffening of lung vasculature represents a novel mechanism of lipoxin antiinflammatory action. PMID:24992633

l-Homocysteine-induced cathepsin V mediates the vascular endothelial inflammation in hyperhomocysteinaemia.

PubMed

Leng, Yi-Ping; Ma, Ye-Shuo; Li, Xiao-Gang; Chen, Rui-Fang; Zeng, Ping-Yu; Li, Xiao-Hui; Qiu, Cheng-Feng; Li, Ya-Pei; Zhang, Zhen; Chen, Alex F

2018-04-01

Vascular inflammation, including the expression of inflammatory cytokines in endothelial cells, plays a critical role in hyperhomocysteinaemia-associated vascular diseases. Cathepsin V, specifically expressed in humans, is involved in vascular diseases through its elastolytic and collagenolytic activities. The aim of this study was to determine the effects of cathepsin V on l-homocysteine-induced vascular inflammation. A high methionine diet-induced hyperhomocysteinaemic mouse model was used to assess cathepsin V expression and vascular inflammation. Cultures of HUVECs were challenged with l-homocysteine and the cathepsin L/V inhibitor SID to assess the pro-inflammatory effects of cathepsin V. Transfection and antisense techniques were utilized to investigate the effects of cathepsin V on the dual-specificity protein phosphatases (DUSPs) and MAPK pathways. Cathepsin L (human cathepsin V homologous) was increased in the thoracic aorta endothelial cells of hyperhomocysteinaemic mice; l-homocysteine promoted cathepsin V expression in HUVECs. SID suppressed the activity of cathepsin V and reversed the up-regulation of inflammatory cytokines (IL-6, IL-8 and TNF-α), adhesion and chemotaxis of leukocytes and vascular inflammation induced by l-homocysteine in vivo and in vitro. Increased cathepsin V promoted the degradation of DUSP6 and DUSP7, phosphorylation and subsequent nuclear translocation of ERK1/2, phosphorylation of STAT1 and expression of IL-6, IL-8 and TNF-α. This study has identified a novel mechanism, which shows that l-homocysteine-induced upregulation of cathepsin V mediates vascular endothelial inflammation under high homocysteine condition partly via ERK 1/2 /STAT1 pathway. This mechanism could represent a potential therapeutic target in hyperaemia-associated vascular diseases. This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc. © 2017 The British Pharmacological Society.

Prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils

NASA Astrophysics Data System (ADS)

Wang, Zhenjia; Li, Jing; Cho, Jaehyung; Malik, Asrar B.

2014-03-01

Inflammatory diseases such as acute lung injury and ischaemic tissue injury are caused by the adhesion of a type of white blood cell--polymorphonuclear neutrophils--to the lining of the circulatory system or vascular endothelium and unchecked neutrophil transmigration. Nanoparticle-mediated targeting of activated neutrophils on vascular endothelial cells at the site of injury may be a useful means of directly inactivating neutrophil transmigration and hence mitigating vascular inflammation. Here, we report a method employing drug-loaded albumin nanoparticles, which efficiently deliver drugs into neutrophils adherent to the surface of the inflamed endothelium. Using intravital microscopy of tumour necrosis factor-α-challenged mouse cremaster post-capillary venules, we demonstrate that fluorescently tagged albumin nanoparticles are largely internalized by neutrophils adherent to the activated endothelium via cell surface Fcɣ receptors. Administration of albumin nanoparticles loaded with the spleen tyrosine kinase inhibitor, piceatannol, which blocks `outside-in' β2 integrin signalling in leukocytes, detached the adherent neutrophils and elicited their release into the circulation. Thus, internalization of drug-loaded albumin nanoparticles into neutrophils inactivates the pro-inflammatory function of activated neutrophils, thereby offering a promising approach for treating inflammatory diseases resulting from inappropriate neutrophil sequestration and activation.

Porcine circovirus 2 (PCV2) increases the expression of endothelial adhesion/junction molecules.

PubMed

Marks, Fernanda S; Almeida, Laura L; Driemeier, David; Canal, Cláudio; Barcellos, David E S N; Guimarães, Jorge A; Reck, José

Porcine circovirus type 2 (PCV2) is the primary causative agent of porcine circovirus disease, a complex multisystem syndrome in domestic pigs. Despite the significant economic losses caused by porcine circovirus disease, the mechanisms of pathogenesis underlying the clinical findings remain largely unclear. As various reports have highlighted the potential key role of vascular lesions in the pathogenesis of porcine circovirus disease, the aim of this work was to investigate effects of PCV2 infection on vascular endothelial cells, focusing on cell viability and expression of adhesion/junction molecules. PCV2 infection reduced endothelial cell viability, while viral infection did not affected the viability of several other classical cell lines. Also, PCV2 infection in endothelial cells displayed a dual/biphasic effect: initially, infection increased ICAM-1 expression, which can favor leukocyte recruitment and emigration to tissues and possibly inducing characteristic porcine circovirus disease inflammatory lesions; then, secondarily, infection caused an increase in zonula occludens 1 tight junction protein (ZO-1) expression, which in turn can result in difficulties for cell traffic across the endothelium and a potential impairment the immune response in peripheral tissues. These virus-induced endothelial changes could directly impact the inflammatory process of porcine circovirus disease and associated vascular/immune system disturbances. Data suggest that, among the wide range of effects induced by PCV2 on the host, endothelial modulation can be a pivotal process which can help to explain PCV2 pathogenesis in some porcine circovirus disease presentations. Copyright © 2016 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.

Sensing of Vascular Permeability in Inflamed Vessel of Live Animal.

PubMed

Park, Sang A; Jeong, Soi; Choe, Young Ho; Hyun, Young-Min

2018-01-01

Increase in vascular permeability is a conclusive response in the progress of inflammation. Under controlled conditions, leukocytes are known to migrate across the vascular barriers to the sites of inflammation without severe vascular rupture. However, when inflammatory state becomes excessive, the leakage of blood components may occur and can be lethal. Basically, vascular permeability can be analyzed based on the intensity of blood outflow. To evaluate the amount and rate of leakage in live mice, we performed cremaster muscle exteriorization to visualize blood flow and neutrophil migration. Using two-photon intravital microscopy of the exteriorized cremaster muscle venules, we found that vascular barrier function is transiently and locally disrupted in the early stage of inflammatory condition induced by N-formylmethionyl-leucyl-phenylalanine (fMLP). Measurement of the concentration of intravenously (i.v.) injected Texas Red dextran inside and outside the vessels resulted in clear visualization of real-time increases in transient and local vascular permeability increase in real-time manner. We successfully demonstrated repeated leakage from a target site on a blood vessel in association with increasing severity of inflammation. Therefore, compared to other methods, two-photon intravital microscopy more accurately visualizes and quantifies vascular permeability even in a small part of blood vessels in live animals in real time.

Obesity and risk of vascular disease: importance of endothelium-dependent vasoconstriction

PubMed Central

Barton, Matthias; Baretella, Oliver; Meyer, Matthias R

2012-01-01

Obesity has become a serious global health issue affecting both adults and children. Recent devolopments in world demographics and declining health status of the world's population indicate that the prevalence of obesity will continue to increase in the next decades. As a disease, obesity has deleterious effects on metabolic homeostasis, and affects numerous organ systems including heart, kidney and the vascular system. Thus, obesity is now regarded as an independent risk factor for atherosclerosis-related diseases such as coronary artery disease, myocardial infarction and stroke. In the arterial system, endothelial cells are both the source and target of factors contributing to atherosclerosis. Endothelial vasoactive factors regulate vascular homeostasis under physiological conditions and maintain basal vascular tone. Obesity results in an imbalance between endothelium-derived vasoactive factors favouring vasoconstriction, cell growth and inflammatory activation. Abnormal regulation of these factors due to endothelial cell dysfunction is both a consequence and a cause of vascular disease processes. Finally, because of the similarities of the vascular pathomechanisms activated, obesity can be considered to cause accelerated, ‘premature’ vascular aging. Here, we will review some of the pathomechanisms involved in obesity-related activation of endothelium-dependent vasoconstriction, the clinical relevance of obesity-associated vascular risk, and therapeutic interventions using ‘endothelial therapy’ aiming at maintaining or restoring vascular endothelial health. LINKED ARTICLES This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3 PMID:21557734

C1q Deficiency Promotes Pulmonary Vascular Inflammation and Enhances the Susceptibility of the Lung Endothelium to Injury.

PubMed

Shah, Dilip; Romero, Freddy; Zhu, Ying; Duong, Michelle; Sun, Jianxin; Walsh, Kenneth; Summer, Ross

2015-12-04

The collectin proteins are innate immune molecules found in high concentrations on the epithelial and endothelial surfaces of the lung. While these proteins are known to have important anti-inflammatory actions in the airways of the lung little is known of their functional importance in the pulmonary circulation. We recently demonstrated that the circulating collectin protein adiponectin has potent anti-inflammatory effects on the lung endothelium, leading us to reason that other structurally related proteins might have similar effects. To test this hypothesis, we investigated the anti-inflammatory actions of C1q in lung endothelial homeostasis and the pulmonary vascular response to LPS or HCl injury. We show that lung endothelium from C1q-deficient (C1q(-/-)) mice expresses higher baseline levels of the vascular adhesion markers ICAM-1, VCAM-1, and E-selectin when compared with wild-type mice. Further, we demonstrate that these changes are associated with enhanced susceptibility of the lung to injury as evident by increased expression of adhesion markers, enhanced production of pro-inflammatory cytokines, and augmented neutrophil recruitment. Additionally, we found that C1q(-/-) mice also exhibited enhanced endothelial barrier dysfunction after injury as manifested by decreased expression of junctional adherens proteins and enhanced vascular leakage. Mechanistically, C1q appears to mediate its effects by inhibiting phosphorylation of p38 mitogen-activated protein kinase (MAPK) and blocking nuclear translocation of the P65 subunit of nuclear factor (NF)-κB. In summary, our findings indicate a previously unrecognized role for C1q in pulmonary vascular homeostasis and provide added support for the hypothesis that circulating collectin proteins have protective effects on the lung endothelium. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

C1q Deficiency Promotes Pulmonary Vascular Inflammation and Enhances the Susceptibility of the Lung Endothelium to Injury*

PubMed Central

Shah, Dilip; Romero, Freddy; Zhu, Ying; Duong, Michelle; Sun, Jianxin; Walsh, Kenneth; Summer, Ross

2015-01-01

The collectin proteins are innate immune molecules found in high concentrations on the epithelial and endothelial surfaces of the lung. While these proteins are known to have important anti-inflammatory actions in the airways of the lung little is known of their functional importance in the pulmonary circulation. We recently demonstrated that the circulating collectin protein adiponectin has potent anti-inflammatory effects on the lung endothelium, leading us to reason that other structurally related proteins might have similar effects. To test this hypothesis, we investigated the anti-inflammatory actions of C1q in lung endothelial homeostasis and the pulmonary vascular response to LPS or HCl injury. We show that lung endothelium from C1q-deficient (C1q−/−) mice expresses higher baseline levels of the vascular adhesion markers ICAM-1, VCAM-1, and E-selectin when compared with wild-type mice. Further, we demonstrate that these changes are associated with enhanced susceptibility of the lung to injury as evident by increased expression of adhesion markers, enhanced production of pro-inflammatory cytokines, and augmented neutrophil recruitment. Additionally, we found that C1q−/− mice also exhibited enhanced endothelial barrier dysfunction after injury as manifested by decreased expression of junctional adherens proteins and enhanced vascular leakage. Mechanistically, C1q appears to mediate its effects by inhibiting phosphorylation of p38 mitogen-activated protein kinase (MAPK) and blocking nuclear translocation of the P65 subunit of nuclear factor (NF)-κB. In summary, our findings indicate a previously unrecognized role for C1q in pulmonary vascular homeostasis and provide added support for the hypothesis that circulating collectin proteins have protective effects on the lung endothelium. PMID:26487714

Infrapatellar fat pad features in osteoarthritis: a histopathological and molecular study.

PubMed

Favero, Marta; El-Hadi, Hamza; Belluzzi, Elisa; Granzotto, Marnie; Porzionato, Andrea; Sarasin, Gloria; Rambaldo, Anna; Iacobellis, Claudio; Cigolotti, Augusto; Fontanella, Chiara Giulia; Natali, Arturo; Ramonda, Roberta; Ruggieri, Pietro; De Caro, Raffaele; Vettor, Roberto; Rossato, Marco; Macchi, Veronica

2017-10-01

The infrapatellar fat pad (IFP) is considered a local producer of adipocytokines, suggesting a potential role in OA. The objective of this study was to evaluate the histopathological and molecular characteristics of OA IFPs compared with controls. The histopathological characteristics of IFPs were evaluated in patients undergoing total knee replacements and in control patients (without OA), considering the following parameters: presence of inflammatory cells, vascularization, adipose lobules dimension and thickness of the interlobular septa. Immunohistochemistry was performed to evaluate VEGF, monocyte chemotactic protein 1 (MCP-1) and IL-6 proteins. Quantitative real time PCR was performed to evaluate the expression levels of adipocytokines in the OA IFPs. OA IFPs showed an increase in inflammatory infiltration, vascularization and thickness of the interlobular septa compared with controls. VEGF, MCP-1 and IL-6 proteins were higher in OA IFPs compared with in controls. Inflammatory infiltration, hyperplasia, vascularization and fibrosis were increased in OA IFP synovial membranes compared with in those of controls. VEGF protein levels were associated with an increased number of vessels in the OA IFPs, while MCP-1 and IL-6 protein levels were associated with higher grades of inflammatory infiltration. Leptin levels were positively correlated with adiponectin and MCP-1expression, while adiponectin positively correlated with peroxisome proliferative activated receptor gamma, MCP-1 and IFP vascularity. MCP-1 showed a positive correlation with peroxisome proliferative activated receptor gamma. IFP lobules dimensions were positively correlated with IL-6 expression and negatively with thickness of interlobular septa. VEGF mRNA levels were positively correlated with increased synovial vascularity. OA IFPs and synovial membranes are more inflamed, vascularized and fibrous compared with those of control patients (without OA). © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Inhibitory effect of indigo naturalis on tumor necrosis factor-α-induced vascular cell adhesion molecule-1 expression in human umbilical vein endothelial cells.

PubMed

Chang, Hsin-Ning; Pang, Jong-Hwei Su; Yang, Sien-Hung; Hung, Chi-Feng; Chiang, Chi-Hsin; Lin, Tung-Yi; Lin, Yin-Ku

2010-09-14

The use of indigo naturalis to treat psoriasis has proved effective in our previous clinical studies. The present study was designed to examine the anti-inflammatory effect of indigo naturalis in primary cultured human umbilical vein endothelial cells (HUVECs). Pretreatment of cells with indigo naturalis extract attenuated TNF-α-induced increase in Jurkat T cell adhesion to HUVECs as well as decreased the protein and messenger (m)RNA expression levels of vascular cell adhesion molecule-1 (VCAM-1) on HUVECs. Indigo naturalis extract also inhibited the protein expression of activator protein-1 (AP-1)/c-Jun, a critical transcription factor for the activation of VCAM-1 gene expression. Since the reduction of lymphocyte adhesion to vascular cells by indigo naturalis extract could subsequently reduce the inflammatory reactions caused by lymphocyte infiltration in the epidermal layer and help to improve psoriasis, this study provides a potential mechanism for the anti-inflammatory therapeutic effect of indigo naturalis extract in psoriasis.

Diabetic retinopathy: could the alpha-1 antitrypsin be a therapeutic option?

PubMed

Ortiz, Gustavo; Salica, Juan P; Chuluyan, Eduardo H; Gallo, Juan E

2014-11-18

Diabetic retinopathy is one of the most important causes of blindness. The underlying mechanisms of this disease include inflammatory changes and remodeling processes of the extracellular-matrix (ECM) leading to pericyte and vascular endothelial cell damage that affects the retinal circulation. In turn, this causes hypoxia leading to release of vascular endothelial growth factor (VEGF) to induce the angiogenesis process. Alpha-1 antitrypsin (AAT) is the most important circulating inhibitor of serine proteases (SERPIN). Its targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, proteinase 3 (PR-3) and plasminogen activator (PAI). AAT modulates the effect of protease-activated receptors (PARs) during inflammatory responses. Plasma levels of AAT can increase 4-fold during acute inflammation then is so-called acute phase protein (APPs). Individuals with low serum levels of AAT could develop disease in lung, liver and pancreas. AAT is involved in extracellular matrix remodeling and inflammation, particularly migration and chemotaxis of neutrophils. It can also suppress nitric oxide (NO) by nitric oxide sintase (NOS) inhibition. AAT binds their targets in an irreversible way resulting in product degradation. The aim of this review is to focus on the points of contact between multiple factors involved in diabetic retinopathy and AAT resembling pleiotropic effects that might be beneficial.

An in vitro evaluation of the anti-inflammatory effects of platelet-rich plasma, ketorolac, and methylprednisolone.

PubMed

Mazzocca, Augustus D; McCarthy, Mary Beth R; Intravia, Jessica; Beitzel, Knut; Apostolakos, John; Cote, Mark P; Bradley, James; Arciero, Robert A

2013-04-01

The purpose of this study was to quantify the extent of the anti-inflammatory effect of platelet-rich plasma (PRP) in a controlled in vitro environment. Through the stimulation of human umbilical vein endothelial cells with inflammatory cytokines (tumor necrosis factor α and interferon γ), cell adhesion molecule expression (E-selectin, vascular cell adhesion molecule, and human leukocyte antigen DR) and PRP's anti-inflammatory effect can be measured. PRP was produced from 3 individuals using a single-spin (PRPLP) process. Treatment groups include negative (unstimulated) controls, positive (stimulated) controls, ketorolac tromethamine, methylprednisolone, PRP, ketorolac-PRP, and methylprednisolone-PRP. A fluorescence assay of the cellular inflammation markers was measured by the BioTek Synergy HT plate reader (BioTek Instruments, Winooski, VT) at 0, 1, 2, and 5 days. At days 2 and 5, methylprednisolone treatment showed a 2.1- to 5.8-fold reduction (P < .05) in inflammation markers over PRP. In addition, PRP and ketorolac showed a 1.4- to 2.5-fold reduction (P < .05) in cellular inflammation markers over the control. There was no statistically significant difference between ketorolac and PRP. Although PRP and ketorolac reduced cellular inflammation markers (E-selectin, vascular cell adhesion molecule, and human leukocyte antigen DR) compared with control, neither caused as great a reduction as methylprednisolone. Although PRP and ketorolac did not produce as significant a reduction in cellular inflammation markers as methylprednisolone, they reduced cellular inflammation compared with the control. These agents may have clinical application as injectable anti-inflammatory medications. Copyright © 2013 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

The adaptor Lnk (SH2B3): an emerging regulator in vascular cells and a link between immune and inflammatory signaling.

PubMed

Devallière, Julie; Charreau, Béatrice

2011-11-15

A better knowledge of the process by which inflammatory extracellular signals are relayed from the plasma membrane to specific intracellular sites is a key step to understand how inflammation develops and how it is regulated. This review focuses on Lnk (SH2B3) a member, with SH2B1 and SH2B2, of the SH2B family of adaptor proteins that influences a variety of signaling pathways mediated by Janus kinase and receptor tyrosine kinases. SH2B adaptor proteins contain conserved dimerization, pleckstrin homology, and SH2 domains. Initially described as a regulator of hematopoiesis and lymphocyte differentiation, Lnk now emerges as a key regulator in hematopoeitic and non hematopoeitic cells such as endothelial cells (EC) moderating growth factor and cytokine receptor-mediated signaling. In EC, Lnk is a negative regulator of TNF signaling that reduce proinflammatory phenotype and prevent EC from apoptosis. Lnk is a modulator in integrin signaling and actin cytoskeleton organization in both platelets and EC with an impact on cell adhesion, migration and thrombosis. In this review, we discuss some recent insights proposing Lnk as a key regulator of bone marrow-endothelial progenitor cell kinetics, including the ability to cell growth, endothelial commitment, mobilization, and recruitment for vascular regeneration. Finally, novel findings also provided evidences that mutations in Lnk gene are strongly linked to myeloproliferative disorders but also autoimmune and inflammatory syndromes where both immune and vascular cells display a role. Overall, these studies emphasize the importance of the Lnk adaptor molecule not only as prognostic marker but also as potential therapeutic target. Copyright © 2011 Elsevier Inc. All rights reserved.

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

PubMed Central

McCarthy, Cameron G.; Webb, R. Clinton

2016-01-01

Toll-like receptors (TLRs) are components of the innate immune system that respond to exogenous infectious ligands (pathogen-associated molecular patterns, PAMPs) and endogenous molecules that are released during host tissue injury/death (damage-associated molecular patterns, DAMPs). Interaction of TLRs with their ligands leads to activation of downstream signaling pathways that induce an immune response by producing inflammatory cytokines, type I interferons (IFN), and other inflammatory mediators. TLR activation affects vascular function and remodeling, and these molecular events prime antigen-specific adaptive immune responses. Despite the presence of TLRs in vascular cells, the exact mechanisms whereby TLR signaling affects the function of vascular tissues are largely unknown. Cardiovascular diseases are considered chronic inflammatory conditions, and accumulating data show that TLRs and the innate immune system play a determinant role in the initiation and development of cardiovascular diseases. This evidence unfolds a possibility that targeting TLRs and the innate immune system may be a novel therapeutic goal for these conditions. TLR inhibitors and agonists are already in clinical trials for inflammatory conditions such as asthma, cancer, and autoimmune diseases, but their study in the context of cardiovascular diseases is in its infancy. In this article, we review the current knowledge of TLR signaling in the cardiovascular system with an emphasis on atherosclerosis, hypertension, and cerebrovascular injury. Furthermore, we address the therapeutic potential of TLR as pharmacological targets in cardiovascular disease and consider intriguing research questions for future study. PMID:26721702

A historical perspective on the role of sensory nerves in neurogenic inflammation.

PubMed

Sousa-Valente, João; Brain, Susan D

2018-05-01

The term 'neurogenic inflammation' is commonly used, especially with respect to the role of sensory nerves within inflammatory disease. However, despite over a century of research, we remain unclear about the role of these nerves in the vascular biology of inflammation, as compared with their interacting role in pain processing and of their potential for therapeutic manipulation. This chapter attempts to discuss the progress in understanding, from the initial discovery of sensory nerves until the present day. This covers pioneering findings that these nerves exist, are involved in vascular events and act as important sensors of environmental changes, including injury and infection. This is followed by discovery of the contents they release such as the established vasoactive neuropeptides substance P and CGRP as well as anti-inflammatory peptides such as the opioids and somatostatin. The more recent emergence of the importance of the transient receptor potential (TRP) channels has revealed some of the mechanisms by which these nerves sense environmental stimuli. This knowledge enables a platform from which to learn of the potential role of neurogenic inflammation in disease and in turn of novel therapeutic targets.

Increased circulating leukocyte-derived microparticles in ischemic cerebrovascular disease.

PubMed

He, Zhangping; Tang, Yanyan; Qin, Chao

2017-06-01

Circulating leukocyte-derived microparticles act as proinflammatory mediators that reflect vascular inflammation. In this study, we examined the hypothesis that the quantity of leukocyte-derived microparticles is increased in patients with ischemic cerebrovascular diseases, and investigated utility of various phenotypes of leukocyte-derived microparticles as specific biomarkers of vascular inflammation injury. Additionally we focused on identifying leukocyte-derived microparticles that may be correlated with stroke severity in acute ischemic stroke patients. The plasma concentration of leukocyte-derived microparticles obtained by a series of centrifugations of 76 consecutive patients with ischemic cerebrovascular diseases and 70 age-, sex-, and race-matched healthy controls were determined by flow cytometry. Significantly elevated numbers of leukocyte (CD45+), monocyte (CD14+), lymphocyte (CD4+), granulocyte (CD15+) derived microparticles were found in the plasma samples of patients ischemic cerebrovascular diseases, compared to healthy controls (p<0.05). Furthermore, the plasma levels of CD14+ microparticles were significantly correlated with stroke severity (r=0.355, p=0.019), cerebral vascular stenosis severity (r=0.255, p=0.025) and stroke subtype (r=0.242, p=0.036). No association with stroke was observed for other leukocyte-derived phenotypes. These results demonstrate that circulating leukocyte-derived microparticles amounts are increased in patients with ischemic cerebrovascular diseases, compared with healthy controls. As proinflammatory mediators, leukocyte-derived microparticles may contribute to vascular inflammatory and the inflammatory process in acute ischemic stroke. Levels of CD14+ microparticles may be a promising biomarker of ischemic severity and outcome of stroke in the clinic. Copyright © 2017 Elsevier Ltd. All rights reserved.

Status epilepticus does not induce acute brain inflammatory response in the Amazon rodent Proechimys, an animal model resistant to epileptogenesis.

PubMed

Scorza, Carla A; Marques, Marcia J G; Gomes da Silva, Sérgio; Naffah-Mazzacoratti, Maria da Graça; Scorza, Fulvio A; Cavalheiro, Esper A

2018-03-06

Mesial temporal lobe epilepsy is a serious brain disorder in adults that is often preceded by an initial brain insult, such as status epilepticus (SE), that after a latent period leads to recurrent seizures. Post-SE models are widely used for studies on epileptogenic processes. Previous findings of our laboratory suggested that the Neotropical rodents Proechimys exhibit endogenous antiepileptogenic mechanisms in post-SE models. Strong body of research supports that SE triggers a rapid and dramatic upregulation of inflammatory mediators and vascular endothelial growth factor (VEGF). In this work we found that, in the epilepsy-resistant Proechimys, hippocampal and cortical levels of inflammatory cytokines (IL-1β, IL-6, IL-10, TNF-α) and VEGF remained unchanged 24h after SE, strongly contrasting to the high levels of post-SE changes observed in Wistar rats. Furthermore, substantial differences in the brain baseline levels of these proteins were encountered between animal species studied. Since inflammatory cytokines and VEGF have been recognized as major orchestrators of the epileptogenic process, our results suggest their role in the antiepileptogenic mechanisms previously described in Proechimys. Copyright © 2017 Elsevier B.V. All rights reserved.

Immunoexpression of vascular endothelial growth factor in periapical granulomas, radicular cysts, and residual radicular cysts.

PubMed

Nonaka, Cassiano Francisco Weege; Maia, Alexandre Pinto; Nascimento, George João Ferreira do; de Almeida Freitas, Roseana; Batista de Souza, Lélia; Galvão, Hébel Cavalcanti

2008-12-01

Our aim was to assess and compare the immunoexpression of vascular endothelial growth factor (VEGF) in periapical granulomas (PGs), radicular cysts (RCs), and residual radicular cysts (RRCs), relating it to the angiogenic index and the intensity of the inflammatory infiltrate. Twenty PGs, 20 RCs, and 10 RRCs were evaluated by immunohistochemistry using anti-VEGF antibody. Angiogenic index was determined by microvessel count (MVC) using anti-von Willebrand factor antibody. The PGs and RCs showed higher expression of VEGF than the RRCs. Lesions presenting few inflammatory infiltrate revealed the lowest immunoexpression of VEGF (P < .05). Irrespective of the intensity of the inflammatory infiltrate, most of the RCs and RRCs showed moderate to strong epithelial expression of VEGF. Lesions showing dense inflammatory infiltrate presented higher MVC indices (P < .05). VEGF expression and MVC did not reveal a significant correlation (P > .05). VEGF is present in periapical inflammatory lesions but at a lower level in RRCs. The expression of this proangiogenic factor is closely related to the intensity of the inflammatory infiltrate in these lesions.

High resolution neurography of the brachial plexus by 3 Tesla magnetic resonance imaging.

PubMed

Cejas, C; Rollán, C; Michelin, G; Nogués, M

2016-01-01

The study of the structures that make up the brachial plexus has benefited particularly from the high resolution images provided by 3T magnetic resonance scanners. The brachial plexus can have mononeuropathies or polyneuropathies. The mononeuropathies include traumatic injuries and trapping, such as occurs in thoracic outlet syndrome due to cervical ribs, prominent transverse apophyses, or tumors. The polyneuropathies include inflammatory processes, in particular chronic inflammatory demyelinating polyneuropathy, Parsonage-Turner syndrome, granulomatous diseases, and radiation neuropathy. Vascular processes affecting the brachial plexus include diabetic polyneuropathy and the vasculitides. This article reviews the anatomy of the brachial plexus and describes the technique for magnetic resonance neurography and the most common pathologic conditions that can affect the brachial plexus. Copyright © 2016 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

Evaluating the Use of Monocytes with a Degradable Polyurethane for Vascular Tissue Regeneration

NASA Astrophysics Data System (ADS)

Battiston, Kyle Giovanni

Monocytes are one of the first cell types present following the implantation of a biomaterial or tissue engineered construct. Depending on the monocyte activation state supported by the biomaterial, monocytes and their derived macrophages (MDMs) can act as positive contributors to tissue regeneration and wound healing, or conversely promote a chronic inflammatory response that leads to fibrous encapsulation and implant rejection. A degradable polar hydrophobic iconic polyurethane (D-PHI) has been shown to reduce pro-inflammatory monocyte/macrophage response compared to tissue culture polystyrene (TCPS), a substrate routinely used for in vitro culture of cells, as well as poly(lactide- co-glycolide) (PLGA), a standard synthetic biodegradable biomaterial in the tissue engineering field. D-PHI has also shown properties suitable for use in a vascular tissue engineering context. In order to understand the mechanism through which D-PHI attenuates pro-inflammatory monocyte response, this thesis investigated the ability of D-PHI to modulate interactions with adsorbed serum proteins and the properties of D-PHI that were important for this activity. D-PHI was shown to regulate protein adsorption in a manner that produced divergent monocyte responses compared to TCPS and PLGA when coated with the serum proteins alpha2-macroglobulin or immunoglobulin G (IgG). In the case of IgG, D-PHI was shown to reduce pro-inflammatory binding site exposure as a function of the material's polar, hydrophobic, and ionic character. Due to the favourable monocyte activation state supported by D-PHI, and the importance of monocytes/macrophages in regulating the response of tissue-specific cell types in vivo, the ability of a D-PHI-stimulated monocyte/macrophage activation state to contribute to modulating the response of vascular smooth muscle cells (VSMCs) in a vascular tissue engineering context was investigated. D-PHI- stimulated monocytes promoted VSMC growth and migration through biomolecule release. Coupling monocyte-VSMC co-culture with biomechanical strain further enhanced these effects, while also promoting extracellular matrix deposition (collagen I, collagen III, and elastin) and enhancing the mechanical properties of VSMC-monocyte seeded tissue constructs. This thesis identifies the use of biomaterials with immunomodulatory capacity to harness the stimulatory potential of MDMs and contribute to tissue engineering strategies in vitro. This latter work in turn has contributed to identifying aspects of biomaterial design that can contribute to supporting desirable monocyte-biomaterial interactions that can facilitate this process.

Inflammatory Stroke Extracellular Vesicles Induce Macrophage Activation.

PubMed

Couch, Yvonne; Akbar, Naveed; Davis, Simon; Fischer, Roman; Dickens, Alex M; Neuhaus, Ain A; Burgess, Annette I; Rothwell, Peter M; Buchan, Alastair M

2017-08-01

Extracellular vesicles (EVs) are protein-lipid complexes released from cells, as well as actively exocytosed, as part of normal physiology, but also during pathological processes such as those occurring during a stroke. Our aim was to determine the inflammatory potential of stroke EVs. EVs were quantified and analyzed in the sera of patients after an acute stroke (<24 hours; OXVASC [Oxford Vascular Study]). Isolated EV fractions were subjected to untargeted proteomic analysis by liquid chromatography mass-spectrometry/mass-spectrometry and then applied to macrophages in culture to investigate inflammatory gene expression. EV number, but not size, is significantly increased in stroke patients when compared to age-matched controls. Proteomic analysis reveals an overall increase in acute phase proteins, including C-reactive protein. EV fractions applied to monocyte-differentiated macrophage cultures induced inflammatory gene expression. Together these data show that EVs from stroke patients are proinflammatory in nature and are capable of inducing inflammation in immune cells. © 2017 American Heart Association, Inc.

Inflammation in the pathophysiology of essential hypertension.

PubMed

Montecucco, Fabrizio; Pende, Aldo; Quercioli, Alessandra; Mach, François

2011-01-01

In spite of the huge amount of research recently performed in this area, the pathogenesis of human hypertension remains elusive. Thus, hypertension has to be defined as "essential" for the majority of patients with high blood pressure. Given the lack of animal models useful to investigate essential hypertension, we analyze and discuss both clinical and basic research studies indicating that essential hypertension should be considered as a potential multifactorial inflammatory disease. The pathophysiology of essential hypertension might result from interactions between genetic and environmental factors. Morphological abnormalities in the renal parenchyma and arteries have also been shown to determine hypertension. Inflammatory processes might induce renal vasoconstriction, ischemia and injury that can sustain systemic hypertension. Arterial and tubulointerstitial infiltration of inflammatory cells in response to renal damage might further increase renal and vascular alterations through the production of oxidants and other soluble inflammatory mediators. The present review gives an update regarding the latest research on the possible direct role of inflammation in the pathophysiology of essential hypertension.

Cardiovascular disease management through restrained inflammatory responses.

PubMed

Jabir, Nasimudeen R; Tabrez, Shams

2016-01-01

Cardio vascular disease (CVD) is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries and remains the leading cause of death worldwide. Vascular inflammation and associated ongoing inflammatory responses have been considered as the critical culprits in the pathogenesis of CVD. Moreover, the activation of inflammatory pathways is not confined to coronary lesions only but involves the activation of neutrophils, monocytes and lymphocytes in peripheral blood. In view of high mortality rate associated with this devastated disease, it is essential that CVD and related complications should be taken care off at its earliest. To achieve that goal, some inflammatory mediators could be potentially targeted. In the current article, we will highlight targeting some inflammatory mediators viz. IL-1, IL-6, TNF-α etc for CVD management. As far as our knowledge goes, we are for the first time reporting the targeting inflammatory mediators especially IL-1, IL-6 and TNF-α together in a single article. Based on our review, we believe that scientific community will come up with certain anti-inflammatory agents against atherosclerosis in near future and hopefully that will be used for the successful management of CVD patients.

Uric acid promotes vascular stiffness, maladaptive inflammatory responses and proteinuria in western diet fed mice.

PubMed

Aroor, Annayya R; Jia, Guanghong; Habibi, Javad; Sun, Zhe; Ramirez-Perez, Francisco I; Brady, Barron; Chen, Dongqing; Martinez-Lemus, Luis A; Manrique, Camila; Nistala, Ravi; Whaley-Connell, Adam T; Demarco, Vincent G; Meininger, Gerald A; Sowers, James R

2017-09-01

Aortic vascular stiffness has been implicated in the development of cardiovascular disease (CVD) and chronic kidney disease (CKD) in obese individuals. However, the mechanism promoting these adverse effects are unclear. In this context, promotion of obesity through consumption of a western diet (WD) high in fat and fructose leads to excess circulating uric acid. There is accumulating data implicating elevated uric acid in the promotion of CVD and CKD. Accordingly, we hypothesized that xanthine oxidase(XO) inhibition with allopurinol would prevent a rise in vascular stiffness and proteinuria in a translationally relevant model of WD-induced obesity. Four-week-old C57BL6/J male mice were fed a WD with excess fat (46%) and fructose (17.5%) with or without allopurinol (125mg/L in drinking water) for 16weeks. Aortic endothelial and extracellular matrix/vascular smooth muscle stiffness was evaluated by atomic force microscopy. Aortic XO activity, 3-nitrotyrosine (3-NT) and aortic endothelial sodium channel (EnNaC) expression were evaluated along with aortic expression of inflammatory markers. In the kidney, expression of toll like receptor 4 (TLR4) and fibronectin were assessed along with evaluation of proteinuria. XO inhibition significantly attenuated WD-induced increases in plasma uric acid, vascular XO activity and oxidative stress, in concert with reductions in proteinuria. Further, XO inhibition prevented WD-induced increases in aortic EnNaC expression and associated endothelial and subendothelial stiffness. XO inhibition also reduced vascular pro-inflammatory and maladaptive immune responses induced by consumption of a WD. XO inhibition also decreased WD-induced increases in renal TLR4 and fibronectin that associated proteinuria. Consumption of a WD leads to elevations in plasma uric acid, increased vascular XO activity, oxidative stress, vascular stiffness, and proteinuria all of which are attenuated with allopurinol administration. Copyright © 2017 Elsevier Inc. All rights reserved.

Zinc deficiency induces vascular pro-inflammatory parameters associated with NF-kappaB and PPAR signaling.

PubMed

Shen, Huiyun; Oesterling, Elizabeth; Stromberg, Arnold; Toborek, Michal; MacDonald, Ruth; Hennig, Bernhard

2008-10-01

Marginal intake of dietary zinc can be associated with increased risk of cardiovascular diseases. In the current study we hypothesized that vascular dysfunction and associated inflammatory events are activated during a zinc deficient state. We tested this hypothesis using both vascular endothelial cells and mice lacking the functional LDL-receptor gene. Zinc deficiency increased oxidative stress and NF-kappaB DNA binding activity, and induced COX-2 and E-selectin gene expression, as well as monocyte adhesion in cultured endothelial cells. The NF-kappaB inhibitor CAPE significantly reduced the zinc deficiency-induced COX-2 expression, suggesting regulation through NF-kappaB signaling. PPAR can inhibit NF-kappaB signaling, and our previous data have shown that PPAR transactivation activity requires adequate zinc. Zinc deficiency down-regulated PPARalpha expression in cultured endothelial cells. Furthermore, the PPARgamma agonist rosiglitazone was unable to inhibit the adhesion of monocytes to endothelial cells during zinc deficiency, an event which could be reversed by zinc supplementation. Our in vivo data support the importance of PPAR dysregulation during zinc deficiency. For example, rosiglitazone induced inflammatory genes (e.g., MCP-1) only during zinc deficiency, and adequate zinc was required for rosiglitazone to down-regulate pro-inflammatory markers such as iNOS. In addition, rosiglitazone increased IkappaBalpha protein expression only in zinc adequate mice. Finally, plasma data from LDL-R-deficient mice suggest an overall pro-inflammatory environment during zinc deficiency and support the concept that zinc is required for proper anti-inflammatory or protective functions of PPAR. These studies suggest that zinc nutrition can markedly modulate mechanisms of the pathology of inflammatory diseases such as atherosclerosis.

AIP1-mediated stress signaling in atherosclerosis and arteriosclerosis

PubMed Central

Zhang, Jiqin; Zhou, Huanjiao Jenny; Ji, Weidong; Min, Wang

2016-01-01

AIP1 (encoded by the DAB2IP gene), a signaling scaffolding protein, is abundantly expressed in vascular endothelial cells (EC). While it was initially discovered as an ASK1-interacting protein, AIP1 broadly suppresses inflammatory responses triggered by cytokines and stresses such as TNF, LPS, VEGF and ER stress in EC (therefore AIP1 is an Anti-Inflammatory Protein). Human genome-wide association study (GWAS) has identified DAB2IP gene variants conferring susceptibility to cardiovascular diseases. Consistently, a global or vascular EC-specific deletion of DAB2IP in mice strongly enhances inflammatory responses and exacerbates atherosclerosis and graft arteriosclerosis progression in mouse models. Mechanisms for AIP1 function and regulation associated with human cardiovascular diseases need further investigations. PMID:25732743

Activation of Nrf2 Attenuates Pulmonary Vascular Remodeling via Inhibiting Endothelial-to-Mesenchymal Transition: an Insight from a Plant Polyphenol

PubMed Central

Chen, Yucai; Yuan, Tianyi; Zhang, Huifang; Yan, Yu; Wang, Danshu; Fang, Lianhua; Lu, Yang; Du, Guanhua

2017-01-01

The endothelial-to-mesenchymal transition (EndMT) has been demonstrated to be involved in pulmonary vascular remodeling. It is partly attributed to oxidative and inflammatory stresses in endothelial cells. In current study, we conducted a series of experiments to clarify the effect of salvianolic acid A (SAA), a kind of polyphenol compound, in the process of EndMT in human pulmonary arterial endothelial cells and in vivo therapeutic efficacy on vascular remodeling in monocrotaline (MCT)-induced EndMT. EndMT was induced by TGFβ1 in human pulmonary arterial endothelial cells (HPAECs). SAA significantly attenuated EndMT, simultaneously inhibited cell migration and reactive oxygen species (ROS) formation. In MCT-induced pulmonary arterial hypertension (PAH) model, SAA improved vascular function, decreased TGFβ1 level and inhibited inflammation. Mechanistically, SAA stimulated Nrf2 translocation and subsequent heme oxygenase-1 (HO-1) up-regulation. The effect of SAA on EndMT in vitro was abolished by ZnPP, a HO-1 inhibitor. In conclusion, this study indicates a deleterious impact of oxidative stress on EndMT. Polyphenol antioxidant treatment may provide an adjunctive action to alleviate pulmonary vascular remodeling via inhibiting EndMT. PMID:28924387

Pentraxin 3 as a Novel Marker in Cardiovascular Diseases?

PubMed Central

Grzesk, Grzegorz; Grzesk, Elzbieta

2011-01-01

Pentraxin 3 (also known as TNFAIP5, TSG-14) belongs to the superfamily of proteins characterized by cyclic multimeric structure. Pentraxin 3 (PTX3) is synthesized locally at the inflammatory sites by endothelial and smooth muscle cells upon exposure to inflammatory signals such as IL-1β, TNF-α or ox-LDL, but not IL-6. Furthermore, PTX3 is highly expressed in vascular cells and myocardial cells in patients with cardiomyopathy. These data suggest that pentraxin 3 may be a useful biomarker for local vascular inflammation and cardiovascular system disorders. PMID:27683398

Imaging the floor of the mouth and the sublingual space.

PubMed

La'porte, Sarah J; Juttla, Jaspal K; Lingam, Ravi K

2011-01-01

A wide range of pathologic processes may involve the floor of the mouth, the part of the oral cavity that is located beneath the tongue. They include lesions that arise uniquely in this location (eg, ranula, submandibular duct obstruction) as well as various malignancies, inflammatory processes, and vascular abnormalities that may also occur elsewhere in the head and neck. Some lesions that arise in superficial tissues such as the mucosa may be easily diagnosed at physical examination. However, computed tomography, magnetic resonance imaging, or ultrasonography may be necessary for a reliable assessment of lesion extension to deeper structures. In such cases, knowledge of the complex muscular, vascular, glandular, ductal, and neural anatomy of the region is important for accurate diagnosis and treatment planning. Familiarity with the radiologic imaging appearances of the floor of the mouth and recognition of anatomic landmarks such as the mylohyoid and hyoglossus muscles are especially useful for localizing disease within this region.

Fermented non-digestible fraction from combined nixtamalized corn (Zea mays L.)/cooked common bean (Phaseolus vulgaris L.) chips modulate anti-inflammatory markers on RAW 264.7 macrophages.

PubMed

Luzardo-Ocampo, I; Campos-Vega, R; Cuellar-Nuñez, M L; Vázquez-Landaverde, P A; Mojica, L; Acosta-Gallegos, J A; Loarca-Piña, G

2018-09-01

Chronic non-communicable diseases (NCDs) are low-level inflammation processes affected by several factors including diet. It has been reported that mixed whole grain and legume consumption, e.g. corn and common bean, might be a beneficial combination due to its content of bioactive compounds. A considerable amount would be retained in the non-digestible fraction (NDF), reaching the colon, where microbiota produce short-chain fatty acids (SCFAs) and phenolic compounds (PC) with known anti-inflammatory effect. The aim of this study was to estimate the anti-inflammatory potential of fermented-NDF of corn-bean chips (FNDFC) in RAW 264.7 macrophages. After 24 h, FNDFC produced SCFAs (0.156-0.222 mmol/l), inhibited nitric oxide production > 80% and H 2 O 2  > 30%, up-regulated anti-inflammatory cytokines (I-TAC, TIMP-1) > 2-fold, and produced angiostatic and protective factors against vascular/tissue damage, and amelioration of tumor necrosis factor signalling and inflammatory bowel disease. These results confirm the anti-inflammatory potential derived from healthy corn-bean chips. Copyright © 2018. Published by Elsevier Ltd.

Inflammation, leukocytes and menstruation.

PubMed

Evans, Jemma; Salamonsen, Lois A

2012-12-01

Menstruation has many of the features of an inflammatory process. The complexity and sequence of inflammatory-type events leading to the final tissue breakdown and bleeding are slowly being unravelled. Progesterone has anti-inflammatory properties, and its rapidly declining levels (along with those of estrogen) in the late secretory phase of each non-conception cycle, initiates a sequence of interdependent events of an inflammatory nature involving local inter-cellular interactions within the endometrium. Intracellular responses to loss of progesterone (in decidualized stromal, vascular and epithelial cells) lead to decreased prostaglandin metabolism and loss of protection from reactive oxygen species (ROS). Increased ROS results in release of NFκB from suppression with activation of target gene transcription and increased synthesis of pro-inflammatory prostaglandins, cytokines, chemokines and matrix metalloproteinases (MMP). The resultant leukocyte recruitment, with changing phenotypes and activation, provide further degradative enzymes and MMP activators, which together with a hypoxic environment induced by prostaglandin actions, lead to the tissue breakdown and bleeding characteristic of menstruation. In parallel, at sites where shedding is complete, microenvironmentally-induced changes in phenotypes of neutrophils and macrophages from pro- to anti-inflammatory, in addition to induction of growth factors, contribute to the very rapid re-epithelialization and restoration of tissue integrity.

Hydrophobic cyanine dye-doped micelles for optical in vivo imaging of plasma leakage and vascular disruption.

PubMed

Botz, Bálint; Bölcskei, Kata; Kemény, Ágnes; Sándor, Zoltán; Tékus, Valéria; Sétáló, György; Csepregi, Janka; Mócsai, Attila; Pintér, Erika; Kollár, László; Helyes, Zsuzsanna

2015-01-01

Vascular leakage is an important feature of various disease conditions. In vivo optical imaging provides a great opportunity for the evaluation of this phenomenon. In the present study, we focus on the development and validation of a near-infrared (NIR) imaging formula to allow reliable, cost-efficient evaluation of vascular leakage in diverse species using the existing small-animal fluorescence imaging technology. IR-676, a moderately hydrophobic NIR cyanine dye, was doped into self-assembling aqueous micelles using a widely employed and safe nonionic emulsifier (Kolliphor HS 15), and was tested in several acute and chronic inflammatory disease models in both mice and rats. The imaging formula is stable and exerts no acute toxic effects in vitro. It accumulated specifically in the inflamed regions in all models, which could be demonstrated by both conventional epifluorescence imaging, and fluorescence tomography both as a standalone technique and also by merging it with computed tomography scans. Ex vivo verification of dye accumulation by confocal fluorescence microscopy was also possible. The present formula allows sensitive and specific detection of inflammatory plasma leakage in diverse models. Its potential for imaging larger animals was also demonstrated. IR-676-doped micelles offer an excellent opportunity to image inflammatory vascular leakage in various models and species.

Low-level laser irradiation effect on endothelial cells under conditions of hyperglycemia.

PubMed

Góralczyk, Krzysztof; Szymańska, Justyna; Szot, Katarzyna; Fisz, Jacek; Rość, Danuta

2016-07-01

Diabetes mellitus is considered to be a very serious lifestyle disease leading to cardiovascular complications and impaired wound healing observed in the diabetic foot syndrome. Chronic hyperglycemia is the source of the endothelial activation. The inflammatory process in diabetes is associated with the secretion of inflammatory cytokines by endothelial cells, e.g., tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6). The method of phototherapy using laser beam of low power (LLLT-low-level laser therapy) effectively supports the conventional treatment of diabetic vascular complications such as diabetic foot syndrome. The aim of our study was to evaluate the effect of low-power laser irradiation at two wavelengths (635 and 830 nm) on the secretion of inflammatory factors (TNF-α and IL-6) by the endothelial cell culture-HUVEC line (human umbilical vein endothelial cell)-under conditions of hyperglycemia. It is considered that adverse effects of hyperglycemia on vascular endothelial cells may be corrected by the action of LLLT, especially with the wavelength of 830 nm. It leads to the reduction of TNF-α concentration in the supernatant and enhancement of cell proliferation. Endothelial cells play an important role in the pathogenesis of diabetes; however, a small number of studies evaluate an impact of LLLT on these cells under conditions of hyperglycemia. Further work on this subject is warranted.

Obesity and risk of vascular disease: importance of endothelium-dependent vasoconstriction.

PubMed

Barton, Matthias; Baretella, Oliver; Meyer, Matthias R

2012-02-01

Obesity has become a serious global health issue affecting both adults and children. Recent devolopments in world demographics and declining health status of the world's population indicate that the prevalence of obesity will continue to increase in the next decades. As a disease, obesity has deleterious effects on metabolic homeostasis, and affects numerous organ systems including heart, kidney and the vascular system. Thus, obesity is now regarded as an independent risk factor for atherosclerosis-related diseases such as coronary artery disease, myocardial infarction and stroke. In the arterial system, endothelial cells are both the source and target of factors contributing to atherosclerosis. Endothelial vasoactive factors regulate vascular homeostasis under physiological conditions and maintain basal vascular tone. Obesity results in an imbalance between endothelium-derived vasoactive factors favouring vasoconstriction, cell growth and inflammatory activation. Abnormal regulation of these factors due to endothelial cell dysfunction is both a consequence and a cause of vascular disease processes. Finally, because of the similarities of the vascular pathomechanisms activated, obesity can be considered to cause accelerated, 'premature' vascular aging. Here, we will review some of the pathomechanisms involved in obesity-related activation of endothelium-dependent vasoconstriction, the clinical relevance of obesity-associated vascular risk, and therapeutic interventions using 'endothelial therapy' aiming at maintaining or restoring vascular endothelial health. This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Inflammation in renal atherosclerotic disease.

PubMed

Udani, Suneel M; Dieter, Robert S

2008-07-01

The study of renal atherosclerotic disease has conventionally focused on the diagnosis and management of renal artery stenosis. With the increased understanding of atherosclerosis as a systemic inflammatory process, there has been increased interest in vascular biology at the microvasculature level. While different organ beds share some features, the inflammation and injury in the microvasculature of the kidney has unique elements as well. Understanding of the pathogenesis yields a better understanding of the clinical manifestations of renal atherosclerotic disease, which can be very subtle. Furthermore, identifying the molecular mechanisms responsible for the progression of kidney damage can also direct clinicians and scientists toward targeted therapies. Existing therapies used to treat atherosclerotic disease in other vascular beds may also play a role in the treatment of renal atherosclerotic disease.

Immune-regulating effects of exercise on cigarette smoke-induced inflammation

PubMed Central

Madani, Ashkan; Alack, Katharina; Richter, Manuel Jonas; Krüger, Karsten

2018-01-01

Long-term cigarette smoking (LTCS) represents an important risk factor for cardiac infarction and stroke and the central risk factor for the development of a bronchial carcinoma, smoking-associated interstitial lung fibrosis, and chronic obstructive pulmonary disease. The pathophysiologic development of these diseases is suggested to be promoted by chronic and progressive inflammation. Cigarette smoking induces repetitive inflammatory insults followed by a chronic and progressive activation of the immune system. In the pulmonary system of cigarette smokers, oxidative stress, cellular damage, and a chronic activation of pattern recognition receptors are described which are followed by the translocation of the NF-kB, the release of pro-inflammatory cytokines, chemokines, matrix metalloproteases, and damage-associated molecular patterns. In parallel, smoke pollutants cross directly through the alveolus–capillary interface and spread through the systemic bloodstream targeting different organs. Consequently, LTCS induces a systemic low-grade inflammation and increased oxidative stress in the vascular system. In blood, these processes promote an increased coagulation and endothelial dysfunction. In muscle tissue, inflammatory processes activate catabolic signaling pathways followed by muscle wasting and sarcopenia. In brain, several characteristics of neuroinflammation were described. Regular exercise training has been shown to be an effective nonpharmacological treatment strategy in smoke-induced pulmonary diseases. It is well established that exercise training exerts immune-regulating effects by activating anti-inflammatory signaling pathways. In this regard, the release of myokines from contracting skeletal muscle, the elevations of cortisol and adrenalin, the reduced expression of Toll-like receptors, and the increased mobilization of immune-regulating leukocyte subtypes might be of vital importance. Exercise training also increases the local and systemic antioxidative capacity and several compensatory mechanisms in tissues such as an increased anabolic signaling in muscle or an increased compliance of the vascular system. Accordingly, regular exercise training seems to protect long-term smokers against some important negative local and systemic consequences of smoking. Data suggest that it seems to be important to start exercise training as early as possible. PMID:29731655

Angiotensin II modulates interleukin-1{beta}-induced inflammatory gene expression in vascular smooth muscle cells via interfering with ERK-NF-{kappa}B crosstalk

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Shanqin; Zhi, Hui; Hou, Xiuyun

2011-07-08

Highlights: {yields} We examine how angiotensin II modulates ERK-NF-{kappa}B crosstalk and gene expression. {yields} Angiotensin II suppresses IL-1{beta}-induced prolonged ERK and NF-{kappa}B activation. {yields} ERK-RSK1 signaling is required for IL-1{beta}-induced prolonged NF-{kappa}B activation. {yields} Angiotensin II modulates NF-{kappa}B responsive genes via regulating ERK-NF-{kappa}B crosstalk. {yields} ERK-NF-{kappa}B crosstalk is a novel mechanism regulating inflammatory gene expression. -- Abstract: Angiotensin II is implicated in cardiovascular diseases, which is associated with a role in increasing vascular inflammation. The present study investigated how angiotensin II modulates vascular inflammatory signaling and expression of inducible nitric oxide synthase (iNOS) and vascular cell adhesion molecule (VCAM)-1. Inmore » cultured rat aortic vascular smooth muscle cells (VSMCs), angiotensin II suppressed interleukin-1{beta}-induced prolonged phosphorylation of extracellular signal-regulated kinase (ERK) and ribosomal S6 kinase (RSK)-1, and nuclear translocation of nuclear factor (NF)-{kappa}B, leading to decreased iNOS but enhanced VCAM-1 expression, associated with an up-regulation of mitogen-activated protein kinase phosphatase-1 expression. Knock-down of RSK1 selectively down regulated interleukin-1{beta}-induced iNOS expression without influencing VCAM-1 expression. In vivo experiments showed that interleukin-1{beta}, iNOS, and VCAM-1 expression were detectable in the aortic arches of both wild-type and apolipoprotein E-deficient (ApoE{sup -/-}) mice. VCAM-1 and iNOS expression were higher in ApoE{sup -/-} than in wild type mouse aortic arches. Angiotensin II infusion (3.2 mg/kg/day, for 6 days, via subcutaneous osmotic pump) in ApoE{sup -/-} mice enhanced endothelial and adventitial VCAM-1 and iNOS expression, but reduced medial smooth muscle iNOS expression associated with reduced phosphorylation of ERK and RSK-1. These results indicate that angiotensin II can differentially modulate inflammatory gene expression in aortic smooth muscle cells through influencing ERK-NF-{kappa}B crosstalk, which may contribute to angiotensin II-induced inflammatory disorders related to cardiovascular diseases.« less

Immunomodulatory Effects of Soybeans and Processed Soy Food Compounds.

PubMed

Tezuka, Hiroyuki; Imai, Shinjiro

2015-01-01

Inflammation is an immune response against both internal and external antigens in organisms, particularly in mammals, and includes both uncontrolled chronic and low-grade inflammations. Uncontrolled chronic inflammation often leads to severe diseases such as vascular disease, arthritis, cancer, diabete, allergy, and autoimmunity. On the other hand, low-grade inflammation is recognized as a relationship between obesity and risk of metabolic syndrome. Elevated production of pro-inflammatory cytokines and mediators is commonly observed in patients with uncontrolled or low-grade inflammation-associated diseases. Plants have been generated phytochemicals to overcome inflammations and infections through evolution. Phytochemicals belong to alkaloids, polyphenols, flavonoids, coumarins, and terpenoids. The consumption of soybeans plays a role in immune modulation through their components such as isoflavones, saponins, and anthocyanins. Recently, it was reported that the application of phytochemicals into patients with inflammatory diseases improves their symptoms. Therefore, it is important to identify novel phytochemicals with immunomodulatory activities. This review introduces and discusses recent advances and patents regarding soybean or processed soy food compounds which exhibit immunomodulatory activity in immune diseases, particularly allergy, by mediating the suppression of inflammatory pathways.

Vascular barrier protective effects of baicalin, baicalein and wogonin in vitro and in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kwak, Soyoung; Ku, Sae-Kwang; Han, Min-Su

Inhibition of high mobility group box 1 (HMGB1) protein and restoration of endothelial integrity is emerging as an attractive therapeutic strategy in the management of sepsis. Here, three structurally related polyphenols found in the Chinese herb Huang Qui, baicalin (BCL), baicalein (BCN), and wogonin (WGN), were examined for their effects on lipopolysaccharide (LPS)- or cecal ligation and puncture (CLP)-mediated release of HMGB1 and on modulation of HMGB1-mediated inflammatory responses. According to our data, BCL, BCN, and WGN inhibited the release of HMGB1 and down-regulated HMGB1-dependent inflammatory responses in human endothelial cells. BCL, BCN, and WGN also inhibited HMGB1-mediated hyperpermeability andmore » leukocyte migration in mice. In addition, treatment with BCL, BCN, and WGN reduced CLP-induced release of HMGB1 and sepsis-related mortality and pulmonary injury in mice. These results indicate that BCL, BCN, and WGN could be candidate therapeutic agents for various severe vascular inflammatory diseases owing to their inhibition of the HMGB1 signaling pathway. - Highlights: • HMGB1 is an inflammatory mediator for vascular inflammation. • Baicalin, baicalein and wogonin inhibited HMGB1-induced hyperpermeability in vitro and in vivo. • Baicalin, baicalein and wogonin inhibited HMGB1-mediated inflammatory responses. • Baicalin, baicalein and wogonin suppressed the activation of NF-κB and ERK1/2 and production of TNF-α and IL-6. • Baicalin, baicalein and wogonin prevent CLP-induced septic mortality.« less

Oscillation of Angiogenesis and Vascular Dropout in Progressive Human Vascular Disease. [Vascular Pattern as Useful Read-Out of Complex Molecular Signaling

NASA Technical Reports Server (NTRS)

Parsons-Wingerter, Patricia

2010-01-01

When analyzed by VESsel GENeration Analysis (VESGEN) software, vascular patterns provide useful integrative read-outs of complex, interacting molecular signaling pathways. Using VESGEN, we recently discovered and published our innovative, surprising findings that angiogenesis oscillated with vascular dropout throughout progression of diabetic retinopathy, a blinding vascular disease. Our findings provide a potential paradigm shift in the current prevailing view on progression and treatment of this disease, and a new early-stage window of regenerative therapeutic opportunities. The findings also suggest that angiogenesis may oscillate with vascular disease in a homeostatic-like manner during early stages of other inflammatory progressive diseases such as cancer and coronary vascular disease.

The molecular mechanisms of action of PPAR-γ agonists in the treatment of corneal alkali burns (Review)

PubMed Central

Zhou, Hongyan; Zhang, Wensong; Bi, Miaomiao; Wu, Jie

2016-01-01

Corneal alkali burns (CAB) are characterized by injury-induced inflammation, fibrosis and neovascularization (NV), and may lead to blindness. This review evaluates the current knowledge of the molecular mechanisms responsible for CAB. The processes of cytokine production, chemotaxis, inflammatory responses, immune response, cell signal transduction, matrix metalloproteinase production and vascular factors in CAB are discussed. Previous evidence indicates that peroxisome proliferator-activated receptor γ (PPAR-γ) agonists suppress immune responses, inflammation, corneal fibrosis and NV. This review also discusses the role of PPAR-γ as an anti-inflammatory, anti-fibrotic and anti-angiogenic agent in the treatment of CAB, as well as the potential role of PPAR-γ in the pathological process of CAB. There have been numerous studies evaluating the clinical profiles of CAB, and the aim of this systematic review was to summarize the evidence regarding the treatment of CAB with PPAR-γ agonists. PMID:27499172

Atorvastatin restores arsenic-induced vascular dysfunction in rats: Modulation of nitric oxide signaling and inflammatory mediators

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kesavan, Manickam; Sarath, Thengumpallil Sasindran; Kannan, Kandasamy

We evaluated whether atorvastatin, an extensively prescribed statin for reducing the risks of cardiovascular diseases, can reduce the risk of arsenic-induced vascular dysfunction and inflammation in rats and whether the modulation could be linked to improvement in vascular NO signaling. Rats were exposed to sodium arsenite (100 ppm) through drinking water for 90 consecutive days. Atorvastatin (10 mg/kg bw, orally) was administered once daily during the last 30 days of arsenic exposure. On the 91{sup st} day, blood was collected for measuring serum C-reactive protein. Thoracic aorta was isolated for assessing reactivity to phenylephrine, sodium nitroprusside and acetylcholine; evaluating eNOSmore » and iNOS mRNA expression and measuring NO production, while abdominal aorta was used for ELISA of cytokines, chemokine and vascular cell adhesion molecules. Histopathology was done in aortic arches. Arsenic did not alter phenylephrine-elicited contraction. Atorvastatin inhibited E{sub max} of phenylephrine, but it augmented the contractile response in aortic rings from arsenic-exposed animals. Sodium nitroprusside-induced relaxation was not altered with any treatment. However, arsenic reduced acetylcholine-induced relaxation and affected aortic eNOS at the levels of mRNA expression, protein concentration, phosphorylation and NO production. Further, it increased aortic iNOS mRNA expression, iNOS-derived NO synthesis, production of pro-inflammatory mediators (IL-1β, IL-6, MCP-1, VCAM, sICAM) and serum C-reactive protein and aortic vasculopathic lesions. Atorvastatin attenuated these arsenic-mediated functional, biochemical and structural alterations. Results show that atorvastatin has the potential to ameliorate arsenic-induced vascular dysfunction and inflammation by restoring endothelial function with improvement in NO signaling and attenuating production of pro-inflammatory mediators and cell adhesion molecules. - Highlights: • We evaluated if atorvastatin reduce arsenic-induced vascular dysfunction. • Arsenic reduced ACh-induced aortic relaxation but didn’t alter response to SNP and PE. • Arsenic affected aortic NO signalling and production of inflammatory mediators. • Arsenic produced vasculopathic lesions in aorta. • Atorvastatin restored arsenic-induced functional, biochemical and structural changes.« less

Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age☆

PubMed Central

Sikka, Gautam; Miller, Karen L.; Steppan, Jochen; Pandey, Deepesh; Jung, Sung M.; Fraser, Charles D.; Ellis, Carla; Ross, Daniel; Vandegaer, Koenraad; Bedja, Djahida; Gabrielson, Kathleen; Walston, Jeremy D.; Berkowitz, Dan E.; Barouch, Lili A.

2013-01-01

Cardiovascular dysfunction is a primary independent predictor of age-related morbidity and mortality. Frailty is associated with activation of inflammatory pathways and fatigue that commonly presents and progresses with age. Interleukin 10 (IL-10), the cytokine synthesis inhibitory factor, is an anti-inflammatory cytokine produced by immune and non-immune cells. Homozygous deletion of IL-10 in mice yields a phenotype that is consistent with human frailty, including age-related increases in serum inflammatory mediators, muscular weakness, higher levels of IGF-1 at midlife, and early mortality. While emerging evidence suggests a role for IL-10 in vascular protection, a clear mechanism has not yet been elucidated. Methods In order to evaluate the role of IL-10 in maintenance of vascular function, force tension myography was utilized to access ex-vivo endothelium dependent vasorelaxation in vessels isolated from IL-10 knockout IL-10(tm/tm) and control mice. Pulse wave velocity ((PWV), index of stiffness) of vasculature was measured using ultrasound and blood pressure was measured using the tail cuff method. Echocardiography was used to elucidated structure and functional changes in the heart. Results Mean arterial pressures were significantly higher in IL-10(tm/tm) mice as compared to C57BL6/wild type (WT) controls. PWV was increased in IL-10(tm/tm) indicating stiffer vasculature. Endothelial intact aortic rings isolated from IL-10(tm/tm) mice demonstrated impaired vasodilation at low acetylcholine doses and vasoconstriction at higher doses whereas vasorelaxation responses were preserved in rings from WT mice. Cyclo-oxygenase (COX-2)/thromboxane A2 inhibitors improved endothelial dependent vasorelaxation and reversed vasoconstriction. Left ventricular end systolic diameter, left ventricular mass, isovolumic relaxation time, fractional shortening and ejection fraction were all significantly different in the aged IL-10(tm/tm) mice compared to WT mice. Conclusion Aged IL-10(tm/tm) mice have stiffer vessels and decreased vascular relaxation due to an increase in eicosanoids, specifically COX-2 activity and resultant thromboxane A2 receptor activation. Our results also suggest that aging IL-10(tm/tm) mice have an increased heart size and impaired cardiac function compared to age-matched WT mice. While further studies will be necessary to determine if this age-related phenotype develops as a result of inflammatory pathway activation or lack of IL-10, it is essential for maintaining the vascular compliance and endothelial function during the aging process. Given that a similar cardiovascular phenotype is present in frail, older adults, these findings further support the utility of the IL-10(tm/tm) mouse as a model of frailty. PMID:23159957

Annexin A5 prevents post-interventional accelerated atherosclerosis development in a dose-dependent fashion in mice.

PubMed

Ewing, M M; Karper, J C; Sampietro, M L; de Vries, M R; Pettersson, K; Jukema, J W; Quax, P H A

2012-04-01

Activated cells in atherosclerotic lesions expose phosphatidylserine (PS) on their surface. Annexin A5 (AnxA5) binds to PS and is used for imaging atherosclerotic lesions. Recently, AnxA5 was shown to inhibit vascular inflammatory processes after vein grafting. Here, we report a therapeutic role for AnxA5 in post-interventional vascular remodeling in a mouse model mimicking percutaneous coronary intervention (PCI). Associations between the rs4833229 (OR = 1.29 (CI 95%), p(allelic) = 0.011) and rs6830321 (OR = 1.35 (CI 95%), p(allelic) = 0.003) SNPs in the AnxA5 gene and increased restenosis-risk in patients undergoing PCI were found in the GENDER study. To evaluate AnxA5 effects on post-interventional vascular remodeling and accelerated atherosclerosis development in vivo, hypercholesterolemic ApoE(-/-) mice underwent femoral arterial cuff placement to induce intimal thickening. Dose-dependent effects were investigated after 3 days (effects on inflammation and leukocyte recruitment) or 14 days (effects on remodeling) after cuff placement. Systemically administered AnxA5 in doses of 0.1, 0.3 and 1.0mg/kg compared to vehicle reduced early leukocyte and macrophage adherence up to 48.3% (p = 0.001) and diminished atherosclerosis development by 71.2% (p = 0.012) with a reduction in macrophage/foam cell presence. Moreover, it reduced the expression of the endoplasmic reticulum stress marker GRP78/BiP, indicating lower inflammatory activity of the cells present. AnxA5 SNPs could serve as markers for restenosis after PCI and AnxA5 therapeutically prevents vascular remodeling in a dose-dependent fashion, together indicating clinical potential for AnxA5 against post-interventional remodeling. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Statins suppress apolipoprotein CIII-induced vascular endothelial cell activation and monocyte adhesion.

PubMed

Zheng, Chunyu; Azcutia, Veronica; Aikawa, Elena; Figueiredo, Jose-Luiz; Croce, Kevin; Sonoki, Hiroyuki; Sacks, Frank M; Luscinskas, Francis W; Aikawa, Masanori

2013-02-01

Activation of vascular endothelial cells (ECs) contributes importantly to inflammation and atherogenesis. We previously reported that apolipoprotein CIII (apoCIII), found abundantly on circulating triglyceride-rich lipoproteins, enhances adhesion of human monocytes to ECs in vitro. Statins may exert lipid-independent anti-inflammatory effects. The present study examined whether statins suppress apoCIII-induced EC activation in vitro and in vivo. Physiologically relevant concentrations of purified human apoCIII enhanced attachment of the monocyte-like cell line THP-1 to human saphenous vein ECs (HSVECs) or human coronary artery ECs (HCAECs) under both static and laminar shear stress conditions. This process mainly depends on vascular cell adhesion molecule-1 (VCAM-1), as a blocking VCAM-1 antibody abolished apoCIII-induced monocyte adhesion. ApoCIII significantly increased VCAM-1 expression in HSVECs and HCAECs. Pre-treatment with statins suppressed apoCIII-induced VCAM-1 expression and monocyte adhesion, with two lipophilic statins (pitavastatin and atorvastatin) exhibiting inhibitory effects at lower concentration than those of hydrophilic pravastatin. Nuclear factor κB (NF-κB) mediated apoCIII-induced VCAM-1 expression, as demonstrated via loss-of-function experiments, and pitavastatin treatment suppressed NF-κB activation. Furthermore, in the aorta of hypercholesterolaemic Ldlr(-/-) mice, pitavastatin administration in vivo suppressed VCAM-1 mRNA and protein, induced by apoCIII bolus injection. Similarly, in a subcutaneous dorsal air pouch mouse model of leucocyte recruitment, apoCIII injection induced F4/80+ monocyte and macrophage accumulation, whereas pitavastatin administration reduced this effect. These findings further establish the direct role of apoCIII in atherogenesis and suggest that anti-inflammatory effects of statins could improve vascular disease in the population with elevated plasma apoCIII.

Chlorella 11-Peptide Inhibits the Production of Macrophage-Induced Adhesion Molecules and Reduces Endothelin-1 Expression and Endothelial Permeability

PubMed Central

Shih, Mei Fen; Chen, Lih Chi; Cherng, Jong Yuh

2013-01-01

The inflammation process in large vessels involves the up-regulation of vascular adhesion molecules such as endothelial cell selectin (E-selectin), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) which are also known as the markers of atherosclerosis. We have reported that Chlorella 11-peptide exhibited effective anti-inflammatory effects. This peptide with an amino sequence Val-Glu-Cys-Tyr-Gly-Pro-Asn-Arg-Pro-Gln-Phe was further examined for its potential in preventing atherosclerosis in this study. In particular, the roles of Chlorella 11-peptide in lowering the production of vascular adhesion molecules, monocyte chemoattractant protein (MCP-1) and expression of endothelin-1 (ET-1) from endothelia (SVEC4-10 cells) were studied. The production of E-selectin, ICAM-1, VCAM-1 and MCP-1 in SVEC4-10 cells was measured with ELISA. The mRNA expression of ET-1 was analyzed by RT-PCR and agarose gel. Results showed that Chlorella 11-peptide significantly suppressed the levels of E-selectin, ICAM, VCAM, MCP-1 as well as ET-1 gene expression. The inhibition of ICAM-1 and VCAM-1 production by Chlorella 11-peptide was reversed in the presence of protein kinase A inhibitor (H89) which suggests that the cAMP pathway was involved in the inhibitory cause of the peptide. In addition, this peptide was shown to reduce the extent of increased intercellular permeability induced by combination of 50% of lipopolysaccharide (LPS)-activated RAW 264.7 cells medium and 50% normal SEVC cell culture medium (referred to as 50% RAW-conditioned medium). These data demonstrate that Chlorella 11-peptide is a promising biomolecule in preventing chronic inflammatory-related vascular diseases. PMID:24129228

Nanostructures to modulate vascular inflammation: Multifunctional nanoparticles for quantifiable siRNA delivery and molecular imaging

NASA Astrophysics Data System (ADS)

Kaneda, Megan Marie

Early steps in the progression of inflammatory diseases such as atherosclerosis involve the recruitment of leukocytes to the vascular endothelium through the expression or up-regulation of adhesion molecules. These adhesion molecules are critical mediators of leukocyte attachment and subsequent extravasation through transendothelial migration. One of these adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) is particularly attractive as a marker of early atherosclerotic activity due to its low expression level on normal endothelium and up-regulation prior to and during the development of early lesions. With this in mind, the purpose of this thesis was to develop nanostructures for the detection and down-regulation of adhesion molecules by the vascular endothelium. To detect early inflammation we designed a perfluorocarbon nanoparticle (PFC-NP) probe, which was used for in vivo targeting of VCAM-1. Nanoparticles were detected ex vivo by the magnetic resonance (MR) signature from the fluorine core of the particle. Nanoparticles accumulated in tissues characterized by early inflammatory processes. To down-regulate VCAM-1 expression by vascular endothelial cells, cationic PFC-NP were produced through the addition of the cationic lipid 1,2-Dioleoyl-3-Trimethylammonium-Propane. Cationic PFC-NP were able to deliver anti-VCAM-1 siRNA to endothelial cells through a non-standard lipid raft mediated endocytic pathway. VCAM-1 levels were significantly reduced in treated cells indicating that this delivery mechanism may be advantageous for delivery of cargo into the cytoplasm. Using the fluorine signature from the core of the cationic PFC-NP, we were able to quantify and localize this siRNA delivery agent both in vitro and in vivo. The ability to quantify the local concentrations of these particles could be of great benefit for estimating local drug concentrations and developing new pharmacokinetic and pharmacodynamic paradigms to describe this new class of nucleotide agents.

Imaging of the Posterior Skull Base.

PubMed

Job, Joici; Branstetter, Barton F

2017-01-01

The posterior skull base can be involved by a variety of pathologic processes. They can be broadly classified as: traumatic, neoplastic, vascular, and inflammatory. Pathology in the posterior skull base usually involves the lower cranial nerves, either as a source of pathology or a secondary source of symptoms. This review will categorize pathology arising in the posterior skull base and describe how it affects the skull base itself and surrounding structures. Copyright © 2016 Elsevier Inc. All rights reserved.

Impact of processing parameters on the haemocompatibility of Bombyx mori silk films.

PubMed

Seib, F Philipp; Maitz, Manfred F; Hu, Xiao; Werner, Carsten; Kaplan, David L

2012-02-01

Silk has traditionally been used for surgical sutures due to its lasting strength and durability; however, the use of purified silk proteins as a scaffold material for vascular tissue engineering goes beyond traditional use and requires application-orientated biocompatibility testing. For this study, a library of Bombyx mori silk films was generated and exposed to various solvents and treatment conditions to reflect current silk processing techniques. The films, along with clinically relevant reference materials, were exposed to human whole blood to determine silk blood compatibility. All substrates showed an initial inflammatory response comparable to polylactide-co-glycolide (PLGA), and a low to moderate haemostasis response similar to polytetrafluoroethylene (PTFE) substrates. In particular, samples that were water annealed at 25 °C for 6 h demonstrated the best blood compatibility based on haemostasis parameters (e.g. platelet decay, thrombin-antithrombin complex, platelet factor 4, granulocytes-platelet conjugates) and inflammatory parameters (e.g. C3b, C5a, CD11b, surface-associated leukocytes). Multiple factors such as treatment temperature and solvent influenced the biological response, though no single physical parameter such as β-sheet content, isoelectric point or contact angle accurately predicted blood compatibility. These findings, when combined with prior in vivo data on silk, support a viable future for silk-based vascular grafts. Copyright © 2011 Elsevier Ltd. All rights reserved.

Activation of Cell Surface Bound 20S Proteasome Inhibits Vascular Cell Growth and Arteriogenesis

PubMed Central

Ito, Wulf D.; Lund, Natalie; Zhang, Ziyang; Buck, Friedrich; Lellek, Heinrich; Horst, Andrea; Machens, Hans-Günther; Schunkert, Heribert; Schaper, Wolfgang; Meinertz, Thomas

2015-01-01

Arteriogenesis is an inflammatory process associated with rapid cellular changes involving vascular resident endothelial progenitor cells (VR-EPCs). Extracellular cell surface bound 20S proteasome has been implicated to play an important role in inflammatory processes. In our search for antigens initially regulated during collateral growth mAb CTA 157-2 was generated against membrane fractions of growing collateral vessels. CTA 157-2 stained endothelium of growing collateral vessels and the cell surface of VR-EPCs. CTA 157-2 bound a protein complex (760 kDa) that was identified as 26 kDa α7 and 21 kDa β3 subunit of 20S proteasome in mass spectrometry. Furthermore we demonstrated specific staining of 20S proteasome after immunoprecipitation of VR-EPC membrane extract with CTA 157-2 sepharose beads. Functionally, CTA 157-2 enhanced concentration dependently AMC (7-amino-4-methylcoumarin) cleavage from LLVY (N-Succinyl-Leu-Leu-Val-Tyr) by recombinant 20S proteasome as well as proteasomal activity in VR-EPC extracts. Proliferation of VR-EPCs (BrdU incorporation) was reduced by CTA 157-2. Infusion of the antibody into the collateral circulation reduced number of collateral arteries, collateral proliferation, and collateral conductance in vivo. In conclusion our results indicate that extracellular cell surface bound 20S proteasome influences VR-EPC function in vitro and collateral growth in vivo. PMID:26146628

Endoplasmic Reticulum Stress Mediates the Anti-Inflammatory Effect of Ethyl Pyruvate in Endothelial Cells

PubMed Central

Yi, Wei; Yang, Yang; Zhao, Dajun; Yang, Honggang; Geng, Ting; Xing, Jianzhou; Zhang, Yu; Tan, Songtao; Yi, Dinghua

2014-01-01

Ethyl pyruvate (EP) is a simple aliphatic ester of the metabolic intermediate pyruvate that has been demonstrated to be a potent anti-inflammatory agent in a variety of in vivo and in vitro model systems. However, the protective effects and mechanisms underlying the actions of EP against endothelial cell (EC) inflammatory injury are not fully understood. Previous studies have confirmed that endoplasmic reticulum stress (ERS) plays an important role in regulating the pathological process of EC inflammation. In this study, our aim was to explore the effects of EP on tumor necrosis factor-α (TNF-α)-induced inflammatory injury in human umbilical vein endothelial cells (HUVECs) and to explore the role of ERS in this process. TNF-α treatment not only significantly increased the adhesion of monocytes to HUVECs and inflammatory cytokine (sICAM1, sE-selectin, MCP-1 and IL-8) production in cell culture supernatants but it also increased ICAM and MMP9 protein expression in HUVECs. TNF-α also effectively increased the ERS-related molecules in HUVECs (GRP78, ATF4, caspase12 and p-PERK). EP treatment effectively reversed the effects of the TNF-α-induced adhesion of monocytes on HUVECs, inflammatory cytokines and ERS-related molecules. Furthermore, thapsigargin (THA, an ERS inducer) attenuated the protective effects of EP against TNF-α-induced inflammatory injury and ERS. The PERK siRNA treatment not only inhibited ERS-related molecules but also mimicked the protective effects of EP to decrease TNF-α-induced inflammatory injury. In summary, we have demonstrated for the first time that EP can effectively reduce vascular endothelial inflammation and that this effect at least in part depends on the attenuation of ERS. PMID:25470819

Relationship between vascular endothelium and periodontal disease in atherosclerotic lesions: Review article

PubMed Central

Saffi, Marco Aurélio Lumertz; Furtado, Mariana Vargas; Polanczyk, Carisi Anne; Montenegro, Márlon Munhoz; Ribeiro, Ingrid Webb Josephson; Kampits, Cassio; Haas, Alex Nogueira; Rösing, Cassiano Kuchenbecker; Rabelo-Silva, Eneida Rejane

2015-01-01

Inflammation and endothelial dysfunction are linked to the pathogenesis of atherosclerotic disease. Recent studies suggest that periodontal infection and the ensuing increase in the levels of inflammatory markers may be associated with myocardial infarction, peripheral vascular disease and cerebrovascular disease. The present article aimed at reviewing contemporary data on the pathophysiology of vascular endothelium and its association with periodontitis in the scenario of cardiovascular disease. PMID:25632316

Local injections of corticotropin releasing factor reduce doxorubicin-induced acute inflammation in the eyelid.

PubMed

McLoon, L K; Wirtschafter, J

1997-04-01

Doxorubicin chemomyectomy is an effective alternative treatment option for patients with blepharospasm and hemifacial spasm. One side effect of the use of doxorubicin in localized injections is the development of acute inflammation and skin injury at the injection site. Corticotropin releasing factor (CRF) was reported to reduce inflammation after acute inflammatory injuries due to other causes and at other sites. This study was performed to assess the potential of CRF to prevent the development of skin injury and eyelid soreness after local doxorubicin injection. Rabbits received lower eyelid injections of either 75 or 150 micrograms CRF followed by injection of either 0.5, 1, or 2 mg doxorubicin or doxorubicin alone. Eyelids were assessed for changes in acute inflammation by immunohistochemical localization of macrophages and monocytes using anti-CD11, an antibody specific for these cell types. Short-term alterations in vascular permeability were assessed using an Evans blue assay. Additional eyelids were followed daily for changes in the skin over the injection site to determine day of onset of skin injury and the total duration of skin injury. After 1 month, the eyelids were processed histologically for morphometric analysis of muscle fiber loss. Monkey eyelids also were examined for the effect of CRF and doxorubicin injections. Doxorubicin alone produced an acute inflammatory reaction in the treated eyelids, with a large influx of macrophages and monocytes throughout the connective tissue at 1 and 2 days. Corticotropin releasing factor pretreatment significantly reduced this influx of inflammatory cells into the connective tissue. Doxorubicin produced a large increase in vascular permeability in the treated eyelids, with resultant edema. Corticotropin releasing factor did not alter this change in vascular permeability, indicating that CRF appears to have a specific effect on migration of inflammatory cells rather than just a generalized effect on vascular permeability. Corticotropin releasing factor and doxorubicin cotreatments delayed the onset of skin injury and decreased the total duration of injury to the skin compared to doxorubicin alone. The effectiveness of doxorubicin chemomyectomy was maintained; muscle loss was significant at all doses of CRF combined with doxorubicin. Corticotropin releasing factor dramatically decreased the acute inflammatory reaction that results in the eyelid from local doxorubicin injections. Not only did CRF reduce the acute influx of monocytes and macrophages, but it protected the skin overlying the injection site, substantially reducing the extent of skin injury. The efficacy of doxorubicin-induced muscle toxicity was maintained. A treatment protocol that combines myotoxicity with antiinflammatory activity in the treated eyelids may lead to a more effective patient treatment by increasing patient acceptance. The potential should be explored that CRF may be of clinical use in limiting tissue injury when administered immediately after extravasation during cancer chemotherapy.

Tumors: Wounds that do not heal--Redux

PubMed Central

Dvorak, Harold F.

2014-01-01

Similarities between tumors and the inflammatory response associated with wound healing have been recognized for more than 150 years and continue to intrigue. Some years ago, based on our then recent discovery of vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF), I suggested that tumors behaved as wounds that do not heal. More particularly, I proposed that tumors co-opted the wound healing response in order to induce the stroma they required for maintenance and growth. Work over the past few decades has supported this hypothesis and has put it on a firmer molecular basis. In outline, VPF/VEGF initiates a sequence of events in both tumors and wounds that includes the following: increased vascular permeability; extravasation of plasma, fibrinogen and other plasma proteins; activation of the clotting system outside the vascular system; deposition of an extravascular fibrin gel which serves as a provisional stroma and a favorable matrix for cell migration; induction of angiogenesis and arterio-venogenesis; subsequent degradation of fibrin and its replacement by “granulation tissue” (highly vascular connective tissue); and, finally, vascular resorption and collagen synthesis, resulting in the formation of dense fibrous connective tissue (called “scar tissue” in wounds and “desmoplasia” in cancer). A similar sequence of events also takes place in a variety of important inflammatory diseases that involve cellular immunity. PMID:25568067

Idiopathic Canalicular Inflammatory Disease: New Disease Description of Clinical Patterns, Investigations, Management, and Outcomes.

PubMed

Ali, Mohammad Javed

2018-01-25

The objective of this perspective is to present a separate disease description of "idiopathic canalicular inflammatory disease" and outline the diagnostic criteria and early experiences with its investigations and management. Retrospective case series of 44 canaliculi of 22 eyes of 11 patients presenting at a tertiary care Dacryology service over a period of 2 years with typical clinical patterns of inflammatory canaliculitis and its outcomes were studied. All the patients underwent microbiological work-up with culture and sensitivity, dacryoendoscopy imaging, serial Fourier domain ocular coherence tomography, and collagen vascular profiles. Stages in the evolution of the disease were studied. All patients were treated initially with topical steroids followed by punctal dilatation and placement of mini-monoka stents. Five patients in addition had a small biopsy from the inflamed portion of the vertical canaliculus. Stents were extubated at 6 weeks. Forty-four canaliculi were diagnosed to have idiopathic canalicular inflammatory disease during the study period. There was a female preponderance (81.8%, 9/11) and the mean age at presentation was 57 years. All patients presented with unilateral epiphora without any discharge, pain, or swelling. Collagen vascular profiles and screening for autoimmune diseases were negative. Clinical picture ranged from stages 1 to 5, consisting of edema, progressive centripetal vascularization, pouting of vascularized mucosa, membrane formation, and progressive scarring. The presentation begins in 1 eye and usually involves the other eye at a mean of 6 months. Ocular coherence tomography and dacryoendoscopy were of adjunctive value in the diagnosis. Histopathological examination was suggestive of a chronic inflammation. All patients had relentless progression to end-stage disease, although delayed significantly by steroids and monoka intubation. Idiopathic canalicular inflammatory disease has a distinct and typical clinical behavior and the current study proposed diagnostic features and disease staging. The use of topical and systemic immunosuppressive agents needs to be explored to formulate effective protocols for its management.

Copper chelation by tetrathiomolybdate inhibits lipopolysaccharide-induced inflammatory responses in vivo

PubMed Central

Wei, Hao; Beckman, Joseph S.; Zhang, Wei-Jian

2011-01-01

Redox-active transition metal ions, such as iron and copper, may play an important role in vascular inflammation, which is an etiologic factor in atherosclerotic vascular diseases. In this study, we investigated whether tetrathiomolybdate (TTM), a highly specific copper chelator, can act as an anti-inflammatory agent, preventing lipopolysaccharide (LPS)-induced inflammatory responses in vivo. Female C57BL/6N mice were daily gavaged with TTM (30 mg/kg body wt) or vehicle control. After 3 wk, animals were injected intraperitoneally with 50 μg LPS or saline buffer and killed 3 h later. Treatment with TTM reduced serum ceruloplasmin activity by 43%, a surrogate marker of bioavailable copper, in the absence of detectable hepatotoxicity. The concentrations of both copper and molybdenum increased in various tissues, whereas the copper-to-molybdenum ratio decreased, consistent with reduced copper bioavailability. TTM treatment did not have a significant effect on superoxide dismutase activity in heart and liver. Furthermore, TTM significantly inhibited LPS-induced inflammatory gene transcription in aorta and heart, including vascular and intercellular adhesion molecule-1 (VCAM-1 and ICAM-1, respectively), monocyte chemotactic protein-1 (MCP-1), interleukin-6, and tumor necrosis factor (TNF)-α (ANOVA, P < 0.05); consistently, protein levels of VCAM-1, ICAM-1, and MCP-1 in heart were also significantly lower in TTM-treated animals. Similar inhibitory effects of TTM were observed on activation of nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) in heart and lungs. Finally, TTM significantly inhibited LPS-induced increases of serum levels of soluble ICAM-1, MCP-1, and TNF-α (ANOVA, P < 0.05). These data indicate that copper chelation with TTM inhibits LPS-induced inflammatory responses in aorta and other tissues of mice, most likely by inhibiting activation of the redox-sensitive transcription factors, NF-κB and AP-1. Therefore, copper appears to play an important role in vascular inflammation, and TTM may have value as an anti-inflammatory or anti-atherogenic agent. PMID:21724870

The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension

PubMed Central

Martin, Damien H.; Wadsworth, Roger; Bryson, Gareth; Fisher, Andrew J.; Welsh, David J.; Peacock, Andrew J.

2015-01-01

The p38 mitogen-activated protein kinase (MAPK) system is increasingly recognized as an important inflammatory pathway in systemic vascular disease but its role in pulmonary vascular disease is unclear. Previous in vitro studies suggest p38 MAPKα is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod). In this study the role of the p38 MAPK pathway was investigated in both in vitro and in vivo models of pulmonary hypertension and human disease. Pharmacological inhibition of p38 MAPKα in both chronic hypoxic and monocrotaline rodent models of pulmonary hypertension prevented and reversed the pulmonary hypertensive phenotype. Furthermore, with the use of a novel and clinically available p38 MAPKα antagonist, reversal of pulmonary hypertension was obtained in both experimental models. Increased expression of phosphorylated p38 MAPK and p38 MAPKα was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in the PVremod A reduction of IL-6 levels in serum and lung tissue was found in the drug-treated animals, suggesting a potential mechanism for this reversal in PVremod. This study suggests that the p38 MAPK and the α-isoform plays a pathogenic role in both human disease and rodent models of pulmonary hypertension potentially mediated through IL-6. Selective inhibition of this pathway may provide a novel therapeutic approach that targets both remodeling and inflammatory pathways in pulmonary vascular disease. PMID:26024891

Vascular and inflammatory high fat meal responses in young healthy men; a discriminative role of IL-8 observed in a randomized trial.

PubMed

Esser, Diederik; Oosterink, Els; op 't Roodt, Jos; Henry, Ronald M A; Stehouwer, Coen D A; Müller, Michael; Afman, Lydia A

2013-01-01

High fat meal challenges are known to induce postprandial low-grade inflammation and endothelial dysfunction. This assumption is largely based on studies performed in older populations or in populations with a progressed disease state and an appropriate control meal is often lacking. Young healthy individuals might be more resilient to such challenges. We therefore aimed to characterize the vascular and inflammatory response after a high fat meal in young healthy individuals. In a double-blind randomized cross-over intervention study, we used a comprehensive phenotyping approach to determine the vascular and inflammatory response after consumption of a high fat shake and after an average breakfast shake in 20 young healthy subjects. Both interventions were performed three times. Many features of the vascular postprandial response, such as FMD, arterial stiffness and micro-vascular skin blood flow were not different between shakes. High fat/high energy shake consumption was associated with a more pronounced increase in blood pressure, heart rate, plasma concentrations of IL-8 and PBMCs gene expression of IL-8 and CD54 (ICAM-1), whereas plasma concentrations of sVCAM1 were decreased compared to an average breakfast. Whereas no difference in postprandial response were observed on classical markers of endothelial function, we did observe differences between consumption of a HF/HE and an average breakfast meal on blood pressure and IL-8 in young healthy volunteers. IL-8 might play an important role in dealing with high fat challenges and might be an early marker for endothelial stress, a stage preceding endothelial dysfunction.

6-Methylsulfinylhexyl isothiocyanate modulates endothelial cell function and suppresses leukocyte adhesion.

PubMed

Okamoto, Takayuki; Akita, Nobuyuki; Nagai, Masashi; Hayashi, Tatsuya; Suzuki, Koji

2014-01-01

6-Methylsulfinylhexyl isothiocyanate (6-MSITC) is an active compound in wasabi (Wasabia japonica Matsum.), which is one of the most popular spices in Japan. 6-MSITC suppresses lipopolysaccharide-induced macrophage activation, arachidonic- or adenosine diphosphate-induced platelet activation, and tumor cell proliferation. These data indicate that 6-MSITC has several biological activities involving anti-inflammatory, anti-coagulant, and anti-apoptosis properties. Endothelial cells (ECs) maintain vascular homeostasis and play crucial roles in crosstalk between blood coagulation and vascular inflammation. In this study, we determined the anti-coagulant and anti-inflammatory effects of 6-MSITC on human umbilical vein endothelial cells (HUVECs). 6-MSITC slightly reduced tissue factor expression, but did not alter von Willebrand factor release in activated HUVECs. 6-MSITC modulated the generation of activated protein C, which is essential for negative regulation of blood coagulation, on normal ECs. In addition, 6-MSITC reduced tumor necrosis factor-α (TNF-α)-induced interleukin-6 and monocyte chemoattractant protein-1 expression. 6-MSITC markedly attenuated TNF-α-induced adhesion of human monoblast U937 cells to HUVECs and reduced vascular cell adhesion molecule-1 and E-selectin mRNA expression in activated ECs. These results showed that 6-MSITC modulates EC function and suppresses cell adhesion. This study provides new insight into the mechanism of the anti-inflammatory effect of 6-MSITC, suggesting that 6-MSITC has therapeutic potential as a treatment for vasculitis and vascular inflammation.

Aldosterone induces a vascular inflammatory phenotype in the rat heart.

PubMed

Rocha, Ricardo; Rudolph, Amy E; Frierdich, Gregory E; Nachowiak, Denise A; Kekec, Beverly K; Blomme, Eric A G; McMahon, Ellen G; Delyani, John A

2002-11-01

Vascular inflammation was examined as a potential mechanism of aldosterone-mediated myocardial injury in uninephrectomized rats receiving 1% NaCl-0.3% KCl to drink for 1, 2, or 4 wk and 1) vehicle, 2) aldosterone infusion (0.75 microg/h), or 3) aldosterone infusion (0.75 microg/h) plus the selective aldosterone blocker eplerenone (100 mg. kg(-1). day(-1)). Aldosterone induced severe hypertension at 4 wk [systolic blood pressure (SBP), 210 +/- 3 mmHg vs. vehicle, 131 +/- 2 mmHg, P < 0.001], which was partially attenuated by eplerenone (SBP, 180 +/- 7 mmHg; P < 0.001 vs. aldosterone alone and vehicle). No significant increases in myocardial interstitial collagen fraction or hydroxyproline concentration were detected throughout the study. However, histopathological analysis of the heart revealed severe coronary inflammatory lesions, which were characterized by monocyte/macrophage infiltration and resulted in focal ischemic and necrotic changes. The histological evidence of coronary lesions was preceded by and associated with the elevation of cyclooxygenase-2 (up to approximately 4-fold), macrophage chemoattractant protein-1 (up to approximately 4-fold), and osteopontin (up to approximately 13-fold) mRNA expression. Eplerenone attenuated proinflammatory molecule expression in the rat heart and subsequent vascular and myocardial damage. Thus aldosterone and salt treatment in uninephrectomized rats led to severe hypertension and the development of a vascular inflammatory phenotype in the heart, which may represent one mechanism by which aldosterone contributes to myocardial disease.

Possible role of mechanical force in regulating regeneration of the vascularized fat flap inside a tissue engineering chamber.

PubMed

Ye, Yuan; Yuan, Yi; Lu, Feng; Gao, Jianhua

2015-12-01

In plastic and reconstructive surgery, adipose tissue is widely used as effective filler for tissue defects. Strategies for treating soft tissue deficiency, which include free adipose tissue grafts, use of hyaluronic acid, collagen injections, and implantation of synthetic materials, have several clinical limitations. With the aim of overcoming these limitations, researchers have recently utilized tissue engineering chambers to produce large volumes of engineered vascularized fat tissue. However, the process of growing fat tissue in a chamber is still relatively limited, and can result in unpredictable or dissatisfactory final tissue volumes. Therefore, detailed understanding of the process is both necessary and urgent. Many studies have shown that mechanical force can change the function of cells via mechanotransduction. Here, we hypothesized that, besides the inflammatory response, one of the key factors to control the regeneration of vascularized fat flap inside a tissue engineering chamber might be the balance of mechanical forces. To test our hypothesis, we intend to change the balance of forces by means of measures in order to make the equilibrium point in favor of the direction of regeneration. If those measures proved to be feasible, they could be applied in clinical practice to engineer vascularized adipose tissue of predictable size and shape, which would in turn help in the advancement of tissue engineering. Copyright © 2015 Elsevier Ltd. All rights reserved.

Macrophage deficiency of miR-21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis.

PubMed

Canfrán-Duque, Alberto; Rotllan, Noemi; Zhang, Xinbo; Fernández-Fuertes, Marta; Ramírez-Hidalgo, Cristina; Araldi, Elisa; Daimiel, Lidia; Busto, Rebeca; Fernández-Hernando, Carlos; Suárez, Yajaira

2017-09-01

Atherosclerosis, the major cause of cardiovascular disease, is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells in the artery wall. Aberrant expression of microRNAs has been implicated in the pathophysiological processes underlying the progression of atherosclerosis. Here, we define the contribution of miR-21 in hematopoietic cells during atherogenesis. Interestingly, we found that miR-21 is the most abundant miRNA in macrophages and its absence results in accelerated atherosclerosis, plaque necrosis, and vascular inflammation. miR-21 expression influences foam cell formation, sensitivity to ER-stress-induced apoptosis, and phagocytic clearance capacity. Mechanistically, we discovered that the absence of miR-21 in macrophages increases the expression of the miR-21 target gene, MKK3, promoting the induction of p38-CHOP and JNK signaling. Both pathways enhance macrophage apoptosis and promote the post-translational degradation of ABCG1, a transporter that regulates cholesterol efflux in macrophages. Altogether, these findings reveal a major role for hematopoietic miR-21 in atherogenesis. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

Potential Mechanisms Linking Atherosclerosis and Increased Cardiovascular Risk in COPD: Focus On Sirtuins

PubMed Central

Corbi, Graziamaria; Bianco, Andrea; Turchiarelli, Viviana; Cellurale, Michele; Fatica, Federica; Daniele, Aurora; Mazzarella, Gennaro; Ferrara, Nicola

2013-01-01

The development of atherosclerosis is a multi-step process, at least in part controlled by the vascular endothelium function. Observations in humans and experimental models of atherosclerosis have identified monocyte recruitment as an early event in atherogenesis. Chronic inflammation is associated with ageing and its related diseases (e.g., atherosclerosis and chronic obstructive pulmonary disease). Recently it has been discovered that Sirtuins (NAD+-dependent deacetylases) represent a pivotal regulator of longevity and health. They appear to have a prominent role in vascular biology and regulate aspects of age-dependent atherosclerosis. Many studies demonstrate that SIRT1 exhibits anti-inflammatory properties in vitro (e.g., fatty acid-induced inflammation), in vivo (e.g., atherosclerosis, sustainment of normal immune function in knock-out mice) and in clinical studies (e.g., patients with chronic obstructive pulmonary disease). Because of a significant reduction of SIRT1 in rodent lungs exposed to cigarette smoke and in lungs of patients with chronic obstructive pulmonary disease (COPD), activation of SIRT1 may be a potential target for chronic obstructive pulmonary disease therapy. We review the inflammatory mechanisms involved in COPD-CVD coexistence and the potential role of SIRT1 in the regulation of these systems. PMID:23774840

Central role of endogenous Toll-like receptor-2 activation in regulating inflammation, reactive oxygen species production, and subsequent neointimal formation after vascular injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shishido, Tetsuro; Nozaki, Naoki; Takahashi, Hiroki

2006-07-14

Background: It is now evident that inflammation after vascular injury has significant impact on the restenosis after revascularization procedures such as angioplasty, stenting, and bypass grafting. However, the mechanisms that regulate inflammation and repair after vascular injury are incompletely understood. Here, we report that vascular injury-mediated cytokine expression, reactive oxygen species (ROS) production, as well as subsequent neointimal formation requires Toll-like receptor-2 (TLR-2) mediated signaling pathway in vivo. Methods and results: Vascular injury was induced by cuff-placement around the femoral artery in non-transgenic littermates (NLC) and TLR-2 knockout (TLR-2KO) mice. After cuff-placement in NLC mice, expression of TLR-2 was significantlymore » increased in both smooth muscle medial layer and adventitia. Interestingly, we found that inflammatory genes expression such as tumor necrosis factor-{alpha}, interleukin-1{beta} (IL-1{beta}), IL-6, and monocyte chemoattractant protein-1 were markedly decreased in TLR-2KO mice compared with NLC mice. In addition, ROS production after vascular injury was attenuated in TLR-2KO mice compared with NLC mice. Since we observed the significant role of endogenous TLR-2 activation in regulating inflammatory responses and ROS production after vascular injury, we determined whether inhibition of endogenous TLR-2 activation can inhibit neointimal proliferation after vascular injury. Neointimal hyperplasia was markedly suppressed in TLR-2KO mice compared with WT mice at both 2 and 4 weeks after vascular injury. Conclusions: These findings suggested that endogenous TLR-2 activation might play a central role in the regulation of vascular inflammation as well as subsequent neointimal formation in injured vessels.« less

Neutrophil proteinase 3 (PR3) acts on protease-activated receptor-2 (PAR-2) to enhance vascular endothelial cell barrier function

PubMed Central

Kuckleburg, Christopher J.; Newman, Peter J.

2013-01-01

The principle role of the vascular endothelium is to present a semi-impermeable barrier to soluble factors and circulating cells, while still permitting the passage of leukocytes from the bloodstream into the tissue. The process of diapedesis involves the selective disruption of endothelial cell junctions, an event that could in theory compromise vascular integrity. It is therefore somewhat surprising that neutrophil transmigration does not significantly impair endothelial barrier function. We examined whether neutrophils might secrete factors that promote vascular integrity during the latter stages of neutrophil transmigration, and found that neutrophil proteinase 3 (PR3) – a serine protease harbored in azurophilic granules – markedly enhanced barrier function in endothelial cells. PR3 functioned in this capacity both in its soluble form and in a complex with cell-surface NB1. PR3-mediated enhancement of endothelial cell junctional integrity required its proteolytic activity, as well as endothelial cell expression of the protease-activated receptor, PAR-2. Importantly, PR3 suppressed the vascular permeability changes and disruption of junctional proteins induced by the action of PAR-1 agonists. These findings establish the potential for neutrophil-derived PR3 to play a role in reestablishing vascular integrity following leukocyte transmigration, and in protecting endothelial cells from PAR-1-induced permeability changes that occur during thrombotic and inflammatory events. PMID:23202369

Anti-inflammatory treatment improves high-density lipoprotein function in rheumatoid arthritis

PubMed Central

O'Neill, Francis; Charakida, Marietta; Topham, Eric; McLoughlin, Eve; Patel, Neha; Sutill, Emma; Kay, Christopher W M; D'Aiuto, Francesco; Landmesser, Ulf; Taylor, Peter C; Deanfield, John

2017-01-01

Objective Patients with rheumatoid arthritis (RA) are at increased cardiovascular risk. Recent studies suggest that high-density lipoprotein (HDL) may lose its protective vascular phenotype in inflammatory conditions. However, the effects of common anti-inflammatory treatments on HDL function are not yet known. Methods We compared the function of HDL in 18 patients with RA and 18 matched healthy controls. Subsequently, patients were randomised to (methotrexate+infliximab (M+I) (5 mg/kg)) or methotrexate+placebo (M+P) infusions for 54 weeks. At week 54 and thereafter, all patients received infliximab therapy until completion of the trial (110 weeks), enabling assessment of the impact of 1 year of infliximab therapy in all patients. HDL functional properties were assessed at baseline, 54 weeks and 110 weeks by measuring the impact on endothelial nitric oxide (NO) bioavailability and superoxide production (SO), paraoxonase activity (PON-1) and cholesterol efflux. Results All HDL vascular assays were impaired in patients compared with controls. After 54 weeks, NO in response to HDL was significantly greater in patients who received M+I compared with those who received M+P. Endothelial SO in response to HDL was reduced in both groups, but PON-1 and cholesterol efflux remained unchanged. All vascular measures improved compared with baseline after ≥1 infliximab therapy in the analysis at 110 weeks. No significant trend was noted for cholesterol efflux. Conclusions HDL function can be improved with anti-inflammatory treatment in patients with RA. The M+I combination was superior to the M+P alone, suggesting that the tumour necrosis factor-α pathway may have a role in HDL vascular properties. PMID:27852695

ELECTROACUPUNCTURE AT THE WANGU ACUPOINT SUPPRESSES EXPRESSION OF INFLAMMATORY CYTOKINES IN THE HIPPOCAMPUS OF RATS WITH VASCULAR DEMENTIA.

PubMed

Fang, Yanan; Sui, Rubo

2016-01-01

Vascular dementia (VD) is the most frequent psychiatric complication of stroke, and is often difficult to treat. Incidence rate of vascular cognition impairment is still 70% after stroke in one year (Sui R et al.2011). Stroke patients with VD suffer from a higher mortality rate and have worse functional outcomes and quality of life. However, despite the extensive literatures on this topic, there is no agreement on the causal mechanisms and effective therapy for VD. The objective of this study is to examine if electroacupuncture at the Wangu acupoint (GB 12), whose position is similar to the cerebellar fastigial nucleus, could reduce inflammatory cytokines in the hippocampus of rats with vascular dementia (VD). The 54 healthy, male, Sprague-Dawley (SD) rats, 9 months old, and of clean grade (300-450) g, were randomly divided into three groups: sham surgery group, VD group and electro-acupuncture group. The ethology scores of VD rats were evaluated and the mRNA expressions of inflammatory cytokines (TNF-α, IL-6 and IL-1β) in the hippocampus were assessed and the hippocampal tissues were observed by hematoxylin-eosin staining. Compared with the VD group, in the electroacupuncture group, the rats' learning ability improved significantly and the mRNA expression of TNF-α, IL-6 and IL-1β decreased. Simultaneously, the damage extent of nerve cells in the hippocampal tissues decreased, with their morphology recovered to nearly normal. Electro-acupuncture at the Wangu acupoint can decrease the levels of inflammatory cytokines in the hippocampus, reduce the damage extent of nerve cells in the hippocampus, and thus provide a new neuroprotective method in VD.

Evaluation of magnetic resonance imaging for the differentiation of inflammatory, neoplastic, and vascular intradural spinal cord diseases in the dog.

PubMed

Masciarelli, Amanda E; Griffin, John F; Fosgate, Geoffrey T; Hecht, Silke; Mankin, Joseph M; Holmes, Shannon P; Platt, Simon R; Kent, Marc; Pancotto, Theresa E; Chen, Annie V; Levine, Jonathan M

2017-07-01

Magnetic resonance imaging (MRI) is a common test for dogs with suspected intradural spinal cord lesions, however studies on diagnostic performance for this test are lacking. Objectives of this multi-institutional, retrospective, case-control study were to estimate sensitivity and specificity of MRI for (1) distinguishing between histopathologically confirmed intradural spinal cord disease versus degenerative myelopathy in dogs, (2) categorizing intradural spinal cord diseases as neoplastic, inflammatory, or vascular; and (3) determining tumor type within the etiologic category of neoplasia. Additional aims were to (1) determine whether knowledge of clinical data affects sensitivity and specificity of MRI diagnoses; and (2) report interrater agreement for MRI classification of intradural spinal lesions. Cases were recruited from participating hospital databases over a 7-year period. Three reviewers independently evaluated each MRI study prior to and after provision of clinical information. A total of 87 cases were sampled (17 degenerative myelopathy, 53 neoplasia, nine inflammatory, and eight vascular). Magnetic resonance imaging had excellent (>97.6%) sensitivity for diagnosis of intradural spinal cord lesions but specificity varied before and after provision of clinical data (68.6% vs. 82.4%, P = 0.023). Magnetic resonance imaging had good sensitivity (86.8%) and moderate specificity (64.7-72.5%) for diagnosing neoplasia. Sensitivity was lower for classifying inflammatory lesions but improved with provision of clinical data (48.1% vs. 81.5%, P = 0.015). Magnetic resonance imaging was insensitive for diagnosing vascular lesions (25.0%). Interrater agreement was very good for correctly diagnosing dogs with intradural lesions (ĸ = 0.882-0.833), and good (ĸ = 0.726-0.671) for diagnosing dogs with neoplasia. © 2017 American College of Veterinary Radiology.

Nonclinical safety biomarkers of drug-induced vascular injury: current status and blueprint for the future.

PubMed

Mikaelian, Igor; Cameron, Mark; Dalmas, Deidre A; Enerson, Bradley E; Gonzalez, Raymond J; Guionaud, Silvia; Hoffmann, Peter K; King, Nicholas M P; Lawton, Michael P; Scicchitano, Marshall S; Smith, Holly W; Thomas, Roberta A; Weaver, James L; Zabka, Tanja S

2014-06-01

Better biomarkers are needed to identify, characterize, and/or monitor drug-induced vascular injury (DIVI) in nonclinical species and patients. The Predictive Safety Testing Consortium (PSTC), a precompetitive collaboration of pharmaceutical companies and the U.S. Food and Drug Administration (FDA), formed the Vascular Injury Working Group (VIWG) to develop and qualify translatable biomarkers of DIVI. The VIWG focused its research on acute DIVI because early detection for clinical and nonclinical safety monitoring is desirable. The VIWG developed a strategy based on the premise that biomarkers of DIVI in rat would be translatable to humans due to the morphologic similarity of vascular injury between species regardless of mechanism. The histomorphologic lexicon for DIVI in rat defines degenerative and adaptive findings of the vascular endothelium and smooth muscles, and characterizes inflammatory components. We describe the mechanisms of these changes and their associations with candidate biomarkers for which advanced analytical method validation was completed. Further development is recommended for circulating microRNAs, endothelial microparticles, and imaging techniques. Recommendations for sample collection and processing, analytical methods, and confirmation of target localization using immunohistochemistry and in situ hybridization are described. The methods described are anticipated to aid in the identification and qualification of translational biomarkers for DIVI. © 2014 by The Author(s).

Diabetic Retinopathy: Vascular and Inflammatory Disease

PubMed Central

Semeraro, F.; Cancarini, A.; dell'Omo, R.; Rezzola, S.; Romano, M. R.; Costagliola, C.

2015-01-01

Diabetic retinopathy (DR) is the leading cause of visual impairment in the working-age population of the Western world. The pathogenesis of DR is complex and several vascular, inflammatory, and neuronal mechanisms are involved. Inflammation mediates structural and molecular alterations associated with DR. However, the molecular mechanisms underlying the inflammatory pathways associated with DR are not completely characterized. Previous studies indicate that tissue hypoxia and dysregulation of immune responses associated with diabetes mellitus can induce increased expression of numerous vitreous mediators responsible for DR development. Thus, analysis of vitreous humor obtained from diabetic patients has made it possible to identify some of the mediators (cytokines, chemokines, and other factors) responsible for DR pathogenesis. Further studies are needed to better understand the relationship between inflammation and DR. Herein the main vitreous-related factors triggering the occurrence of retinal complication in diabetes are highlighted. PMID:26137497

Lemongrass (Cymbopogon flexuosus) essential oil demonstrated anti-inflammatory effect in pre-inflamed human dermal fibroblasts.

PubMed

Han, Xuesheng; Parker, Tory L

2017-06-01

Lemongrass ( Cymbopogon flexuosus ) essential oil (LEO), which has citral as its main component, has exhibited anti-inflammatory effect in both animal and human cells. In this study, we evaluated the anti-inflammatory activity of a commercially available LEO in pre-inflamed human dermal fibroblasts. We first studied the impact of LEO on 17 protein biomarkers that are critically associated with inflammation and tissue remodeling. LEO significantly inhibited production of the inflammatory biomarkers vascular cell adhesion molecule 1 (VCAM-1), interferon gamma-induced protein 10 (IP-10), interferon-inducible T-cell alpha chemoattractant (I-TAC), and monokine induced by gamma interferon (MIG); decreased levels of the tissue remodeling biomarkers collagen-I and III, epidermal growth factor receptor (EGFR), and plasminogen activator inhibitor (PAI-1); and inhibited the immunomodulatory biomarker macrophage colony-stimulating factor (M-CSF). Furthermore, we studied the impact of LEO on genome-wide gene expression profiles. LEO significantly modulated global gene expression and robustly impacted signaling pathways, many of which are critical for inflammation and tissue remodeling processes. This study provides the first evidence of the anti-inflammatory activity of LEO in human skin cells and indicates that it is a good therapeutic candidate for treating inflammatory conditions of the skin.

Vascular Cell Adhesion Molecule-1 Expression and Signaling During Disease: Regulation by Reactive Oxygen Species and Antioxidants

PubMed Central

Marchese, Michelle E.; Abdala-Valencia, Hiam

2011-01-01

Abstract The endothelium is immunoregulatory in that inhibiting the function of vascular adhesion molecules blocks leukocyte recruitment and thus tissue inflammation. The function of endothelial cells during leukocyte recruitment is regulated by reactive oxygen species (ROS) and antioxidants. In inflammatory sites and lymph nodes, the endothelium is stimulated to express adhesion molecules that mediate leukocyte binding. Upon leukocyte binding, these adhesion molecules activate endothelial cell signal transduction that then alters endothelial cell shape for the opening of passageways through which leukocytes can migrate. If the stimulation of this opening is blocked, inflammation is blocked. In this review, we focus on the endothelial cell adhesion molecule, vascular cell adhesion molecule-1 (VCAM-1). Expression of VCAM-1 is induced on endothelial cells during inflammatory diseases by several mediators, including ROS. Then, VCAM-1 on the endothelium functions as both a scaffold for leukocyte migration and a trigger of endothelial signaling through NADPH oxidase-generated ROS. These ROS induce signals for the opening of intercellular passageways through which leukocytes migrate. In several inflammatory diseases, inflammation is blocked by inhibition of leukocyte binding to VCAM-1 or by inhibition of VCAM-1 signal transduction. VCAM-1 signal transduction and VCAM-1-dependent inflammation are blocked by antioxidants. Thus, VCAM-1 signaling is a target for intervention by pharmacological agents and by antioxidants during inflammatory diseases. This review discusses ROS and antioxidant functions during activation of VCAM-1 expression and VCAM-1 signaling in inflammatory diseases. Antioxid. Redox Signal. 15, 1607–1638. PMID:21050132

The Effects of Extracellular Matrix Proteins on Neutrophil-Endothelial Interaction ― A Roadway To Multiple Therapeutic Opportunities

PubMed Central

Padmanabhan, Jagannath; Gonzalez, Anjelica L.

2012-01-01

Polymorphoneuclear leukocytes or neutrophils, a major component of white blood cells, contribute to the innate immune response in humans. Upon sensing changes in the microenvironment, neutrophils adhere to the vascular wall, migrate through the endothelial cell (EC)-pericyte bilayer, and subsequently through the extracellular matrix to reach the site of inflammation. These cells are capable of destroying microbes, cell debris, and foreign proteins by oxidative and non-oxidative processes. While primarily mediators of tissue homeostasis, there are an increasing number of studies indicating that neutrophil recruitment and transmigration can also lead to host-tissue injury and subsequently inflammation-related diseases. Neutrophil-induced tissue injury is highly regulated by the microenvironment of the infiltrated tissue, which includes cytokines, chemokines, and the provisional extracellular matrix, remodeled through increased vascular permeability and other cellular infiltrates. Thus, investigation of the effects of matrix proteins on neutrophil-EC interaction and neutrophil transmigration may help identify the proteins that induce pro- or anti-inflammatory responses. This area of research presents an opportunity to identify therapeutic targets in inflammation-related diseases. This review will summarize recent literature on the role of neutrophils and the effects of matrix proteins on neutrophil-EC interactions, with focus on three different disease models: 1) atherosclerosis, 2) COPD, and 3) tumor growth and progression. For each disease model, inflammatory molecules released by neutrophils, important regulatory matrix proteins, current anti-inflammatory treatments, and the scope for further research will be summarized. PMID:22737047

Cues for cellular assembly of vascular elastin networks

NASA Astrophysics Data System (ADS)

Kothapalli, Chandrasekhar R.

Elastin, a structural protein distributed in the extracellular matrix of vascular tissues is critical to the maintenance of vascular mechanics, besides regulation of cell-signaling pathways involved in injury response and morphogenesis. Thus, congenital absence or disease-mediated degradation of vascular elastin and its malformation within native vessels due to innately poor elastin synthesis by adult vascular cells compromise vascular homeostasis. Current elastin regenerative strategies using tissue engineering principles are limited by the progressive destabilization of tropoelastin mRNA expression in adult vascular cells and the unavailability of scaffolds that can provide cellular cues necessary to up-regulate elastin synthesis and regenerate faithful mimics of native elastin. Since our earlier studies demonstrated the elastogenic utility of hyaluronan (HA)-based cues, we have currently sought to identify a unique set of culture conditions based on HA fragments (0.756-2000 kDa), growth factors (TGF-beta1, IGF-1) and other biomolecules (Cu2+ ions, LOX), which will together enhance synthesis, crosslinking, maturation and fibrous elastin matrix formation by adult SMCs, under both healthy and inflammatory conditions. It was observed that TGF-beta1 (1 ng/mL) together with HA oligomers (0.2 microg/mL) synergistically suppressed SMC proliferation, enhanced tropoelastin (8-fold) and matrix elastin synthesis (5.5-fold), besides improving matrix yield (4.5-fold), possibly by increasing production and activity of lysyl oxidase (LOX). Though addition of IGF-1 alone did not offer any advantage, HA fragments (20-200 kDa) in the presence of IGF-1 stimulated tropoelastin and soluble elastin synthesis more than 2.2-fold, with HMW HA contributing for ˜5-fold increase in crosslinked matrix elastin synthesis. Similarly, 0.1 M of Cu2+ ions, alone or together with HA fragments stimulated synthesis of tropoelastin (4-fold) and crosslinked matrix elastin (4.5-fold), via increases in LOX protein synthesis (2.5-fold); these cues also enhanced deposition of mature elastic fibers (˜1 mum diameter) within these cultures. Interestingly, instead of copper salt addition, even release of Cu 2+ ions (˜0.1 M) from copper nanoparticles (400 ng/mL), concurrent with HA oligomers, promoted crosslinking of elastin into mature matrix, with multiple bundles of highly-crosslinked elastin fiber formation observed (diameter ˜200-500 nm). These results strongly attest to the potential individual and combined benefits of these cues to faithful elastin matrix regeneration by healthy, patient-derived cells within tissue-engineered vascular constructs. When these cues (TGF-beta1 and HA oligomers) were added to TNF-alpha-stimulated SMC cultures, model cell culture systems mimicking phenotypically-altered cells within aneurysms, they upregulated elastin matrix production, organized elastin protein into fibers, and simultaneously stabilized this matrix by attenuating production of elastolytic enzymes. Similarly these cues also attenuated inflammatory cytokines release within cells isolated from induced-aortic aneurysms in rats, and significantly upregulated elastin synthesis and matrix formation by upregulating LOX and desmosine protein amounts. The cues were also highly effective in organizing the elastin into fibrous matrix structures mimicking the native elastin deposition process. The outcomes of this study might be of tremendous use in optimizing design of HA constructs to modulate vascular healing and matrix synthesis following revascularization, and in enabling repair of elastin networks within diseased or inflammatory (aneurysmal) adult vascular tissues.

Crude Fucoidan Extracts Impair Angiogenesis in Models Relevant for Bone Regeneration and Osteosarcoma via Reduction of VEGF and SDF-1.

PubMed

Wang, Fanlu; Schmidt, Harald; Pavleska, Dijana; Wermann, Thees; Seekamp, Andreas; Fuchs, Sabine

2017-06-20

The marine origin polysaccharide fucoidan combines multiple biological activities. As demonstrated by various studies in vitro and in vivo, fucoidans show anti-viral, anti-tumor, anti-oxidant, anti-inflammatory and anti-coagulant properties, although the detailed molecular action remains to be elucidated. The aim of the present study is to assess the impact of crude fucoidan extracts, on the formation of vascular structures in co-culture models relevant for bone vascularization during bone repair and for vascularization processes in osteosarcoma. The co-cultures consisted of bone marrow derived mesenchymal stem cells, respectively the osteosarcoma cell line MG63, and human blood derived outgrowth endothelial cells (OEC). The concentration dependent effects on the metabolic activity on endothelial cells and osteoblast cells were first assessed using monocultures of OEC, MSC and MG63 suggesting a concentration of 100 µg/mL as a suitable concentration for further experiments. In co-cultures fucoidan significantly reduced angiogenesis in MSC/OEC but also in MG63/OEC co-cultures suggesting a potential application of fucoidan to lower the vascularization in bone tumors such as osteosarcoma. This was associated with a decrease in VEGF (vascular endothelial growth factor) and SDF-1 (stromal derived factor-1) on the protein level, both related to the control of angiogenesis and furthermore discussed as crucial factors in osteosarcoma progression and metastasis. In terms of bone formation, fucoidan slightly lowered on the calcification process in MSC monocultures and MSC/OEC co-cultures. In summary, these data suggest the suitability of lower fucoidan doses to limit angiogenesis for instance in osteosarcoma.

[Acute non-traumatic myelopathy in children and adolescents].

PubMed

Arroyo, Hugo A

2013-09-06

The term 'acute myelopathies'--referred to a spinal cord dysfunction--represent a heterogeneous group of disorders with distinct etiologies, clinical and radiologic features, and prognoses. The objective of this review is to discuss the non-traumatic acute myelopathies. Acute myelopathy can be due to several causes as infective agents or inflammatory processes, such as in acute myelitis, compressive lesions, vascular lesions, etc. The clinical presentation is often dramatic with tetraparesis or paraparesis, sensory disturbances and bladder and/or bowel dysfunction. History and physical examination are used to localize the lesion to the root or specific level of the cord, which can guide imaging. Different syndromes are recognized: complete transverse lesion, central grey matter syndrome, anterior horn syndrome, anterior spinal artery syndrome, etc). The first priority is to rule out a compressive lesion. If a myelopathy is suspected, a gadolinium-enhanced MRI of the spinal cord should be obtained as soon as possible. If there is no structural lesion such as epidural blood or a spinal mass, then the presence or absence of spinal cord inflammation should be documented with a lumbar puncture. The absence of pleocytosis would lead to consideration of non inflammatory causes of myelopathy such as arteriovenous malformations, fibrocartilaginous embolism, or possibly early inflammatory myelopathy. In the presence of an inflammatory process (defined by gadolinium enhancement, cerebrospinal fluid pleocytosis, or elevated cerebrospinal fluid immunoglobulin index), one should determine whether there is an inflammatory or an infectious cause. Different virus, bacterias, parasites and fungi have to be considered as autoimmune and inflammatory diseases that involve the central nervous system.

De Novo Lipogenesis Maintains Vascular Homeostasis through Endothelial Nitric-oxide Synthase (eNOS) Palmitoylation*♦

PubMed Central

Wei, Xiaochao; Schneider, Jochen G.; Shenouda, Sherene M.; Lee, Ada; Towler, Dwight A.; Chakravarthy, Manu V.; Vita, Joseph A.; Semenkovich, Clay F.

2011-01-01

Endothelial dysfunction leads to lethal vascular complications in diabetes and related metabolic disorders. Here, we demonstrate that de novo lipogenesis, an insulin-dependent process driven by the multifunctional enzyme fatty-acid synthase (FAS), maintains endothelial function by targeting endothelial nitric-oxide synthase (eNOS) to the plasma membrane. In mice with endothelial inactivation of FAS (FASTie mice), eNOS membrane content and activity were decreased. eNOS and FAS were physically associated; eNOS palmitoylation was decreased in FAS-deficient cells, and incorporation of labeled carbon into eNOS-associated palmitate was FAS-dependent. FASTie mice manifested a proinflammatory state reflected as increases in vascular permeability, endothelial inflammatory markers, leukocyte migration, and susceptibility to LPS-induced death that was reversed with an NO donor. FAS-deficient endothelial cells showed deficient migratory capacity, and angiogenesis was decreased in FASTie mice subjected to hindlimb ischemia. Insulin induced FAS in endothelial cells freshly isolated from humans, and eNOS palmitoylation was decreased in mice with insulin-deficient or insulin-resistant diabetes. Thus, disrupting eNOS bioavailability through impaired lipogenesis identifies a novel mechanism coordinating nutritional status and tissue repair that may contribute to diabetic vascular disease. PMID:21098489

Ubiquitin carboxyl terminal hydrolase L1 negatively regulates TNF{alpha}-mediated vascular smooth muscle cell proliferation via suppressing ERK activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ichikawa, Tomonaga; Li, Jinqing; Dong, Xiaoyu

2010-01-01

Deubiquitinating enzymes (DUBs) appear to be critical regulators of a multitude of processes such as proliferation, apoptosis, differentiation, and inflammation. We have recently demonstrated that a DUB of ubiquitin carboxyl terminal hydrolase L1 (UCH-L1) inhibits vascular lesion formation via suppressing inflammatory responses in vasculature. However, the precise underlying mechanism remains to be defined. Herein, we report that a posttranscriptional up-regulation of UCH-L1 provides a negative feedback to tumor necrosis factor alpha (TNF{alpha})-mediated activation of extracellular signal-regulated kinases (ERK) and proliferation in vascular smooth muscle cells (VSMCs). In rat adult VSMCs, adenoviral over-expression of UCH-L1 inhibited TNF{alpha}-induced activation of ERK andmore » DNA synthesis. In contrast, over-expression of UCH-L1 did not affect platelet derived growth factor (PDGF)-induced VSMC proliferation and activation of growth stimulating cascades including ERK. TNF{alpha} hardly altered UCH-L1 mRNA expression and stability; however, up-regulated UCH-L1 protein expression via increasing UCH-L1 translation. These results uncover a novel mechanism by which UCH-L1 suppresses vascular inflammation.« less

Microvascular Remodeling and Wound Healing: A Role for Pericytes

PubMed Central

Dulmovits, Brian M.; Herman, Ira M.

2012-01-01

Physiologic wound healing is highly dependent on the coordinated functions of vascular and non-vascular cells. Resolution of tissue injury involves coagulation, inflammation, formation of granulation tissue, remodeling and scarring. Angiogenesis, the growth of microvessels the size of capillaries, is crucial for these processes, delivering blood-borne cells, nutrients and oxygen to actively remodeling areas. Central to angiogenic induction and regulation is microvascular remodeling, which is dependent upon capillary endothelial cell and pericyte interactions. Despite our growing knowledge of pericyte-endothelial cell crosstalk, it is unclear how the interplay among pericytes, inflammatory cells, glia and connective tissue elements shape microvascular injury response. Here, we consider the relationships that pericytes form with the cellular effectors of healing in normal and diabetic environments, including repair following injury and vascular complications of diabetes, such as diabetic macular edema and proliferative diabetic retinopathy. In addition, pericytes and stem cells possessing “pericyte-like” characteristics are gaining considerable attention in experimental and clinical efforts aimed at promoting healing or eradicating ocular vascular proliferative disorders. As the origin, identification and characterization of microvascular pericyte progenitor populations remains somewhat ambiguous, the molecular markers, structural and functional characteristics of pericytes will be briefly reviewed. PMID:22750474

Current advances in orthodontic pain

PubMed Central

Long, Hu; Wang, Yan; Jian, Fan; Liao, Li-Na; Yang, Xin; Lai, Wen-Li

2016-01-01

Orthodontic pain is an inflammatory pain that is initiated by orthodontic force-induced vascular occlusion followed by a cascade of inflammatory responses, including vascular changes, the recruitment of inflammatory and immune cells, and the release of neurogenic and pro-inflammatory mediators. Ultimately, endogenous analgesic mechanisms check the inflammatory response and the sensation of pain subsides. The orthodontic pain signal, once received by periodontal sensory endings, reaches the sensory cortex for pain perception through three-order neurons: the trigeminal neuron at the trigeminal ganglia, the trigeminal nucleus caudalis at the medulla oblongata and the ventroposterior nucleus at the thalamus. Many brain areas participate in the emotion, cognition and memory of orthodontic pain, including the insular cortex, amygdala, hippocampus, locus coeruleus and hypothalamus. A built-in analgesic neural pathway—periaqueductal grey and dorsal raphe—has an important role in alleviating orthodontic pain. Currently, several treatment modalities have been applied for the relief of orthodontic pain, including pharmacological, mechanical and behavioural approaches and low-level laser therapy. The effectiveness of nonsteroidal anti-inflammatory drugs for pain relief has been validated, but its effects on tooth movement are controversial. However, more studies are needed to verify the effectiveness of other modalities. Furthermore, gene therapy is a novel, viable and promising modality for alleviating orthodontic pain in the future. PMID:27341389

The interaction of transient receptor potential melastatin 7 with macrophages promotes vascular adventitial remodeling in transverse aortic constriction rats.

PubMed

Li, Yan; Jiang, Hui; Ruan, Chengchao; Zhong, Jiuchang; Gao, Pingjin; Zhu, Dingliang; Niu, Wenquan; Guo, Shujie

2014-01-01

Transient receptor potential melastatin 7 (TRPM7), a novel channel kinase, has been recently identified in the vasculature. However, its regulation and function in vascular diseases remain poorly understood. To address this lack of knowledge, we sought to examine whether TRPM7 can mediate the vascular remodeling process induced by pressure overload in the right common carotid artery proximal to the band (RCCA-B) in male Sprague-Dawley rats with transverse aortic constriction (TAC). The contribution of TRPM7 to amplified vascular remodeling after TAC was tested using morphometric and western blot analyses. Pressure overload-induced vascular wall thickening, especially in the adventitia, was readily detected in RCCA-B. The TRPM7 level was increased with a simultaneous accumulation of macrophages in the adventitia of RCCA-B, whereas the anti-inflammatory molecule annexin-1, a TRPM7 downstream target, was decreased. After the addition of the TRPM7 inhibitor 2-aminoethoxydiphenyl borate (2-APB), significant reductions in macrophage accumulation as well as the expression of monocyte chemotactic protein-1, SM-22-α and collagen I were observed, whereas annexin-1 was rescued. Finally, in cultured vascular adventitial fibroblasts treated with macrophage-conditioned medium, there were marked increases in the expression of TRPM7 and SM-22-α with a concurrent reduction in annexin-1 expression; these effects were largely prevented by treatment with 2-APB and specific anti-TRPM7 small interfering RNA. Our findings provide the first demonstration of the potential regulatory roles of TRPM7 in the vascular inflammation, pressure overload-mediated vascular adventitial collagen accumulation and cell phenotypic transformation in TAC rats. The targeting of TRPM7 has potential therapeutic importance for vascular diseases.

Lifestyle and metabolic approaches to maximizing erectile and vascular health.

PubMed

Meldrum, D R; Gambone, J C; Morris, M A; Esposito, K; Giugliano, D; Ignarro, L J

2012-01-01

Oxidative stress and inflammation, which disrupt nitric oxide (NO) production directly or by causing resistance to insulin, are central determinants of vascular diseases including ED. Decreased vascular NO has been linked to abdominal obesity, smoking and high intakes of fat and sugar, which all cause oxidative stress. Men with ED have decreased vascular NO and circulating and cellular antioxidants. Oxidative stress and inflammatory markers are increased in men with ED, and all increase with age. Exercise increases vascular NO, and more frequent erections are correlated with decreased ED, both in part due to stimulation of endothelial NO production by shear stress. Exercise and weight loss increase insulin sensitivity and endothelial NO production. Potent antioxidants or high doses of weaker antioxidants increase vascular NO and improve vascular and erectile function. Antioxidants may be particularly important in men with ED who smoke, are obese or have diabetes. Omega-3 fatty acids reduce inflammatory markers, decrease cardiac death and increase endothelial NO production, and are therefore critical for men with ED who are under age 60 years, and/or have diabetes, hypertension or coronary artery disease, who are at increased risk of serious or even fatal cardiac events. Phosphodiesterase inhibitors have recently been shown to improve antioxidant status and NO production and allow more frequent and sustained penile exercise. Some angiotensin II receptor blockers decrease oxidative stress and improve vascular and erectile function and are therefore preferred choices for lowering blood pressure in men with ED. Lifestyle modifications, including physical and penile-specific exercise, weight loss, omega-3 and folic acid supplements, reduced intakes of fat and sugar, and improved antioxidant status through diet and/or supplements should be integrated into any comprehensive approach to maximizing erectile function, resulting in greater overall success and patient satisfaction, as well as improved vascular health and longevity.

PAR-2 mediates increased inflammatory cell adhesion and neointima formation following vascular injury in the mouse.

PubMed

Tennant, Gail M; Wadsworth, Roger M; Kennedy, Simon

2008-05-01

Activation of PAR-2 in the vasculature affects vascular tone and adhesion of leukocytes to the endothelium. Since adhesion of leukocytes is increased following vascular injury and is important in determining the extent of neointima formation, we hypothesised that mice lacking PAR-2 may have reduced neointima formation following vascular injury. PAR-2 activating peptides and trypsin induced endothelium-dependent relaxation of mouse carotid artery which was absent in the knockout mouse. Lack of a PAR-2 receptor did not affect lymphocyte adhesion under basal conditions, but reduced the contractile response produced by lymphocytes. Twenty-eight days after denuding injury, vessel contraction to lymphocytes was reduced in both strains while lymphocyte adhesion was significantly greater in PAR-2(+/+) mice compared to the PAR-2 knockout mice. Neointimal area was markedly reduced in the PAR-2 knockout mouse. Our data show that PAR-2 modulates inflammatory cell adhesion when stimulated and in mice lacking the PAR-2 receptor, adhesion to injured vessels is reduced with a consequent reduction in neointima formation.

Microsecond-pulsed dielectric barrier discharge plasma stimulation of tissue macrophages for treatment of peripheral vascular disease

PubMed Central

Miller, V.; Lin, A.; Kako, F.; Gabunia, K.; Kelemen, S.; Brettschneider, J.; Fridman, G.; Fridman, A.; Autieri, M.

2015-01-01

Angiogenesis is the formation of new blood vessels from pre-existing vessels and normally occurs during the process of inflammatory reactions, wound healing, tissue repair, and restoration of blood flow after injury or insult. Stimulation of angiogenesis is a promising and an important step in the treatment of peripheral artery disease. Reactive oxygen species have been shown to be involved in stimulation of this process. For this reason, we have developed and validated a non-equilibrium atmospheric temperature and pressure short-pulsed dielectric barrier discharge plasma system, which can non-destructively generate reactive oxygen species and other active species at the surface of the tissue being treated. We show that this plasma treatment stimulates the production of vascular endothelial growth factor, matrix metalloproteinase-9, and CXCL 1 that in turn induces angiogenesis in mouse aortic rings in vitro. This effect may be mediated by the direct effect of plasma generated reactive oxygen species on tissue. PMID:26543345

Microsecond-pulsed dielectric barrier discharge plasma stimulation of tissue macrophages for treatment of peripheral vascular disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, V., E-mail: vmiller@coe.drexel.edu; Lin, A.; Brettschneider, J.

Angiogenesis is the formation of new blood vessels from pre-existing vessels and normally occurs during the process of inflammatory reactions, wound healing, tissue repair, and restoration of blood flow after injury or insult. Stimulation of angiogenesis is a promising and an important step in the treatment of peripheral artery disease. Reactive oxygen species have been shown to be involved in stimulation of this process. For this reason, we have developed and validated a non-equilibrium atmospheric temperature and pressure short-pulsed dielectric barrier discharge plasma system, which can non-destructively generate reactive oxygen species and other active species at the surface of themore » tissue being treated. We show that this plasma treatment stimulates the production of vascular endothelial growth factor, matrix metalloproteinase-9, and CXCL 1 that in turn induces angiogenesis in mouse aortic rings in vitro. This effect may be mediated by the direct effect of plasma generated reactive oxygen species on tissue.« less

Arctium lappa ameliorates endothelial dysfunction in rats fed with high fat/cholesterol diets.

PubMed

Lee, Yun Jung; Choi, Deok Ho; Cho, Guk Hyun; Kim, Jin Sook; Kang, Dae Gill; Lee, Ho Sub

2012-08-06

Arctium lappa L. (Asteraceae), burdock, is a medicinal plant that is popularly used for treating hypertension, gout, hepatitis, and other inflammatory disorders. This study was performed to test the effect of ethanol extract of Arctium lappa L. (EAL) seeds on vascular reactivity and inflammatory factors in rats fed a high fat/cholesterol diet (HFCD). EAL-I (100 mg·kg-1/day), EAL-II (200 mg·kg-1/day), and fluvastatin (3 mg·kg-1/day) groups initially received HFCD alone for 8 weeks, with EAL supplementation provided during the final 6 weeks. Treatment with low or high doses of EAL markedly attenuated plasma levels of triglycerides and augmented plasma levels of high-density lipoprotein (HDL) in HFCD-fed rats. Chronic treatment with EAL markedly reduced impairments of acetylcholine (ACh)-induced relaxation of aortic rings. Furthermore, chronic treatment with EAL significantly lowered systolic blood pressure (SBP) and maintained smooth and flexible intimal endothelial layers in HFCD-fed rats. Chronic treatment with EAL suppressed upregulation of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin in the aorta. Chronic treatment with EAL also suppressed increases in matrix metalloproteinase (MMP)-2 expression. These results suggested that EAL can inhibit HFCD-induced vascular inflammation in the rat model. The present study provides evidence that EAL ameliorates HFCD-induced vascular dysfunction through protection of vascular relaxation and suppression of vascular inflammation.

Vascular Involvement in Axial Spondyloarthropathies.

PubMed

Prati, Clément; Demougeot, Céline; Guillot, Xavier; Sondag, Maxime; Verhoeven, Frank; Wendling, Daniel

2018-05-19

Ankylosing spondylitis (AS) is a chronic inflammatory joint disease that involves the entheses, causing inflammatory pain and functional impairments. Patients may experience extraarticular manifestations such as uveitis, psoriasis, and inflammatory bowel disease. These, together with the increased risk of cardiovascular disease and osteoporosis and the development of spinal fusion, are the main determinants of adverse disease outcomes. As with many systemic inflammatory diseases, AS is associated with excess cardiovascular mortality due to increased risks of myocardial infarction, stroke, and venous thromboembolism. Studies of markers for subclinical atheroma (endothelial dysfunction, arterial stiffness, and intima-media thickness) have shown earlier onset of arterial disease compared to healthy controls, with the difference being greatest for patients with active AS. The potential vascular effects of drugs used to treat AS have not been established. Few studies have focused on nonsteroidal antiinflammatory drugs and biologics in patients with AS, and their results do not conclusively establish a beneficial or deleterious effect in axial spondyloarthritis. Statins have been found to improve endothelial dysfunction and to decrease mortality. The latest EULAR recommendations on cardiovascular risk management in patients with inflammatory joint disease indicate that statins should be used in compliance with national guidelines. Copyright © 2018. Published by Elsevier SAS.

Blood vessel control of macrophage maturation promotes arteriogenesis in ischemia.

PubMed

Krishnasamy, Kashyap; Limbourg, Anne; Kapanadze, Tamar; Gamrekelashvili, Jaba; Beger, Christian; Häger, Christine; Lozanovski, Vladimir J; Falk, Christine S; Napp, L Christian; Bauersachs, Johann; Mack, Matthias; Haller, Hermann; Weber, Christian; Adams, Ralf H; Limbourg, Florian P

2017-10-16

Ischemia causes an inflammatory response that is intended to restore perfusion and homeostasis yet often aggravates damage. Here we show, using conditional genetic deletion strategies together with adoptive cell transfer experiments in a mouse model of hind limb ischemia, that blood vessels control macrophage differentiation and maturation from recruited monocytes via Notch signaling, which in turn promotes arteriogenesis and tissue repair. Macrophage maturation is controlled by Notch ligand Dll1 expressed in vascular endothelial cells of arteries and requires macrophage canonical Notch signaling via Rbpj, which simultaneously suppresses an inflammatory macrophage fate. Conversely, conditional mutant mice lacking Dll1 or Rbpj show proliferation and transient accumulation of inflammatory macrophages, which antagonizes arteriogenesis and tissue repair. Furthermore, the effects of Notch are sufficient to generate mature macrophages from monocytes ex vivo that display a stable anti-inflammatory phenotype when challenged with pro-inflammatory stimuli. Thus, angiocrine Notch signaling fosters macrophage maturation during ischemia.Molecular mechanisms of macrophage-mediated regulation of artery growth in response to ischemia are poorly understood. Here the authors show that vascular endothelium controls macrophage maturation and differentiation via Notch signaling, which in turn promotes arteriogenesis and ischemic tissue recovery.

Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Straub, Adam C.; Stolz, Donna B.; Vin, Harina

2007-08-01

The vascular effects of arsenic in drinking water are global health concerns contributing to human disease worldwide. Arsenic targets the endothelial cells lining blood vessels, and endothelial cell activation or dysfunction may underlie the pathogenesis of both arsenic-induced vascular diseases and arsenic-enhanced tumorigenesis. The purpose of the current studies was to demonstrate that exposing mice to drinking water containing environmentally relevant levels of arsenic promoted endothelial cell dysfunction and pathologic vascular remodeling. Increased angiogenesis, neovascularization, and inflammatory cell infiltration were observed in Matrigel plugs implanted in C57BL/6 mice following 5-week exposures to 5-500 ppb arsenic [Soucy, N.V., Mayka, D., Klei,more » L.R., Nemec, A.A., Bauer, J.A., Barchowsky, A., 2005. Neovascularization and angiogenic gene expression following chronic arsenic exposure in mice. Cardiovasc.Toxicol 5, 29-42]. Therefore, functional in vivo effects of arsenic on endothelial cell function and vessel remodeling in an endogenous vascular bed were investigated in the liver. Liver sinusoidal endothelial cells (LSEC) became progressively defenestrated and underwent capillarization to decrease vessel porosity following exposure to 250 ppb arsenic for 2 weeks. Sinusoidal expression of PECAM-1 and laminin-1 proteins, a hallmark of capillarization, was also increased by 2 weeks of exposure. LSEC caveolin-1 protein and caveolae expression were induced after 2 weeks of exposure indicating a compensatory change. Likewise, CD45/CD68-positive inflammatory cells did not accumulate in the livers until after LSEC porosity was decreased, indicating that inflammation is a consequence and not a cause of the arsenic-induced LSEC phenotype. The data demonstrate that the liver vasculature is an early target of pathogenic arsenic effects and that the mouse liver vasculature is a sensitive model for investigating vascular health effects of arsenic.« less

Stroke with polyvascular atherothrombotic disease.

PubMed

Blanco, Miguel; Sobrino, Tomás; Montaner, Joan; Medrano, Vicente; Jiménez, Carmen; Masjuán, Jaime; Gómez-Escalonilla, Carlos; de Luis, Pilar; Arboix, Adriá; Castillo, José

2010-02-01

To study the influence of polyvascular atherothrombotic disease on stroke patient prognosis, its relation with inflammatory markers, and to analyze the progression of atherothrombotic disease. MITICO is a multi-centered prospective observational study recruiting non-anticoagulated ischemic stroke patients. Blood samples were obtained at baseline and at one year follow-up for determination of high sensitivity C reactive protein (hs-CRP), interleukin 6 (IL-6), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), matrix metalloproteinase 9 (MMP-9), and cellular fibronectin (c-Fn). Patients with polyvascular atherothrombotic disease were considered when presented a history of angina-myocardial infarction, intermittent claudication or ischemic limbs-amputation at inclusion. The sample consisted of 863 patients, 121 of them considered as polyvascular atherothrombotic disease (14.02%). Recurrence and vascular death were higher in patients with polyvascular atherothrombotic disease, as compared to patients with monovascular atherothrombotic disease (19.8% vs. 12.4%, p=0.022). Baseline plasma levels of IL-6 and VCAM-1 were higher in patients with polyvascular atherothrombotic disease. IL-6 and VCAM-1 levels were independently associated with a new vascular episode/vascular death. This association was stronger in the group of patients with polyvascular atherothrombotic disease. Baseline levels of IL-6, VCAM-1 and c-Fn were significantly higher in patients who developed progression of atherothrombotic disease. The increase from baseline in MMP-9 and c-Fn levels after one year follow-up was associated to progression of atherothrombotic disease. Stroke patients with polyvascular atherothrombotic disease showed higher rates of vascular recurrence and a stronger association with inflammatory markers. Progression of atherothrombotic disease was associated with inflammatory markers. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

4-Chloro-DL-phenylalanine protects against monocrotaline‑induced pulmonary vascular remodeling and lung inflammation.

PubMed

Bai, Yang; Wang, Han-Ming; Liu, Ming; Wang, Yun; Lian, Guo-Chao; Zhang, Xin-Hua; Kang, Jian; Wang, Huai-Liang

2014-02-01

The present study was performed to investigate the effects of 4-chloro-DL-phenylalanine (PCPA), a tryptophan hydroxylase (Tph) inhibitor (TphI), on pulmonary vascular remodeling and lung inflammation in monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats. Animal models of PAH were established using Sprague-Dawley (SD) rats by a single intraperitoneal injection of MCT (60 mg/kg). PCPA (50 or 100 mg/kg/day) was administered to the rats with PAH. On day 22, hemodynamic measurements and morphological observations of the lung tissues were performed. The levels of Tph-1 and serotonin transporter (SERT) in the lungs were analyzed by immunohistochemistry and western blot analysis. The expression of matrix metalloproteinase (MMP)-2 and MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 and inflammatory cytokines were assayed by western blot analysis. The activity of MMP-2 and MMP-9 was evaluated by gelatin zymography (GZ). MCT markedly promoted PAH, increased the right ventricular hypertrophy index, pulmonary vascular remodeling, lung inflammation and mortality, which was associated with the increased expression of Tph-1, SERT, MMP-2/-9, TIMP-1/-2 and inflammatory cytokines. PCPA markedly attenuated MCT-induced pulmonary vascular remodeling and lung inflammation, inhibited the expression of Tph-1 and SERT and suppressed the expression of MMP-2/-9, TIMP-1/-2, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1). These findings suggest that the amelioration of MCT-induced pulmonary vascular remodeling and lung inflammation by PCPA is associated with the downregulation of Tph-1, SERT, MMP/TIMP and inflammatory cytokine expression in rats.

Cystoid edema, neovascularization and inflammatory processes in the murine Norrin-deficient retina.

PubMed

Beck, Susanne C; Karlstetter, Marcus; Garcia Garrido, Marina; Feng, Yuxi; Dannhausen, Katharina; Mühlfriedel, Regine; Sothilingam, Vithiyanjali; Seebauer, Britta; Berger, Wolfgang; Hammes, Hans-Peter; Seeliger, Mathias W; Langmann, Thomas

2018-04-13

Mutations in the Norrin (NDP) gene cause severe developmental blood vessel defects in the retina leading to congenital blindness. In the retina of Ndph-knockout mice only the superficial capillary network develops. Here, a detailed characterization of this mouse model at late stages of the disease using in vivo retinal imaging revealed cystoid structures that closely resemble the ovoid cysts in the inner nuclear layer of the human retina with cystoid macular edema (CME). In human CME an involvement of Müller glia cells is hypothesized. In Ndph-knockout retinae we could demonstrate that activated Müller cells were located around and within these cystoid spaces. In addition, we observed extensive activation of retinal microglia and development of neovascularization. Furthermore, ex vivo analyses detected extravasation of monocytic cells suggesting a breakdown of the blood retina barrier. Thus, we could demonstrate that also in the developmental retinal vascular pathology present in the Ndph-knockout mouse inflammatory processes are active and may contribute to further retinal degeneration. This observation delivers a new perspective for curative treatments of retinal vasculopathies. Modulation of inflammatory responses might reduce the symptoms and improve visual acuity in these diseases.

Nonesterified fatty acids modify inflammatory response and eicosanoid biosynthesis in bovine endothelial cells.

PubMed

Contreras, G A; Raphael, W; Mattmiller, S A; Gandy, J; Sordillo, L M

2012-09-01

Intense lipid mobilization during the transition period in dairy cows is associated with increased disease susceptibility. The potential impact of altered plasma nonesterified fatty acids (NEFA) concentrations and composition on host inflammatory responses that may contribute to disease incidence and severity are not known. The objective of this study was to evaluate if increased NEFA concentrations could modify vascular inflammatory responses in vitro by changing the expression of important inflammatory mediators that are important in the pathogenesis of infectious diseases of transition cows such as mastitis and metritis. Bovine aortic endothelial cells (BAEC) were cultured with different concentrations of a NEFA mixture that reflected the plasma NEFA composition during different stages of lactation. The expression of cytokines, adhesion molecules, and eicosanoids were measured to assess changes in BAEC inflammatory phenotype. Addition of NEFA mixtures altered the fatty acid profile of BAEC by increasing the concentration of stearic acid (C18:0) and decreasing the content of arachidonic acid (C20:4n6c) and other long-chain polyunsaturated fatty acids in the phospholipid fraction. A significant increase also occurred in mRNA expression of cytokine and adhesion molecules that are associated with increased inflammatory responses during the transition period. Expression of cyclooxygenase 2, an important enzyme associated with eicosanoid biosynthesis, was increased in a NEFA concentration-dependent manner. The production of linoleic acid-derived eicosanoids 9- and 13-hydroxyoctadecadienoic acids also was increased significantly after treatment with NEFA mixtures. This research described for the first time specific changes in vascular inflammatory response during in vitro exposure to NEFA mixtures that mimic the composition and concentration found in cows during the transition period. These findings could explain, in part, alterations in inflammatory responses observed during intense lipid mobilization stages such as in the transition period of dairy cows. Future studies should analyze specific mechanisms by which high NEFA concentrations induce a vascular proinflammatory phenotype including the effect of 9 and 13-hydroxyoctadecadienoic acids and other lipid mediators. Copyright © 2012 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Statin withdrawal: clinical implications and molecular mechanisms.

PubMed

Cubeddu, Luigi X; Seamon, Matthew J

2006-09-01

Retrospective analyses of data from the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM), the National Registry of Myocardial Infarction 4, and the Global Registry of Acute Coronary Events (GRACE) trials revealed that the benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) on acute coronary outcomes are rapidly lost and outcomes worsened if statins are discontinued during a patient's hospitalization for an acute coronary syndrome. Withdrawal of statin therapy in the first 24 hours of hospitalization for non-ST-elevation myocardial infarction increased the hospital morbidity and mortality rate versus continued therapy (11.9% vs 5.7%, p<0.01). Data from the Treating New Targets (TNT) study, however, suggested that short-term discontinuation of statin therapy in patients with stable cardiac conditions may not substantially increase the risk of acute coronary syndromes. In patients with acute coronary syndromes who discontinue statins, the rapid increase in risk of an event may result not only from the lost benefits from the therapy, but also from rebound inhibition of vascular protective substances and activation of vascular deleterious substances. Statins inhibit cholesterol synthesis in vascular cells. By reducing levels of isoprenoid intermediates, statins increase the production of nitric oxide and downregulate angiotensin II AT(1) receptors, endothelin-1, vascular inflammatory adhesion molecules, and inflammatory cytokines. These benefits are rapidly lost and often transiently reversed when statins are acutely discontinued. Acute removal of pleiotropic effects and rebound vascular dysfunction may be more important in an acute coronary event, where inflammation promotes rupture of atherosclerotic plaques and inflammatory and prothrombosis markers are present in high concentration, than in stable chronic vascular disease. In the absence of data from randomized controlled trials, current information suggests that statin therapy should be continued, and possibly boosted, during hospitalization for an acute coronary syndrome. Because statins are discontinued during the early hospitalization of many patients, practitioners must ensure that statins are not omitted, unless contraindicated, from the treatment of patients with acute coronary syndromes.

[Acute abdomen caused by eosinophilic enteritis: six observations].

PubMed

Martínez-Ubieto, Fernando; Bueno-Delgado, Alvaro; Jiménez-Bernadó, Teresa; Santero Ramírez, María Pilar; Arribas-Del Amo, Dolores; Martínez-Ubieto, Javier

2013-01-01

Eosinophilic enteritis is a rather rare condition characterized by infiltration of the gastrointestinal tract by eosinophils; as a casue of acute abdomen it is really exceptional. The etiology is unclear and its description in the literature is sparse, but associations have been made with collagen vascular disease, inflammatory bowel disease, food allergy and parasitic infections as it was confirmed in one of our pathologic studies. From 1997 to 2011 six cases of eosinophilic enteritis that involved a small bowel segment were diagnosed. A partial resection by an irreversible necrosis was necessary in three of them; in the other three only a biopsy was necessary due to the inflammatory aspect of the affected loop causing the acute abdomen. Eosinophilic enteritis can originate acute abdomen processes where an urgent surgical treatment is necessary. The intraoperative aspect can be from a segment of small bowel with inflammatory signs up to a completely irrecoverable loop, where removing of the affected segment is the correct treatment, which can be done laparoscopically.

Effect of cerium oxide nanoparticles on inflammation in vascular endothelial cells

PubMed Central

Gojova, Andrea; Lee, Jun-Tae; Jung, Heejung S.; Guo, Bing; Barakat, Abdul I.; Kennedy, Ian M.

2010-01-01

Because vascular endothelial cell inflammation is critical in the development of cardiovascular pathology, we hypothesized that direct exposure of human aortic endothelial cells (HAECs) to ultrafine particles induces an inflammatory response. To test the hypothesis, we incubated HAECs for 4 h with different concentrations (0.001–50 μg/ml) of CeO2 nanoparticles and subsequently measured mRNA levels of the three inflammatory markers intercellular adhesion molecule 1 (ICAM-1), interleukin (IL)-8, and monocyte chemotactic protein (MCP-1) using real-time polymerase chain reaction (PCR). Ceria nanoparticles caused very little inflammatory response in HAECs, even at the highest dose. This material is apparently rather benign in comparison with Y2O3 and ZnO nanoparticles that we have studied previously. These results suggest that inflammation in HAECs following acute exposure to metal oxide nanoparticles depends strongly on particle composition. PMID:19558244

G-protein coupled receptor 30 (GPR30): a novel regulator of endothelial inflammation.

PubMed

Chakrabarti, Subhadeep; Davidge, Sandra T

2012-01-01

Estrogen, the female sex hormone, is known to exert anti-inflammatory and anti-atherogenic effects. Traditionally, estrogen effects were believed to be largely mediated through the classical estrogen receptors (ERs). However, there is increasing evidence that G-protein coupled receptor 30 (GPR30), a novel estrogen receptor, can mediate many estrogenic effects on the vasculature. Despite this, the localization and functional significance of GPR30 in the human vascular endothelium remains poorly understood. Given this background, we examined the subcellular location and potential anti-inflammatory roles of GPR30 using human umbilical vein endothelial cells as a model system. Inflammatory changes were induced by treatment with tumor necrosis factor (TNF), a pro-inflammatory cytokine involved in atherogenesis and many other inflammatory conditions. We found that GPR30 was located predominantly in the endothelial cell nuclei. Treatment with the selective GPR30 agonist G-1 partially attenuated the TNF induced upregulation of pro-inflammatory proteins such as intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). This effect was completely abolished by the selective GPR30 antagonist G-15, suggesting that it was indeed mediated in a GPR30 dependent manner. Interestingly, estrogen alone had no effects on TNF-treated endothelium. Concomitant activation of the classical ERs blocked the anti-inflammatory effects of G-1, indicating opposing effects of GPR30 and the classical ERs. Our findings demonstrate that endothelial GPR30 is a novel regulator of the inflammatory response which could be a potential therapeutic target against atherosclerosis and other inflammatory diseases.

Laminar shear stress regulates endothelial kinin B1 receptor expression and function: potential implication in atherogenesis

PubMed Central

Duchene, Johan; Cayla, Cécile; Vessillier, Sandrine; Scotland, Ramona; Yamashiro, Kazuo; Lecomte, Florence; Syed, Irfan; Vo, Phuong; Marrelli, Alessandra; Pitzalis, Costantino; Cipollone, Francesco; Schanstra, Joost; Bascands, Jean-Loup; Hobbs, Adrian J; Perretti, Mauro; Ahluwalia, Amrita

2009-01-01

OBJECTIVE The pro-inflammatory phenotype induced by low laminar shear stress (LSS) is implicated in atherogenesis. The kinin B1 receptor (B1R), known to be induced by inflammatory stimuli, exerts many pro-inflammatory effects including vasodilatation and leukocyte recruitment. We investigated whether low LSS is a stimulus for endothelial B1R expression and function. METHODS AND RESULTS Human and mouse atherosclerotic plaques expressed high level of B1R mRNA and protein. In addition, B1R expression was upregulated in the aortic arch (low LSS region) of ApoE-/- mice fed a high fat diet compared to vascular regions of high LSS and animals fed normal chow. Of interest, a greater expression of B1R was noticed in endothelial cells from regions of low LSS in aortic arch of ApoE-/- mice. B1R was also upregulated in human umbilical vein endothelial cells (HUVEC) exposed to low LSS (0-2dyn/cm2) compared to physiological LSS (6-10dyn/cm2): an effect similarly evident in murine vascular tissue perfused ex vivo. Functionally, B1R activation increased prostaglandin and CXCL5 expression in cells exposed to low, but not physiological, LSS. IL-1β and ox-LDL induced B1R expression and function in HUVECs, a response substantially enhanced under low LSS conditions and inhibited by blockade of NFκB activation. CONCLUSION Herein, we show that LSS is a major determinant of functional B1R expression in endothelium. Furthermore, whilst physiological high LSS is a powerful repressor of this inflammatory receptor, low LSS at sites of atheroma are associated with substantial upregulation, identifying this receptor as a potential therapeutic target. CONDENSED ABSTRACT Low laminar shear stress (LSS) underlies the pro-inflammatory processes in atherogenesis. Herein, we demonstrate that whilst physiological LSS represses inflammatory kinin B1 receptor (B1R) expression/function, low atherogenic LSS is associated with profound upregulation of both in atherosclerosis in both humans and animal models, highlighting B1R as an exciting potential therapeutic target. PMID:19661485

Electroacupuncture decreases the progression of ovarian hyperstimulation syndrome in a rat model.

PubMed

Chen, Li; Sun, Hai-Xiang; Xia, You-Bing; Sui, Liu-Cai; Zhou, Ji; Huang, Xuan; Zhou, Jing-Wei; Shao, Yi-Dan; Shen, Tao; Sun, Qin; Liang, Yuan-Jiao; Yao, Bing

2016-05-01

This study aimed to elucidate the effect of electroacupuncture treatment on preventing early ovarian hyperstimulation syndrome (OHSS) and the potential mechanisms involved using an induced rat model. The ovarian response was examined by measuring ovary weight, vascular permeability, levels of inflammation (interleukin-6), tumour necrosis factor alpha, chemokine ligand 2 (also known as monocyte chemoactic protein 1), vascular endothelial growth factor and hormone concentrations (oestradiol, progesterone, testosterone and prolactin). Sprague-Dawley female rats underwent ovarian stimulation to induce OHSS. Hyperstimulated rats received consecutive electroacupuncture treatment from 3 days before the beginning of pregnant mare serum gonadotrophin treatment or the time point of pregnant mare serum gonadotrophin treatment respectively, and last until 3 days after HCG administration. Electroacupuncture treatment reduced ovary weight and vascular permeability in hyperstimulated rats. Electroacupuncture treatment also reduced the levels of serum steroid hormones (progesterone and testosterone), inflammatory cytokines (interleukin-6, tumour necrosis factor alpha and monocyte chemotactic protein 1 and vascular endothelial growth factor in hyperstimulated rats. The results indicate that electroacupuncture can modulate endocrine hormone secretion and affect the secretion of inflammatory cytokines and vascular endothelial growth factor, and thus prevent the progress of OHSS. Electroacupuncture may provide a simple and effective method for the prevention and treatment of OHSS. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Green tea catechins: defensive role in cardiovascular disorders.

PubMed

Bhardwaj, Pooja; Khanna, Deepa

2013-07-01

Green tea, Camellia sinensis (Theaceae), a major source of flavonoids such as catechins, has recently shown multiple cardiovascular health benefits through various experimental and clinical studies. These studies suggest that green tea catechins prevent the incidence of detrimental cardiovascular events, and also lower the cardiovascular mortality rate. Catechins present in green tea have the ability to prevent atherosclerosis, hypertension, endothelial dysfunction, ischemic heart diseases, cardiomyopathy, cardiac hypertrophy and congestive heart failure by decreasing oxidative stress, preventing inflammatory events, reducing platelet aggregation and halting the proliferation of vascular smooth muscle cells. Catechins afford an anti-oxidant effect by inducing anti-oxidant enzymes, inhibiting pro-oxidant enzymes and scavenging free radicals. Catechins present anti-inflammatory activity through the inhibition of transcriptional factor NF-κB-mediated production of cytokines and adhesion molecules. Green tea catechins interfere with vascular growth factors and thus inhibit vascular smooth muscle cell proliferation, and also inhibit thrombogenesis by suppressing platelet adhesion. Additionally, catechins could protect vascular endothelial cells and enhance vascular integrity and regulate blood pressure. In this review various experimental and clinical studies suggesting the role of green tea catechins against the markers of cardiovascular disorders and the underlying mechanisms for these actions are discussed. Copyright © 2013 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Tumors: wounds that do not heal-redux.

PubMed

Dvorak, Harold F

2015-01-01

Similarities between tumors and the inflammatory response associated with wound healing have been recognized for more than 150 years and continue to intrigue. Some years ago, based on our then recent discovery of vascular permeability factor (VPF)/VEGF, I suggested that tumors behaved as wounds that do not heal. More particularly, I proposed that tumors co-opted the wound-healing response to induce the stroma they required for maintenance and growth. Work over the past few decades has supported this hypothesis and has put it on a firmer molecular basis. In outline, VPF/VEGF initiates a sequence of events in both tumors and wounds that includes the following: increased vascular permeability; extravasation of plasma, fibrinogen and other plasma proteins; activation of the clotting system outside the vascular system; deposition of an extravascular fibrin gel that serves as a provisional stroma and a favorable matrix for cell migration; induction of angiogenesis and arterio-venogenesis; subsequent degradation of fibrin and its replacement by "granulation tissue" (highly vascular connective tissue); and, finally, vascular resorption and collagen synthesis, resulting in the formation of dense fibrous connective tissue (called "scar tissue" in wounds and "desmoplasia" in cancer). A similar sequence of events also takes place in a variety of important inflammatory diseases that involve cellular immunity. ©2015 American Association for Cancer Research.

Effects of Swimming and Cycling Exercise Intervention on Vascular Function in Patients With Osteoarthritis.

PubMed

Alkatan, Mohammed; Machin, Daniel R; Baker, Jeffrey R; Akkari, Amanda S; Park, Wonil; Tanaka, Hirofumi

2016-01-01

Swimming exercise is an ideal and excellent form of exercise for patients with osteoarthritis (OA). However, there is no scientific evidence that regular swimming reduces vascular dysfunction and inflammation and elicits similar benefits compared with land-based exercises such as cycling in terms of reducing vascular dysfunction and inflammation in patients with OA. Forty-eight middle-aged and older patients with OA were randomly assigned to swimming or cycling training groups. Cycling training was included as a non-weight-bearing land-based comparison group. After 12 weeks of supervised exercise training, central arterial stiffness, as determined by carotid-femoral pulse wave velocity, and carotid artery stiffness, through simultaneous ultrasound and applanation tonometry, decreased significantly after both swimming and cycling training. Vascular endothelial function, as determined by brachial flow-mediated dilation, increased significantly after swimming but not after cycling training. Both swimming and cycling interventions reduced interleukin-6 levels, whereas no changes were observed in other inflammatory markers. In conclusion, these results indicate that regular swimming exercise can exert similar or even superior effects on vascular function and inflammatory markers compared with land-based cycling exercise in patients with OA who often has an increased risk of developing cardiovascular disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Blood Flow Modulation of Vascular Dynamics

PubMed Central

Lee, Juhyun; Sevag Packard, René R.; Hsiai, Tzung K.

2015-01-01

Purpose of review Blood flow is intimately linked with cardiovascular development, repair, and dysfunction. The current review will build on the fluid mechanical principle underlying hemodynamic shear forces, mechanotransduction, and metabolic effects. Recent findings Pulsatile flow produces both time- (∂τ /∂t)and spatial-varying shear stress (∂τ /∂x) to modulate vascular oxidative stress and inflammatory response with pathophysiological significance to atherosclerosis. The characteristics of hemodynamic shear forces; namely, steady laminar (∂τ /∂t= 0), pulsatile (PSS: unidirectional forward flow), and oscillatory shear stress (OSS: bidirectional with a near net 0 forward flow) modulate mechano-signal transduction to influence metabolic effects on vascular endothelial function. Atheroprotective PSS promotes anti-oxidant, anti-inflammatory, and anti-thrombotic responses, whereas atherogenic OSS induces NADPH oxidase–JNK signaling to increase mitochondrial superoxide production, protein degradation of manganese superoxide dismutase (MnSOD), and post-translational protein modifications of LDL particles in the disturbed flow-exposed regions of vasculature. In the era of tissue regeneration, shear stress has been implicated in re-activation of developmental genes; namely, Wnt and Notch signaling, for vascular development and repair. Summary Blood flow imparts a dynamic continuum from vascular development to repair. Augmentation of PSS confers atheroprotection and re-activation of developmental signaling pathways for regeneration. PMID:26218416

Regulation of lung endothelial permeability and inflammatory responses by prostaglandin A2: role of EP4 receptor

PubMed Central

Ohmura, Tomomi; Tian, Yufeng; Sarich, Nicolene; Ke, Yunbo; Meliton, Angelo; Shah, Alok S.; Andreasson, Katrin; Birukov, Konstantin G.; Birukova, Anna A.

2017-01-01

The role of prostaglandin A2 (PGA2) in modulation of vascular endothelial function is unknown. We investigated effects of PGA2 on pulmonary endothelial cell (EC) permeability and inflammatory activation and identified a receptor mediating these effects. PGA2 enhanced the EC barrier and protected against barrier dysfunction caused by vasoactive peptide thrombin and proinflammatory bacterial wall lipopolysaccharide (LPS). Receptor screening using pharmacological and molecular inhibitory approaches identified EP4 as a novel PGA2 receptor. EP4 mediated barrier-protective effects of PGA2 by activating Rap1/Rac1 GTPase and protein kinase A targets at cell adhesions and cytoskeleton: VE-cadherin, p120-catenin, ZO-1, cortactin, and VASP. PGA2 also suppressed LPS-induced inflammatory signaling by inhibiting the NFκB pathway and expression of EC adhesion molecules ICAM1 and VCAM1. These effects were abolished by pharmacological or molecular inhibition of EP4. In vivo, PGA2 was protective in two distinct models of acute lung injury (ALI): LPS-induced inflammatory injury and two-hit ALI caused by suboptimal mechanical ventilation and injection of thrombin receptor–activating peptide. These protective effects were abolished in mice with endothelial-specific EP4 knockout. The results suggest a novel role for the PGA2–EP4 axis in vascular EC protection that is critical for improvement of pathological states associated with increased vascular leakage and inflammation. PMID:28428256

EGCG protects endothelial cells against PCB 126-induced inflammation through inhibition of AhR and induction of Nrf2-regulated genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han, Sung Gu; Department of Animal and Food Sciences, College of Agriculture, University of Kentucky, Lexington, KY 40536; Han, Seong-Su

Tea flavonoids such as epigallocatechin gallate (EGCG) protect against vascular diseases such as atherosclerosis via their antioxidant and anti-inflammatory functions. Persistent and widespread environmental pollutants, including polychlorinated biphenyls (PCB), can induce oxidative stress and inflammation in vascular endothelial cells. Even though PCBs are no longer produced, they are still detected in human blood and tissues and thus considered a risk for vascular dysfunction. We hypothesized that EGCG can protect endothelial cells against PCB-induced cell damage via its antioxidant and anti-inflammatory properties. To test this hypothesis, primary vascular endothelial cells were pretreated with EGCG, followed by exposure to the coplanar PCBmore » 126. Exposure to PCB 126 significantly increased cytochrome P450 1A1 (Cyp1A1) mRNA and protein expression and superoxide production, events which were significantly attenuated following pretreatment with EGCG. Similarly, EGCG also reduced DNA binding of NF-κB and downstream expression of inflammatory markers such as monocyte chemotactic protein-1 (MCP-1) and vascular cell adhesion protein-1 (VCAM-1) after PCB exposure. Furthermore, EGCG decreased endogenous or base-line levels of Cyp1A1, MCP-1 and VCAM-1 in endothelial cells. Most of all, treatment of EGCG upregulated expression of NF-E2-related factor 2 (Nrf2)-controlled antioxidant genes, including glutathione S transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1), in a dose-dependent manner. In contrast, silencing of Nrf2 increased Cyp1A1, MCP-1 and VCAM-1 and decreased GST and NQO1 expression, respectively. These data suggest that EGCG can inhibit AhR regulated genes and induce Nrf2-regulated antioxidant enzymes, thus providing protection against PCB-induced inflammatory responses in endothelial cells. -- Highlights: ► PCBs cause endothelial inflammation and subsequent atherosclerosis. ► Nutrition can modulate toxicity by environmental pollutants. ► We demonstrated that EGCG can decrease PCB-induced inflammation. ► EGCG protection was via inhibition of AhR and induction of Nrf2 regulatory genes.« less

Inflammation-induced lymphangiogenesis and lymphatic dysfunction

PubMed Central

Liao, Shan; von der Weid, Pierre-Yves

2014-01-01

The lymphatic system is intimately linked to tissue fluid homeostasis and immune cell trafficking. These functions are paramount in the establishment and development of an inflammatory response. In the past decade, an increasing number of reports has revealed that marked changes, such as lymphangiogenesis and lymphatic contractile dysfunction occur in both vascular and nodal parts of the lymphatic system during inflammation, as well as other disease processes. This review provides a critical update on the role of the lymphatic system in disease process such as chronic inflammation and cancer and examines the changes in lymphatic functions the diseases cause and the influence these changes have on the progression of the diseases. PMID:24449090

Arachidonic-acid-derived eicosanoids: roles in biology and immunopathology.

PubMed

Harizi, Hedi; Corcuff, Jean-Benoît; Gualde, Norbert

2008-10-01

Arachidonic acid (AA)-derived eicosanoids belong to a complex family of lipid mediators that regulate a wide variety of physiological responses and pathological processes. They are produced by various cell types through distinct enzymatic pathways and act on target cells via specific G-protein-coupled receptors. Although originally recognized for their capacity to elicit biological responses such as vascular homeostasis, protection of the gastric mucosa and platelet aggregation, eicosanoids are now understood to regulate immunopathological processes ranging from inflammatory responses to chronic tissue remodelling, cancer, asthma, rheumatoid arthritis and autoimmune disorders. Here, we review the major properties of eicosanoids and their expanding roles in biology and medicine.

Activation of the c-Met pathway mobilizes an inflammatory network in the brain microenvironment to promote brain metastasis of breast cancer

PubMed Central

Xing, Fei; Liu, Yin; Sharma, Sambad; Wu, Kerui; Chan, Michael D.; Lo, Hui-Wen; Carpenter, Richard L.; Metheny-Barlow, Linda J.; Zhou, Xiaobo; Qasem, Shadi A.; Pasche, Boris; Watabe, Kounosuke

2016-01-01

Brain metastasis is one of the chief causes of mortality in breast cancer patients, but the mechanisms that drive this process remains poorly understood. Here we report that brain metastatic cells expressing high levels of c-Met promote the metastatic process via inflammatory cytokine upregulation and vascular reprogramming. Activated c-Met signaling promoted adhesion of tumor cells to brain endothelial cells and enhanced neovascularization by inducing the secretion of IL-8 and CXCL1. Additionally, stimulation of IL1β secretion by activation of c-Met induced tumor-associated astrocytes to secrete the c-Met ligand HGF. Thus, a feed-forward mechanism of cytokine release initiated and sustained by c-Met fed a vicious cycle which generated a favorable microenvironment for metastatic cells. Reinforcing our results, we found that pterostilbene, a compound that penetrates the blood-brain barrier, could suppress brain metastasis by targeting c-Met signaling. These findings suggest a potential utility of this natural compound for chemoprevention. PMID:27364556

Experimental research on preventing mechanical phlebitis arising from indwelling needles in intravenous therapy by external application of mirabilite

PubMed Central

Lu, Yanyan; Hao, Chunyan; He, Wubin; Tang, Can; Shao, Zhenya

2018-01-01

Various types of complications arising from intravenous indwelling needles have become a challenge in clinical care. It is urgent to seek a simple and cost-effective method for prevention and treatment of phlebitis. We investigated the roles of mirabilite in preventing and treating phlebitis caused by intravenous indwelling needles and provide guidance for prevention and treatment of mechanical phlebitis caused by intravenous indwelling needles. A total of 57 healthy congeneric big-eared New Zealand rabbits were randomly divided into 3 groups: blank control, indwelling needle, and group with external application of mirabilite. The ear vein of each rabbit was punctured with an intravenous indwelling needle. The ear vein specimens were taken at 3, 5, and 7 days after indwelling. The hematoxylin and eosin stained pathological tissue sections of the ear veins of the rabbits in each group were observed. The expression levels of IL-1 and IL-6, and tumour necrosis factor-α (TNF-α) in the vascular tissue of the ear veins of the rabbits in each group were detected with the immunofluorescence method. In the blank control group, there was no inflammatory cellular infiltration and no proliferation of fibrous tissue around the vascular wall. With the increase of the indwelling time, proliferation of fibrous tissue in vascular wall, increased inflammatory cellular infiltration and organized thrombus in the vascular tissue occurred in the ear veins of the rabbits in the indwelling needle group and group with external application of mirabilite. Compared with the indwelling needle group, the group with external application of mirabilite had significantly decreased fibrous tissue in the vascular wall and significantly decreased inflammatory cellular infiltration. At the same point in indwelling time, the expression levels of IL-1, IL-6, and TNF-α in the indwelling needle and group with external application of mirabilite were significantly higher than that in the blank control group (P<0.05). The expression levels of IL-1, IL-6, and TNF-α in the group with external application of mirabilite were lower than that in the indwelling needle group (P<0.05). The expression levels of IL-1, IL-6, and TNF-α are positively correlated with the indwelling time within the same group at different points in time. In conclusion, external application of mirabilite can significantly decrease infiltration of venous inflammatory cells of the rabbit ear margin, proliferation of fibrous tissue and thrombosis in the vascular wall, significant decrease the expression levels of IL-1, IL-6, and TNF-α in the mechanical phlebitis caused by intravenous indwelling needles, and decrease the inflammatory responses of the ear veins of rabbits. PMID:29250150

Experimental research on preventing mechanical phlebitis arising from indwelling needles in intravenous therapy by external application of mirabilite.

PubMed

Lu, Yanyan; Hao, Chunyan; He, Wubin; Tang, Can; Shao, Zhenya

2018-01-01

Various types of complications arising from intravenous indwelling needles have become a challenge in clinical care. It is urgent to seek a simple and cost-effective method for prevention and treatment of phlebitis. We investigated the roles of mirabilite in preventing and treating phlebitis caused by intravenous indwelling needles and provide guidance for prevention and treatment of mechanical phlebitis caused by intravenous indwelling needles. A total of 57 healthy congeneric big-eared New Zealand rabbits were randomly divided into 3 groups: blank control, indwelling needle, and group with external application of mirabilite. The ear vein of each rabbit was punctured with an intravenous indwelling needle. The ear vein specimens were taken at 3, 5, and 7 days after indwelling. The hematoxylin and eosin stained pathological tissue sections of the ear veins of the rabbits in each group were observed. The expression levels of IL-1 and IL-6, and tumour necrosis factor-α (TNF-α) in the vascular tissue of the ear veins of the rabbits in each group were detected with the immunofluorescence method. In the blank control group, there was no inflammatory cellular infiltration and no proliferation of fibrous tissue around the vascular wall. With the increase of the indwelling time, proliferation of fibrous tissue in vascular wall, increased inflammatory cellular infiltration and organized thrombus in the vascular tissue occurred in the ear veins of the rabbits in the indwelling needle group and group with external application of mirabilite. Compared with the indwelling needle group, the group with external application of mirabilite had significantly decreased fibrous tissue in the vascular wall and significantly decreased inflammatory cellular infiltration. At the same point in indwelling time, the expression levels of IL-1, IL-6, and TNF-α in the indwelling needle and group with external application of mirabilite were significantly higher than that in the blank control group (P<0.05). The expression levels of IL-1, IL-6, and TNF-α in the group with external application of mirabilite were lower than that in the indwelling needle group (P<0.05). The expression levels of IL-1, IL-6, and TNF-α are positively correlated with the indwelling time within the same group at different points in time. In conclusion, external application of mirabilite can significantly decrease infiltration of venous inflammatory cells of the rabbit ear margin, proliferation of fibrous tissue and thrombosis in the vascular wall, significant decrease the expression levels of IL-1, IL-6, and TNF-α in the mechanical phlebitis caused by intravenous indwelling needles, and decrease the inflammatory responses of the ear veins of rabbits.

IGF-1, oxidative stress, and atheroprotection

PubMed Central

Higashi, Yusuke; Sukhanov, Sergiy; Anwar, Asif; Shai, Shaw-Yung; Delafontaine, Patrice

2009-01-01

Atherosclerosis is a chronic inflammatory disease in which early endothelial dysfunction and subintimal modified lipoprotein deposition progress to complex, advanced lesions that are predisposed to erosion, rupture and thrombosis. Oxidative stress plays a critical role not only in initial lesion formation but also in lesion progression and destabilization. While growth factors are thought to promote vascular smooth muscle cell proliferation and migration, thereby increasing neointima, recent animal studies indicate that IGF-1 exerts pleiotropic anti-oxidant effects along with anti-inflammatory effects that together reduce atherosclerotic burden. This review discusses the effects of IGF-1 in vascular injury and atherosclerosis models, emphasizing the relationship between oxidative stress and potential atheroprotective actions of IGF-1. PMID:20071192

Phytochemical genistein in the regulation of vascular function: new insights.

PubMed

Si, Hongwei; Liu, Dongmin

2007-01-01

Genistein, a natural bioactive compound derived from legumes, has drawn wide attention during the last decade because of its potentially beneficial effects on some human degenerative diseases. It has a weak estrogenic effect and is a well-known non-specific tyrosine kinase inhibitor at pharmacological doses. Epidemiological studies show that genistein intake is inversely associated with the risk of cardiovascular diseases. Data from animal and in vitro studies suggest a protective role of genistein in cardiovascular events. However, the mechanisms of the genistein action on vascular protective effects are unclear. Past extensive studies exploring its hypolipidemic effect resulted in contradictory data. Genistein also is a relatively poor antioxidant. However, genistein protects against pro-inflammatory factor-induced vascular endothelial barrier dysfunction and inhibits leukocyte-endothelium interaction, thereby modulating vascular inflammation, a major event in the pathogenesis of atherosclerosis. Recent studies found that genistein exerts a novel non-genomic action by targeting on important signaling molecules in vascular endothelial cells (ECs). Genistein rapidly activates endothelial nitric oxide synthase and production of nitric oxide in ECs. This genistein effect is novel since it is independent of its known effects, but mediated by the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) cascade. Further studies demonstrated that genistein directly stimulates the plasma membrane-associated adenylate cyclases, leading to activation of the cAMP signaling pathway. In addition, genistein activates peroxisome proliferator-activated receptors, ligand-activated nuclear receptors important to normal vascular function. Furthermore, genistein reduces reactive oxygen species (ROS) by attenuating the expression of ROS-producing enzymes. These new findings reveal the novel roles for genistein in the regulation of vascular function and provide a basis for further investigating its therapeutic potential for inflammatory-related vascular disease.

New insight in quantitative analysis of vascular permeability during immune reaction (Conference Presentation)

NASA Astrophysics Data System (ADS)

Kalchenko, Vyacheslav; Molodij, Guillaume; Kuznetsov, Yuri; Smolyakov, Yuri; Israeli, David; Meglinski, Igor; Harmelin, Alon

2016-03-01

The use of fluorescence imaging of vascular permeability becomes a golden standard for assessing the inflammation process during experimental immune response in vivo. The use of the optical fluorescence imaging provides a very useful and simple tool to reach this purpose. The motivation comes from the necessity of a robust and simple quantification and data presentation of inflammation based on a vascular permeability. Changes of the fluorescent intensity, as a function of time is a widely accepted method to assess the vascular permeability during inflammation related to the immune response. In the present study we propose to bring a new dimension by applying a more sophisticated approach to the analysis of vascular reaction by using a quantitative analysis based on methods derived from astronomical observations, in particular by using a space-time Fourier filtering analysis followed by a polynomial orthogonal modes decomposition. We demonstrate that temporal evolution of the fluorescent intensity observed at certain pixels correlates quantitatively to the blood flow circulation at normal conditions. The approach allows to determine the regions of permeability and monitor both the fast kinetics related to the contrast material distribution in the circulatory system and slow kinetics associated with extravasation of the contrast material. Thus, we introduce a simple and convenient method for fast quantitative visualization of the leakage related to the inflammatory (immune) reaction in vivo.

The interleukin-1 receptor antagonist anakinra improves endothelial dysfunction in streptozotocin-induced diabetic rats.

PubMed

Vallejo, Susana; Palacios, Erika; Romacho, Tania; Villalobos, Laura; Peiró, Concepción; Sánchez-Ferrer, Carlos F

2014-12-18

Endothelial dysfunction is a crucial early phenomenon in vascular diseases linked to diabetes mellitus and associated to enhanced oxidative stress. There is increasing evidence about the role for pro-inflammatory cytokines, like interleukin-1β (IL-1β), in developing diabetic vasculopathy. We aimed to determine the possible involvement of this cytokine in the development of diabetic endothelial dysfunction, analysing whether anakinra, an antagonist of IL-1 receptors, could reduce this endothelial alteration by interfering with pro-oxidant and pro-inflammatory pathways into the vascular wall. In control and two weeks evolution streptozotocin-induced diabetic rats, either untreated or receiving anakinra, vascular reactivity and NADPH oxidase activity were measured, respectively, in isolated rings and homogenates from mesenteric microvessels, while nuclear factor (NF)-κB activation was determined in aortas. Plasma levels of IL-1β and tumor necrosis factor (TNF)-α were measured by ELISA. In isolated mesenteric microvessels from control rats, two hours incubation with IL-1β (1 to 10 ng/mL) produced a concentration-dependent impairment of endothelium-dependent relaxations, which were mediated by enhanced NADPH oxidase activity via IL-1 receptors. In diabetic rats treated with anakinra (100 or 160 mg/Kg/day for 3 or 7 days before sacrifice) a partial improvement of diabetic endothelial dysfunction occurred, together with a reduction of vascular NADPH oxidase and NF-κB activation. Endothelial dysfunction in diabetic animals was also associated to higher activities of the pro-inflammatory enzymes cyclooxygenase (COX) and the inducible isoform of nitric oxide synthase (iNOS), which were markedly reduced after anakinra treatment. Circulating IL-1β and TNF-α levels did not change in diabetic rats, but they were lowered by anakinra treatment. In this short-term model of type 1 diabetes, endothelial dysfunction is associated to an IL-1 receptor-mediated activation of vascular NADPH oxidase and NF-κB, as well as to vascular inflammation. Moreover, endothelial dysfunction, vascular oxidative stress and inflammation were reduced after anakinra treatment. Whether this mechanism can be extrapolated to a chronic situation or whether it may apply to diabetic patients remain to be established. However, it may provide new insights to further investigate the therapeutic use of IL-1 receptor antagonists to obtain vascular benefits in patients with diabetes mellitus and/or atherosclerosis.

Treatment with polyamine oxidase inhibitor reduces microglial activation and limits vascular injury in ischemic retinopathy

PubMed Central

Patel, C.; Xu, Z.; Shosha, E.; Xing, J.; Lucas, R.; Caldwell, R.W.; Caldwell, R.B.; Narayanan, S.P.

2016-01-01

Retinal vascular injury is a major cause of vision impairment in ischemic retinopathies. Insults such as hyperoxia, oxidative stress and inflammation contribute to this pathology. Previously, we showed that hyperoxia-induced retinal neurodegeneration is associated with increased polyamine oxidation. Here, we are studying the involvement of polyamine oxidases in hyperoxia-induced injury and death of retinal vascular endothelial cells. Newborn C57BL6/J mice were exposed to hyperoxia (70% O2) from postnatal day (P) 7 to 12 and were treated with the polyamine oxidase inhibitor MDL 72527 or vehicle starting at P6. Mice were sacrificed after different durations of hyperoxia and their retinas were analyzed to determine the effects on vascular injury, microglial cell activation, and inflammatory cytokine profiling. The results of this analysis showed that MDL 72527 treatment significantly reduced hyperoxia-induced retinal vascular injury and enhanced vascular sprouting as compared with the vehicle controls. These protective effects were correlated with significant decreases in microglial activation as well as levels of inflammatory cytokines and chemokines. In order to model the effects of polyamine oxidation in causing microglial activation in vitro, studies were performed using rat brain microvascular endothelial cells treated with conditioned-medium from rat retinal microglia stimulated with hydrogen peroxide. Conditioned-medium from activated microglial cultures induced cell stress signals and cell death in microvascular endothelial cells. These studies demonstrate the involvement of polyamine oxidases in hyperoxia-induced retinal vascular injury and retinal inflammation in ischemic retinopathy, through mechanisms involving cross-talk between endothelial cells and resident retinal microglia. PMID:27239699

Role of training and detraining on inflammatory and metabolic profile in infarcted rats: influences of cardiovascular autonomic nervous system.

PubMed

Rodrigues, Bruno; Santana, Aline Alves; Santamarina, Aline Boveto; Oyama, Lila Missae; Caperuto, Érico Chagas; de Souza, Cláudio Teodoro; Barboza, Catarina de Andrade; Rocha, Leandro Yanase; Figueroa, Diego; Mostarda, Cristiano; Irigoyen, Maria Cláudia; Lira, Fábio Santos

2014-01-01

The aim of this study was to evaluate the effects of exercise training (ET, 50-70% of VO2 max, 5 days/week) and detraining (DT) on inflammatory and metabolic profile after myocardial infarction (MI) in rats. Male Wistar rats were divided into control (C, n = 8), sedentary infarcted (SI, n = 9), trained infarcted (TI, n = 10; 3 months of ET), and detrained infarcted (DI, n = 11; 2 months of ET + 1 month of DT). After ET and DT protocols, ventricular function and inflammation, cardiovascular autonomic modulation (spectral analysis), and adipose tissue inflammation and lipolytic pathway were evaluated. ET after MI improved cardiac and vascular autonomic modulation, and these benefits were correlated with reduced inflammatory cytokines on the heart and adipose tissue. These positive changes were sustained even after 1 month of detraining. No expressive changes were observed in oxidative stress and lipolytic pathway in experimental groups. In conclusion, our results strongly suggest that the autonomic improvement promoted by ET, and maintained even after the detraining period, was associated with reduced inflammatory profile in the left ventricle and adipose tissue of rats subjected to MI. These data encourage enhancing cardiovascular autonomic function as a therapeutic strategy for the treatment of inflammatory process triggered by MI.

Role of Training and Detraining on Inflammatory and Metabolic Profile in Infarcted Rats: Influences of Cardiovascular Autonomic Nervous System

PubMed Central

Santana, Aline Alves; Santamarina, Aline Boveto; Oyama, Lila Missae; Caperuto, Érico Chagas; de Souza, Cláudio Teodoro; Barboza, Catarina de Andrade; Rocha, Leandro Yanase; Figueroa, Diego; Mostarda, Cristiano; Irigoyen, Maria Cláudia; Lira, Fábio Santos

2014-01-01

The aim of this study was to evaluate the effects of exercise training (ET, 50–70% of VO2 max, 5 days/week) and detraining (DT) on inflammatory and metabolic profile after myocardial infarction (MI) in rats. Male Wistar rats were divided into control (C, n = 8), sedentary infarcted (SI, n = 9), trained infarcted (TI, n = 10; 3 months of ET), and detrained infarcted (DI, n = 11; 2 months of ET + 1 month of DT). After ET and DT protocols, ventricular function and inflammation, cardiovascular autonomic modulation (spectral analysis), and adipose tissue inflammation and lipolytic pathway were evaluated. ET after MI improved cardiac and vascular autonomic modulation, and these benefits were correlated with reduced inflammatory cytokines on the heart and adipose tissue. These positive changes were sustained even after 1 month of detraining. No expressive changes were observed in oxidative stress and lipolytic pathway in experimental groups. In conclusion, our results strongly suggest that the autonomic improvement promoted by ET, and maintained even after the detraining period, was associated with reduced inflammatory profile in the left ventricle and adipose tissue of rats subjected to MI. These data encourage enhancing cardiovascular autonomic function as a therapeutic strategy for the treatment of inflammatory process triggered by MI. PMID:25045207

c-Kit modifies the inflammatory status of smooth muscle cells

PubMed Central

Song, Lei; Martinez, Laisel; Zigmond, Zachary M.; Hernandez, Diana R.; Lassance-Soares, Roberta M.; Selman, Guillermo

2017-01-01

Background c-Kit is a receptor tyrosine kinase present in multiple cell types, including vascular smooth muscle cells (SMC). However, little is known about how c-Kit influences SMC biology and vascular pathogenesis. Methods High-throughput microarray assays and in silico pathway analysis were used to identify differentially expressed genes between primary c-Kit deficient (KitW/W–v) and control (Kit+/+) SMC. Quantitative real-time RT-PCR and functional assays further confirmed the differences in gene expression and pro-inflammatory pathway regulation between both SMC populations. Results The microarray analysis revealed elevated NF-κB gene expression secondary to the loss of c-Kit that affects both the canonical and alternative NF-κB pathways. Upon stimulation with an oxidized phospholipid as pro-inflammatory agent, c-Kit deficient SMC displayed enhanced NF-κB transcriptional activity, higher phosphorylated/total p65 ratio, and increased protein expression of NF-κB regulated pro-inflammatory mediators with respect to cells from control mice. The pro-inflammatory phenotype of mutant cells was ameliorated after restoring c-Kit activity using lentiviral transduction. Functional assays further demonstrated that c-Kit suppresses NF-κB activity in SMC in a TGFβ-activated kinase 1 (TAK1) and Nemo-like kinase (NLK) dependent manner. Discussion Our study suggests a novel mechanism by which c-Kit suppresses NF-κB regulated pathways in SMC to prevent their pro-inflammatory transformation. PMID:28626608

c-Kit modifies the inflammatory status of smooth muscle cells.

PubMed

Song, Lei; Martinez, Laisel; Zigmond, Zachary M; Hernandez, Diana R; Lassance-Soares, Roberta M; Selman, Guillermo; Vazquez-Padron, Roberto I

2017-01-01

c-Kit is a receptor tyrosine kinase present in multiple cell types, including vascular smooth muscle cells (SMC). However, little is known about how c-Kit influences SMC biology and vascular pathogenesis. High-throughput microarray assays and in silico pathway analysis were used to identify differentially expressed genes between primary c-Kit deficient (Kit W/W-v ) and control (Kit +/+ ) SMC. Quantitative real-time RT-PCR and functional assays further confirmed the differences in gene expression and pro-inflammatory pathway regulation between both SMC populations. The microarray analysis revealed elevated NF-κB gene expression secondary to the loss of c-Kit that affects both the canonical and alternative NF-κB pathways. Upon stimulation with an oxidized phospholipid as pro-inflammatory agent, c-Kit deficient SMC displayed enhanced NF-κB transcriptional activity, higher phosphorylated/total p65 ratio, and increased protein expression of NF-κB regulated pro-inflammatory mediators with respect to cells from control mice. The pro-inflammatory phenotype of mutant cells was ameliorated after restoring c-Kit activity using lentiviral transduction. Functional assays further demonstrated that c-Kit suppresses NF-κB activity in SMC in a TGFβ-activated kinase 1 (TAK1) and Nemo-like kinase (NLK) dependent manner. Our study suggests a novel mechanism by which c-Kit suppresses NF-κB regulated pathways in SMC to prevent their pro-inflammatory transformation.

Anti-inflammatory activity of the essential oil obtained from Ocimum basilicum complexed with β-cyclodextrin (β-CD) in mice.

PubMed

Rodrigues, Lindaiane Bezerra; Martins, Anita Oliveira Brito Pereira Bezerra; Ribeiro-Filho, Jaime; Cesário, Francisco Rafael Alves Santana; E Castro, Fyama Ferreira; de Albuquerque, Thaís Rodrigues; Fernandes, Maria Neyze Martins; da Silva, Bruno Anderson Fernandes; Quintans Júnior, Lucindo José; Araújo, Adriano Antunes de Sousa; Menezes, Paula Dos Passos; Nunes, Paula Santos; Matos, Isabella Gonçalves; Coutinho, Henrique Douglas Melo; Goncalves Wanderley, Almir; de Menezes, Irwin Rose Alencar

2017-11-01

Cyclodextrins (CDs) are cyclic oligosaccharides can enhance the bioavailability of drugs. Ocimum basilicum is an aromatic plant found in Brazil used in culinary. The essential oil of this plant presents anti-edematogenic and anti-inflammatory activities in acute and chronic inflammation. The aim of this study was to investigate the anti-inflammatory effects of the essential oil obtained from O. basilicum complexed with β - cyclodextrin (OBEO/β-CD) in mice. The complexation with β-cyclodextrin (β-CD) was performed by different methods and analyzed by differential scanning calorimetry (DSC), thermogravimetry (TG) and scanning electron microscopy (SEM). The anti-inflammatory activity was evaluated using mice models of paw edema induced by carrageenan, dextran, histamine and arachidonic acid (AA); vascular permeability and peritonitis induced by carrageenan and granuloma induced by cotton block introduction. The DSC, TG and SEM analysis indicated that the OBEO was successfully complexed with β-CD. The oral administration of OEOB/β-CD prevented paw edema formation by decreasing vascular permeability in vivo, inhibited leukocyte recruitment to the peritoneal cavity, and inhibited granuloma formation in mice. Our results indicate that conjugation with β-CD improves the anti-inflammatory effects of OBEO in mice models of acute and chronic inflammation, indicating that this complex can be used in anti-inflammatory drug development. Copyright © 2017 Elsevier Ltd. All rights reserved.

Advanced Glycation End Products: A Molecular Target for Vascular Complications in Diabetes.

PubMed

Yamagishi, Sho-Ichi; Nakamura, Nobutaka; Suematsu, Mika; Kaseda, Kuniyoshi; Matsui, Takanori

2015-10-27

A nonenzymatic reaction between reducing sugars and amino groups of proteins, lipids and nucleic acids contributes to the aging of macromolecules and subsequently alters their structural integrity and function. This process has been known to progress at an accelerated rate under hyperglycemic and/or oxidative stress conditions. Over a course of days to weeks, early glycation products undergo further reactions such as rearrangements and dehydration to become irreversibly cross-linked, fluorescent and senescent macroprotein derivatives termed advanced glycation end products (AGEs). There is a growing body of evidence indicating that interaction of AGEs with their receptor (RAGE) elicits oxidative stress generation and as a result evokes proliferative, inflammatory, thrombotic and fibrotic reactions in a variety of cells. This evidence supports AGEs' involvement in diabetes- and aging-associated disorders such as diabetic vascular complications, cancer, Alzheimer's disease and osteoporosis. Therefore, inhibition of AGE formation could be a novel molecular target for organ protection in diabetes. This report summarizes the pathophysiological role of AGEs in vascular complications in diabetes and discusses the potential clinical utility of measurement of serum levels of AGEs for evaluating organ damage in diabetes.

Histological and histomorphometrical analysis of a silica matrix embedded nanocrystalline hydroxyapatite bone substitute using the subcutaneous implantation model in Wistar rats.

PubMed

Ghanaati, Shahram; Orth, Carina; Barbeck, Mike; Willershausen, Ines; Thimm, Benjamin W; Booms, Patrick; Stübinger, Stefan; Landes, Constantin; Sader, Robert Anton; Kirkpatrick, Charles James

2010-06-01

The clinical suitability of a bone substitute material is determined by the ability to induce a tissue reaction specific to its composition. The aim of this in vivo study was to analyze the tissue reaction to a silica matrix-embedded, nanocrystalline hydroxyapatite bone substitute.The subcutaneous implantation model in Wistar rats was chosen to assess the effect of silica degradation on the vascularization of the biomaterial and its biodegradation within a time period of 6 months. Already at day 10 after implantation, histomorphometrical analysis showed that the vascularization of the implantation bed reached its peak value compared to all other time points. Both vessel density and vascularization significantly decreased until day 90 after implantation. In this time period, the bone substitute underwent a significant degradation initiated by TRAP-positive and TRAP-negative multinucleated giant cells together with macrophages and lymphocytes. Although no specific tissue reaction could be related to the described silica degradation, the biomaterial was close to being fully degraded without a severe inflammatory response. These characteristics are advantageous for bone regeneration and remodeling processes.

Antioxidant and signal modulation properties of plant polyphenols in controlling vascular inflammation.

PubMed

Kostyuk, Vladimir A; Potapovich, Alla I; Suhan, Tatyana O; de Luca, Chiara; Korkina, Liudmila G

2011-05-11

Oxidized low-density lipoproteins (oxLDL) play a critical role in the initiation of atherosclerosis through activation of inflammatory signaling. In the present work we investigated the role of antioxidant and signal modulation properties of plant polyphenols in controlling vascular inflammation. Significant decrease in intracellular NO level and superoxide overproduction was found in human umbilical vein endothelial cells (HUVEC) treated with oxLDL, but not with LDL. The redox imbalance was prevented by the addition of quercetin or resveratrol. Expression analysis of 14 genes associated with oxidative stress and inflammation revealed oxLDL-mediated up-regulation of genes specifically involved in leukocyte recruitment and adhesion. This up-regulation could be partially avoided by the addition of verbascoside or resveratrol, while treatment with quercetin resulted in a further increase in the expression of these genes. Lipopolysaccharide (LPS)-treated HUVEC were also used for the evaluation of anti-inflammatory potency of plant polyphenols. Significant differences between HUVEC treaded with oxLDL and LPS were found in both the expression pattern of inflammation-related genes and the effects of plant polyphenols on cellular responses. The present data indicate that plant polyphenols may affect vascular inflammation not only as antioxidants but also as modulators of inflammatory redox signaling pathways. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

Triactome: Neuro–Immune–Adipose Interactions. Implication in Vascular Biology

PubMed Central

Chaldakov, George Nikov; Fiore, Marco; Ghenev, Peter I.; Beltowski, Jerzy; Ranćić, Gorana; Tunçel, Neşe; Aloe, Luigi

2014-01-01

Understanding how the precise interactions of nerves, immune cells, and adipose tissue account for cardiovascular and metabolic biology is a central aim of biomedical research at present. A long standing paradigm holds that the vascular wall is composed of three concentric tissue coats (tunicae): intima, media, and adventitia. However, large- and medium-sized arteries, where usually atherosclerotic lesions develop, are consistently surrounded by periadventitial adipose tissue (PAAT), we recently designated tunica adiposa (in brief, adiposa like intima, media, and adventitia). Today, atherosclerosis is considered an immune-mediated inflammatory disease featured by endothelial dysfunction/intimal thickening, medial atrophy, and adventitial lesions associated with adipose dysfunction, whereas hypertension is characterized by hyperinnervation-associated medial thickening due to smooth muscle cell hypertrophy/hyperplasia. PAAT expansion is associated with increased infiltration of immune cells, both adipocytes and immunocytes secreting pro-inflammatory and anti-inflammatory (metabotrophic) signaling proteins collectively dubbed adipokines. However, the role of vascular nerves and their interactions with immune cells and paracrine adipose tissue is not yet evaluated in such an integrated way. The present review attempts to briefly highlight the findings in basic and translational sciences in this area focusing on neuro–immune–adipose interactions, herein referred to as triactome. Triactome-targeted pharmacology may provide a novel therapeutic approach in cardiovascular disease. PMID:24782857

Triactome: neuro-immune-adipose interactions. Implication in vascular biology.

PubMed

Chaldakov, George Nikov; Fiore, Marco; Ghenev, Peter I; Beltowski, Jerzy; Ranćić, Gorana; Tunçel, Neşe; Aloe, Luigi

2014-01-01

Understanding how the precise interactions of nerves, immune cells, and adipose tissue account for cardiovascular and metabolic biology is a central aim of biomedical research at present. A long standing paradigm holds that the vascular wall is composed of three concentric tissue coats (tunicae): intima, media, and adventitia. However, large- and medium-sized arteries, where usually atherosclerotic lesions develop, are consistently surrounded by periadventitial adipose tissue (PAAT), we recently designated tunica adiposa (in brief, adiposa like intima, media, and adventitia). Today, atherosclerosis is considered an immune-mediated inflammatory disease featured by endothelial dysfunction/intimal thickening, medial atrophy, and adventitial lesions associated with adipose dysfunction, whereas hypertension is characterized by hyperinnervation-associated medial thickening due to smooth muscle cell hypertrophy/hyperplasia. PAAT expansion is associated with increased infiltration of immune cells, both adipocytes and immunocytes secreting pro-inflammatory and anti-inflammatory (metabotrophic) signaling proteins collectively dubbed adipokines. However, the role of vascular nerves and their interactions with immune cells and paracrine adipose tissue is not yet evaluated in such an integrated way. The present review attempts to briefly highlight the findings in basic and translational sciences in this area focusing on neuro-immune-adipose interactions, herein referred to as triactome. Triactome-targeted pharmacology may provide a novel therapeutic approach in cardiovascular disease.

Psoriasis and Cardiovascular Comorbidities: Focusing on Severe Vascular Events, Cardiovascular Risk Factors and Implications for Treatment

PubMed Central

Hu, Stephen Chu-Sung; Lan, Cheng-Che E.

2017-01-01

Psoriasis is a common and chronic inflammatory disease of the skin. It may impair the physical and psychosocial function of patients and lead to decreased quality of life. Traditionally, psoriasis has been regarded as a disease affecting only the skin and joints. More recently, studies have shown that psoriasis is a systemic inflammatory disorder which can be associated with various comorbidities. In particular, psoriasis is associated with an increased risk of developing severe vascular events such as myocardial infarction and stroke. In addition, the prevalence rates of cardiovascular risk factors are increased, including hypertension, diabetes mellitus, dyslipidemia, obesity, and metabolic syndrome. Consequently, mortality rates have been found to be increased and life expectancy decreased in patients with psoriasis, as compared to the general population. Various studies have also shown that systemic treatments for psoriasis, including methotrexate and tumor necrosis factor-α inhibitors, may significantly decrease cardiovascular risk. Mechanistically, the presence of common inflammatory pathways, secretion of adipokines, insulin resistance, angiogenesis, oxidative stress, microparticles, and hypercoagulability may explain the association between psoriasis and cardiometabolic disorders. In this article, we review the evidence regarding the association between psoriasis and cardiovascular comorbidities, focusing on severe vascular events, cardiovascular risk factors and implications for treatment. PMID:29065479

Endothelial MMP-9 drives the inflammatory response in abdominal aortic aneurysm (AAA).

PubMed

Ramella, Martina; Boccafoschi, Francesca; Bellofatto, Kevin; Md, Antonia Follenzi; Fusaro, Luca; Boldorini, Renzo; Casella, Francesco; Porta, Carla; Settembrini, Piergiorgio; Cannas, Mario

2017-01-01

Progression of abdominal aortic aneurysm (AAA) is typified by chronic inflammation and extracellular matrix (ECM) degradation of the aortic wall. Vascular inflammation involves complex interactions among inflammatory cells, endothelial cells (ECs), vascular smooth muscle cells (vSMCs), and ECM. Although vascular endothelium and medial neoangiogenesis play a key role in AAA, the molecular mechanisms underlying their involvement are only partially understood. In AAA biopsies, we found increased MMP-9, IL-6, and monocyte chemoattractant protein-1 (MCP-1), which correlated with massive medial neo-angiogenesis (C4d positive staining). In this study, we developed an in vitro model in order to characterize the role of endothelial matrix metalloproteinase-9 (e-MMP-9) as a potential trigger of medial disruption and in the inflammatory response bridging between ECs and vSMC. Lentiviral-mediated silencing of e-MMP-9 through RNA interference inhibited TNF-alpha-mediated activation of NF-κB in EA.hy926 human endothelial cells. In addition, EA.hy926 cells void of MMP-9 failed to migrate in a 3D matrix. Moreover, silenced EA.hy926 affected vSMC behavior in terms of matrix remodeling. In fact, also MMP-9 in vSMC resulted inhibited when endothelial MMP-9 was suppressed.

Mice with targeted inactivation of ppap2b in endothelial and hematopoietic cells display enhanced vascular inflammation and permeability.

PubMed

Panchatcharam, Manikandan; Salous, Abdel K; Brandon, Jason; Miriyala, Sumitra; Wheeler, Jessica; Patil, Pooja; Sunkara, Manjula; Morris, Andrew J; Escalante-Alcalde, Diana; Smyth, Susan S

2014-04-01

Lipid phosphate phosphatase 3 (LPP3), encoded by the PPAP2B gene, is an integral membrane enzyme that dephosphorylates, and thereby terminates, the G-protein-coupled receptor-mediated signaling actions of lysophosphatidic acid (LPA) and sphingosine-1-phosphate. LPP3 is essential for normal vascular development in mice, and a common PPAP2B polymorphism is associated with increased risk of coronary artery disease in humans. Herein, we investigate the function of endothelial LPP3 to understand its role in the development and human disease. We developed mouse models with selective LPP3 deficiency in endothelial and hematopoietic cells. Tyrosine kinase Tek promoter-mediated inactivation of Ppap2b resulted in embryonic lethality because of vascular defects. LPP3 deficiency in adult mice, achieved using a tamoxifen-inducible Cre transgene under the control of the Tyrosine kinase Tek promoter, enhanced local and systemic inflammatory responses. Endothelial, but not hematopoietic, cell LPP3 deficiency led to significant increases in vascular permeability at baseline and enhanced sensitivity to inflammation-induced vascular leak. Endothelial barrier function was restored by pharmacological or genetic inhibition of either LPA production by the circulating lysophospholipase D autotaxin or of G-protein-coupled receptor-dependent LPA signaling. Our results identify a role for the autotaxin/LPA-signaling nexus as a mediator of endothelial permeability in inflammation and demonstrate that LPP3 limits these effects. These findings have implications for therapeutic targets to maintain vascular barrier function in inflammatory states.

Arctium lappa ameliorates endothelial dysfunction in rats fed with high fat/cholesterol diets

PubMed Central

2012-01-01

Background Arctium lappa L. (Asteraceae), burdock, is a medicinal plant that is popularly used for treating hypertension, gout, hepatitis, and other inflammatory disorders. This study was performed to test the effect of ethanol extract of Arctium lappa L. (EAL) seeds on vascular reactivity and inflammatory factors in rats fed a high fat/cholesterol diet (HFCD). Method EAL-I (100 mg·kg−1/day), EAL-II (200 mg·kg−1/day), and fluvastatin (3 mg·kg−1/day) groups initially received HFCD alone for 8 weeks, with EAL supplementation provided during the final 6 weeks. Results Treatment with low or high doses of EAL markedly attenuated plasma levels of triglycerides and augmented plasma levels of high-density lipoprotein (HDL) in HFCD-fed rats. Chronic treatment with EAL markedly reduced impairments of acetylcholine (ACh)-induced relaxation of aortic rings. Furthermore, chronic treatment with EAL significantly lowered systolic blood pressure (SBP) and maintained smooth and flexible intimal endothelial layers in HFCD-fed rats. Chronic treatment with EAL suppressed upregulation of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin in the aorta. Chronic treatment with EAL also suppressed increases in matrix metalloproteinase (MMP)-2 expression. These results suggested that EAL can inhibit HFCD-induced vascular inflammation in the rat model. Conclusion The present study provides evidence that EAL ameliorates HFCD-induced vascular dysfunction through protection of vascular relaxation and suppression of vascular inflammation. PMID:22866890

Plant-derived mPGES-1 inhibitors or suppressors: A new emerging trend in the search for small molecules to combat inflammation.

PubMed

Khan, Haroon; Rengasamy, Kannan R R; Pervaiz, Aini; Nabavi, Seyed Mohammad; Atanasov, Atanas G; Kamal, Mohammad A

2018-06-10

Inflammation comprises the reaction of the body to injury, in which a series of changes of the terminal vascular bed, blood, and connective tissue tends to eliminate the injurious agent and to repair the damaged tissue. It is a complex process, which involves the release of diverse regulatory mediators. The current anti-inflammatory agents are challenged by multiple side effects and thus, new effective therapies are highly needed. The aim of this review is to summarize the described microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors or transcriptional suppressors from medicinal plants, which could be an ideal approach in the management of inflammatory disorders, but need further clinical trials in order to be ultimately validated. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Immunopathologic effects of scorpion venom on hepato-renal tissues: Involvement of lipid derived inflammatory mediators.

PubMed

Lamraoui, Amal; Adi-Bessalem, Sonia; Laraba-Djebari, Fatima

2015-10-01

Scorpion venoms are known to cause different inflammatory disorders through complex mechanisms in various tissues. In the study here, the involvement of phospholipase A2 (PLA2) and cyclo-oxygenase (COX)-derived metabolites in hepatic and renal inflammation responses were examined. Mice were envenomed with Androctonus australis hector scorpion venom in the absence or presence of inhibitors that can interfere with lipid inflammatory mediator synthesis, i.e., dexamethasone (PLA2 inhibitor), indomethacin (non-selective COX-1/COX-2 inhibitor), or celecoxib (selective COX-2 inhibitor). The inflammatory response was assessed by evaluating vascular permeability changes, inflammatory cell infiltration, oxidative/nitrosative stress marker levels, and by histologic and functional analyses of the liver and kidney. Results revealed that the venom alone induced an inflammatory response in this tissues marked by increased microvascular permeability and inflammatory cell infiltration, increases in levels of nitric oxide and lipid peroxidation, and decreases in antioxidant defense. Moreover, significant alterations in the histological architecture of these organs were associated with increased serum levels of some metabolic enzymes, as well as urea and uric acid. Pre-treatment of mice with dexamethasone led to significant decreases of the inflammatory disorders in the hepatic parenchyma; celecoxib pre-treatment seemed to be more effective against renal inflammation. Indomethacin pre-treatment only slightly reduced the inflammatory disorders in the tissues. These results suggest that the induced inflammation response in liver was mediated mainly by PLA2 activation, while the renal inflammatory process was mediated by prostaglandin formation by COX-2. These findings provide additional insight toward the understanding of activated pathways and related mechanisms involved in scorpion envenoming syndrome.

Pro-inflammatory effects of interleukin-17A on vascular smooth muscle cells involve NAD(P)H- oxidase derived reactive oxygen species.

PubMed

Pietrowski, Eweline; Bender, Bianca; Huppert, Jula; White, Robin; Luhmann, Heiko J; Kuhlmann, Christoph R W

2011-01-01

T cells are known for their contribution to the inflammatory element of atherosclerosis. Recently, it has been demonstrated that the Th17 derived cytokine IL-17 is involved in the pro-inflammatory response of vascular smooth muscle cells (VSMC). The aim of the present study was to examine whether reactive oxygen species (ROS) might be involved in this context. The effect of IL-17A on ROS generation was examined using the fluorescent dye 2'7'-dichlorodihydrofluorescein (H(2)DCF) in primary murine VSMC. IL-17A induced an increase in H(2)DCF fluorescence in VSMC, and this effect was blocked by the NAD(P)H-oxidase inhibitor apocynin and siRNA targeting Nox2. The p38-MAPK inhibitors SB203580 and SB202190 dose-dependently reduced the IL-17A induced ROS production. The IL-17A induced release of the pro-inflammatory cytokines IL-6, G-CSF, GM-CSF and MCP-1 from VSMC, as detected by the Luminex technology, was completely abolished by NAD(P)H-oxidase inhibition. Taken together, our data indicate that IL-17A causes the NAD(P)H-oxidase dependent generation of ROS leading to a pro-inflammatory activation of VSMC. Copyright © 2010 S. Karger AG, Basel.

Polymyalgia rheumatica and giant cell arteritis—three challenges—consequences of the vasculitis process, osteoporosis, and malignancy

PubMed Central

Emamifar, Amir; Hess, Søren; Gerke, Oke; Hermann, Anne Pernille; Laustrup, Helle; Hansen, Per Syrak; Thye-Rønn, Peter; Marcussen, Niels; Svendstrup, Frank; Gildberg-Mortensen, Rannveig; Bang, Jacob Christian; Farahani, Ziba Ahangarani; Chrysidis, Stavros; Toftegaard, Pia; Andreasen, Rikke Asmussen; le Greves, Sebastian; Andersen, Hanne Randi; Olsen, Rudolf Nezlo; Hansen, Inger Marie Jensen

2017-01-01

Abstract Introduction: Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are common inflammatory conditions. The diagnosis of PMR/GCA poses many challenges since there are no specific diagnostic tests. Recent literature emphasizes the ability of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to assess global disease activity in inflammatory diseases. 18F-FDG PET/CT may lead to the diagnosis at an earlier stage than conventional imaging and may also assess response to therapy. With respect to the management of PMR/GCA, there are 3 significant areas of concern as follows: vasculitis process/vascular stiffness, malignancy, and osteoporosis. Methods and analysis: All patients with suspected PMR/GCR referred to the Rheumatology section of Medicine Department at Svendborg Hospital, Denmark. The 4 separate studies in the current protocol focus on: the association of clinical picture of PMR/GCA with PET findings; the validity of 18F-FDG PET/CT scan for diagnosis of PMR/GCA compared with temporal artery biopsy; the prevalence of newly diagnosed malignancies in patients with PMR/GCA, or PMR-like syndrome, with the focus on diagnostic accuracy of 18F-FDG PET/CT scan compared with conventional workup (ie, chest X-ray/abdominal ultrasound); and the impact of disease process, and also steroid treatment on bone mineral density, body composition, and vasculitis/vascular stiffness in PMR/GCA patients. Ethics and dissemination: The study has been approved by the Regional Ethics Committee of the Region of Southern Denmark (identification number: S-20160098) and Danish Data Protection Agency (J.nr 16/40522). Results of the study will be disseminated via publications in peer-reviewed journals, and presentation at national and international conferences. PMID:28658131

Frontiers in Drug Research and Development for Inflammatory Bowel Disease

PubMed Central

Currò, Diego; Pugliese, Daniela; Armuzzi, Alessandro

2017-01-01

Inflammatory bowel disease (IBD) is idiopathic, lifelong, immune-mediated diseases, for which curative therapies are not yet available. In the last 15 years, the introduction of monoclonal antibodies targeting tumor necrosis factor-α, a cytokine playing a key role in bowel inflammation, has revolutionized treatment paradigms for IBD. Despite their proven long-term efficacy, however, many patients do not respond or progressively lose response to these drugs. Major advances of knowledge in immunology and pathophysiology of intestinal inflammatory processes have made possible the identification of new molecular targets for drugs, thus opening several new potential therapeutic opportunities for IBD. The abnormal response of intestinal immunity to unknown antigens leads to the activation of T helper lymphocytes and triggers the inflammatory cascade. Sphingosine 1-phosphate receptor agonists negatively modulate the egress of lymphocytes, inducted by antigen-presenting cells, from secondary lymphoid tissues to intestinal wall. Leukocyte adhesion inhibitors (both anti-integrin and anti-Mucosal Vascular Addressin Cell Adhesion Molecule 1) interfere with the tissue homing processes. Activated T helper lymphocytes increase the levels of pro-inflammatory cytokines, such as interleukin 12, 23, and 6, offering several potential pharmacological interventions. The Janus kinases, intracellular enzymes mediating the transduction of several cytokine signals, are other explored targets for treating immune-mediated diseases. Finally, the impact of modulating Smad7 pathway, which is responsible for the down-regulation of the immunosuppressive cytokine transforming growth factor-β signaling, is currently under investigation. The purpose of this review is to discuss the most promising molecules in late-stage clinical development, with a special emphasis on pharmacological properties. PMID:28690543

Protecting against vascular disease in brain

PubMed Central

2011-01-01

Endothelial cells exert an enormous influence on blood vessels throughout the circulation, but their impact is particularly pronounced in the brain. New concepts have emerged recently regarding the role of this cell type and mechanisms that contribute to endothelial dysfunction and vascular disease. Activation of the renin-angiotensin system plays a prominent role in producing these abnormalities. Both oxidative stress and local inflammation are key mechanisms that underlie vascular disease of diverse etiology. Endogenous mechanisms of vascular protection are also present, including antioxidants, anti-inflammatory molecules, and peroxisome proliferator-activated receptor-γ. Despite their clear importance, studies of mechanisms that underlie cerebrovascular disease continue to lag behind studies of vascular biology in general. Identification of endogenous molecules and pathways that protect the vasculature may result in targeted approaches to prevent or slow the progression of vascular disease that causes stroke and contributes to the vascular component of dementia and Alzheimer's disease. PMID:21335467

Pharmacology of Ischemia-Reperfusion. Translational Research Considerations.

PubMed

Prieto-Moure, Beatriz; Lloris-Carsí, José M; Barrios-Pitarque, Carlos; Toledo-Pereyra, Luis-H; Lajara-Romance, José María; Berda-Antolí, M; Lloris-Cejalvo, J M; Cejalvo-Lapeña, Dolores

2016-08-01

Ischemia-reperfusion (IRI) is a complex physiopathological mechanism involving a large number of metabolic processes that can eventually lead to cell apoptosis and ultimately tissue necrosis. Treatment approaches intended to reduce or palliate the effects of IRI are varied, and are aimed basically at: inhibiting cell apoptosis and the complement system in the inflammatory process deriving from IRI, modulating calcium levels, maintaining mitochondrial membrane integrity, reducing the oxidative effects of IRI and levels of inflammatory cytokines, or minimizing the action of macrophages, neutrophils, and other cell types. This study involved an extensive, up-to-date review of the bibliography on the currently most widely used active products in the treatment and prevention of IRI, and their mechanisms of action, in an aim to obtain an overview of current and potential future treatments for this pathological process. The importance of IRI is clearly reflected by the large number of studies published year after year, and by the variety of pathophysiological processes involved in this major vascular problem. A quick study of the evolution of IRI-related publications in PubMed shows that in a single month in 2014, 263 articles were published, compared to 806 articles in the entire 1990.

Endothelial FoxM1 Mediates Bone Marrow Progenitor Cell-Induced Vascular Repair and Resolution of Inflammation following Inflammatory Lung Injury

PubMed Central

Zhao, Yidan D.; Huang, Xiaojia; Yi, Fan; Dai, Zhiyu; Qian, Zhijian; Tiruppathi, Chinnaswamy; Tran, Khiem; Zhao, You-Yang

2015-01-01

Adult stem cell treatment is a potential novel therapeutic approach for acute respiratory distress syndrome. Given the extremely low rate of cell engraftment, it is believed that these cells exert their beneficial effects via paracrine mechanisms. However, the endogenous mediator(s) in the pulmonary vasculature remains unclear. Employing the mouse model with endothelial cell (EC)-restricted disruption of FoxM1 (FoxM1 CKO), here we show that endothelial expression of the reparative transcriptional factor FoxM1 is required for the protective effects of bone marrow progenitor cells (BMPC) against LPS-induced inflammatory lung injury and mortality. BMPC treatment resulted in rapid induction of FoxM1 expression in WT but not FoxM1 CKO lungs. BMPC-induced inhibition of lung vascular injury, resolution of lung inflammation, and survival, as seen in WT mice, were abrogated in FoxM1 CKO mice following LPS challenge. Mechanistically, BMPC treatment failed to induce lung EC proliferation in FoxM1 CKO mice, which was associated with impaired expression of FoxM1 target genes essential for cell cycle progression. We also observed that BMPC treatment enhanced endothelial barrier function in WT, but not in FoxM1-deficient EC monolayers. Restoration of β-catenin expression in FoxM1-deficient ECs normalized endothelial barrier enhancement in response to BMPC treatment. These data demonstrate the requisite role of endothelial FoxM1 in the mechanism of BMPC-induced vascular repair to restore vascular integrity and accelerate resolution of inflammation, thereby promoting survival following inflammatory lung injury. PMID:24578354

Tonic regulation of vascular permeability

PubMed Central

Curry, Fitz-Roy E.; Adamson, Roger H.

2014-01-01

Our major theme is that the layered structure of the endothelial barrier requires continuous activation of signaling pathways regulated by S1P and intracellular cAMP. These pathways modulate the adherens junction, continuity of tight junction strands, and the balance of synthesis and degradation of glycocalyx components. We evaluate recent evidence that baseline permeability is maintained by constant activity of mechanisms involving the small GTPases Rap1 and Rac1. In the basal state, the barrier is compromised when activities of the small GTPases are reduced by low S1P supply or delivery. With inflammatory stimulus, increased permeability can be understood in part as the action of signaling to reduce Rap1 and Rac1 activation. With the hypothesis that microvessel permeability and selectivity under both normal and inflammatory conditions are regulated by mechanisms that are continuously active it follows that when S1P or intracellular cAMP are elevated at the time of inflammatory stimulus, they can buffer changes induced by inflammatory agents and maintain normal barrier stability. When endothelium is exposed to inflammatory conditions and subsequently exposed to elevated S1P or intracellular cAMP, the same processes restore the functional barrier by first reestablishing the adherens junction, then modulating tight junctions and glycocalyx. In more extreme inflammatory conditions, loss of the inhibitory actions of Rac1 dependent mechanisms may promote expression of more inflammatory endothelial phenotypes by contributing to the up-regulation of RhoA dependent contractile mechanisms and the sustained loss of surface glycocalyx allowing access of inflammatory cells to the endothelium. PMID:23374222

Molecular intravascular imaging approaches for atherosclerosis.

PubMed

Press, Marcella Calfon; Jaffer, Farouc A

2014-10-01

Coronary artery disease (CAD) is an inflammatory process that results in buildup of atherosclerosis, typically lipid-rich plaque in the arterial wall. Progressive narrowing of the vessel wall and subsequent plaque rupture can lead to myocardial infarction and death. Recent advances in intravascular fluorescence imaging techniques have provided exciting coronary artery-targeted platforms to further characterize the molecular changes that occur within the vascular wall as a result of atherosclerosis and following coronary stent-induced vascular injury. This review will summarize exciting recent developments in catheter-based imaging of coronary arterial-sized vessels; focusing on two-dimensional near-infrared fluorescence imaging (NIRF) molecular imaging technology as an approach to specifically identify inflammation and fibrin directly within coronary artery-sized vessels. Intravascular NIRF is anticipated to provide new insights into the in vivo biology underlying high-risk plaques, as well as high-risks stents prone to stent restenosis or stent thrombosis.

[Pathophysiology of sickle cell disease].

PubMed

Elion, J; Laurance, S; Lapouméroulie, C

2010-12-01

It has been 100 years since Herrick published the first medical case report of sickle cell disease. In 1949, Pauling discovered hemoglobin S (HbS). As early as the 1960-70s, emerged a coherent detailed molecular-level description of pathophysiology of sickle disease. It involved polymerization of deoxyhemoglobin S with formation of long fibers inside red blood cells (RBC) causing a distorted sickle shape and shortened lifespan. These changes constitute the basic disease process and account for hemolytic anemia and for obstructive events underlying vasoocclusive crises (VOC). However, they do not explain the mechanisms that trigger VOC. The purpose of this review is to present recent data on dehydration of sickle cell RBC, abnormalities in RBC adhesion to the vascular endothelium, the role of inflammatory events and of activation of all cells in the vessel, and abnormalities of vascular tone and carbon monoxide metabolism. These data provide new insight into the pathophysiology of the first molecular disease.

Mast Cells: Pivotal Players in Cardiovascular Diseases

PubMed Central

Bot, Ilze; van Berkel, Theo J.C; Biessen, Erik A.L

2008-01-01

The clinical outcome of cardiovascular diseases as myocardial infarction and stroke are generally caused by rupture of an atherosclerotic plaque. However, the actual cause of a plaque to rupture is not yet established. Interestingly, pathology studies have shown an increased presence of the mast cell, an important inflammatory effector cell in allergy and host defense, in (peri)vascular tissue during plaque progression, which may point towards a causal role for mast cells. Very recent data in mouse models show that mast cells and derived mediators indeed can profoundly impact plaque progression, plaque stability and acute cardiovascular syndromes such as vascular aneurysm or myocardial infarction. In this review, we discuss recent evidence on the role of mast cells in the progression of cardiovascular disorders and give insight in the therapeutic potential of modulation of mast cell function in these processes to improve the resilience of a plaque to rupture. PMID:19936193

Role of Lipid Peroxidation-Derived α, β-Unsaturated Aldehydes in Vascular Dysfunction

PubMed Central

Lee, Seung Eun; Park, Yong Seek

2013-01-01

Vascular diseases are the most prominent cause of death, and inflammation and vascular dysfunction are key initiators of the pathophysiology of vascular disease. Lipid peroxidation products, such as acrolein and other α, β-unsaturated aldehydes, have been implicated as mediators of inflammation and vascular dysfunction. α, β-Unsaturated aldehydes are toxic because of their high reactivity with nucleophiles and their ability to form protein and DNA adducts without prior metabolic activation. This strong reactivity leads to electrophilic stress that disrupts normal cellular function. Furthermore, α, β-unsaturated aldehydes are reported to cause endothelial dysfunction by induction of oxidative stress, redox-sensitive mechanisms, and inflammatory changes such as induction of cyclooxygenase-2 and cytokines. This review provides an overview of the effects of lipid peroxidation products, α, β-unsaturated aldehydes, on inflammation and vascular dysfunction. PMID:23819013

Anti-inflammatory cytokine interleukin-19 inhibits smooth muscle cell migration and activation of cytoskeletal regulators of VSMC motility

PubMed Central

Gabunia, Khatuna; Jain, Surbhi; England, Ross N.

2011-01-01

Vascular smooth muscle cell (VSMC) migration is an important cellular event in multiple vascular diseases, including atherosclerosis, restenosis, and transplant vasculopathy. Little is known regarding the effects of anti-inflammatory interleukins on VSMC migration. This study tested the hypothesis that an anti-inflammatory Th2 interleukin, interleukin-19 (IL-19), could decrease VSMC motility. IL-19 significantly decreased platelet-derived growth factor (PDGF)-stimulated VSMC chemotaxis in Boyden chambers and migration in scratch wound assays. IL-19 significantly decreased VSMC spreading in response to PDGF. To determine the molecular mechanism(s) for these cellular effects, we examined the effect of IL-19 on activation of proteins that regulate VSMC cytoskeletal dynamics and locomotion. IL-19 decreased PDGF-driven activation of several cytoskeletal regulatory proteins that play an important role in smooth muscle cell motility, including heat shock protein-27 (HSP27), myosin light chain (MLC), and cofilin. IL-19 decreased PDGF activation of the Rac1 and RhoA GTPases, important integrators of migratory signals. IL-19 was unable to inhibit VSMC migration nor was able to inhibit activation of cytoskeletal regulatory proteins in VSMC transduced with a constitutively active Rac1 mutant (RacV14), suggesting that IL-19 inhibits events proximal to Rac1 activation. Together, these data are the first to indicate that IL-19 can have important inhibitory effects on VSMC motility and activation of cytoskeletal regulatory proteins. This has important implications for the use of anti-inflammatory cytokines in the treatment of vascular occlusive disease. PMID:21209363

Chemical allergens stimulate human epidermal keratinocytes to produce lymphangiogenic vascular endothelial growth factor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bae, Ok-Nam; Ahn, Seyeon; Jin, Sun Hee

2015-03-01

Allergic contact dermatitis (ACD) is a cell-mediated immune response that involves skin sensitization in response to contact with various allergens. Angiogenesis and lymphangiogenesis both play roles in the allergic sensitization process. Epidermal keratinocytes can produce vascular endothelial growth factor (VEGF) in response to UV irradiation and during wound healing. However, the effect of haptenic chemical allergens on the VEGF production of human keratinocytes, which is the primary contact site of toxic allergens, has not been thoroughly researched. We systematically investigated whether immune-regulatory cytokines and chemical allergens would lead to the production of VEGF in normal human keratinocytes (NHKs) in culture.more » VEGF production significantly increased when NHKs were treated with IFNγ, IL-1α, IL-4, IL-6, IL-17A, IL-22 or TNFα. Among the human sensitizers listed in the OECD Test Guideline (TG) 429, we found that CMI/MI, DNCB, 4-phenylenediamine, cobalt chloride, 2-mercaptobenzothiazole, citral, HCA, cinnamic alcohol, imidazolidinyl urea and nickel chloride all significantly upregulated VEGF production in NHKs. In addition, common human haptenic allergens such as avobenzone, formaldehyde and urushiol, also induced the keratinocyte-derived VEGF production. VEGF upregulation by pro-inflammatory stimuli, IFNγ, DNCB or formaldehyde is preceded by the production of IL-8, an acute inflammatory phase cytokine. Lymphangiogenic VEGF-C gene transcription was significantly increased when NHKs were treated with formaldehyde, DNCB or urushiol, while transcription of VEGF-A and VEGF-B did not change. Therefore, the chemical allergen-induced VEGF upregulation is mainly due to the increase in lymphangiogenic VEGF-C transcription in NHKs. These results suggest that keratinocyte-derived VEGF may regulate the lymphangiogenic process during the skin sensitization process of ACD. - Highlights: • Pro-inflammatory cytokines induced VEGF production in normal human keratinocytes (NHKs). • Chemical allergens stimulate NHKs to produce VEGF. • VEGF production is preceded by IL-8 production in NHKs. • IFNγ, DNCB and formaldehyde increase lymphangiogenic VEGF-C gene transcription. • VEGF production in NHKs may be a biomarker for the prediction of potential contact allergens.« less

IGF-1, oxidative stress and atheroprotection.

PubMed

Higashi, Yusuke; Sukhanov, Sergiy; Anwar, Asif; Shai, Shaw-Yung; Delafontaine, Patrice

2010-04-01

Atherosclerosis is a chronic inflammatory disease in which early endothelial dysfunction and subintimal modified lipoprotein deposition progress to complex, advanced lesions that are predisposed to erosion, rupture and thrombosis. Oxidative stress plays a crucial role not only in initial lesion formation but also in lesion progression and destabilization. Although most growth factors are thought to promote vascular smooth muscle cell proliferation and migration, thereby increasing neointima, recent animal studies indicate that insulin-like growth factor (IGF)-1 exerts both pleiotropic anti-oxidant effects and anti-inflammatory effects, which together reduce atherosclerotic burden. This review discusses the effects of IGF-1 in models of vascular injury and atherosclerosis, emphasizing the relationship between oxidative stress and potential atheroprotective actions of IGF-1. Copyright 2009 Elsevier Ltd. All rights reserved.

Human haemodynamic frequency harmonics regulate the inflammatory phenotype of vascular endothelial cells.

PubMed

Feaver, Ryan E; Gelfand, Bradley D; Blackman, Brett R

2013-01-01

Haemodynamic variations are inherent to blood vessel geometries (such as bifurcations) and correlate with regional development of inflammation and atherosclerosis. However, the complex frequency spectrum characteristics from these haemodynamics have never been exploited to test whether frequency variations are critical determinants of endothelial inflammatory phenotype. Here we utilize an experimental Fourier transform analysis to systematically manipulate individual frequency harmonics from human carotid shear stress waveforms applied in vitro to human endothelial cells. The frequency spectrum, specifically the 0 th and 1st harmonics, is a significant regulator of inflammation, including NF-κB activity and downstream inflammatory phenotype. Further, a harmonic-based regression-model predicts eccentric NF-κB activity observed in the human internal carotid artery. Finally, short interfering RNA-knockdown of the mechanosensor PECAM-1 reverses frequency-dependent regulation of NF-κB activity. Thus, PECAM-1 may have a critical role in the endothelium's exquisite sensitivity to complex shear stress frequency harmonics and provide a mechanism for the focal development of vascular inflammation.

Function-blocking antibodies to human vascular adhesion protein-1: a potential anti-inflammatory therapy.

PubMed

Kirton, Christopher M; Laukkanen, Marja-Leena; Nieminen, Antti; Merinen, Marika; Stolen, Craig M; Armour, Kathryn; Smith, David J; Salmi, Marko; Jalkanen, Sirpa; Clark, Michael R

2005-11-01

Human vascular adhesion protein-1 (VAP-1) is a homodimeric 170-kDa sialoglycoprotein that is expressed on the surface of endothelial cells and functions as a semicarbazide-sensitive amine oxidase and as an adhesion molecule. Blockade of VAP-1 has been shown to reduce leukocyte adhesion and transmigration in in vivo and in vitro models, suggesting that VAP-1 is a potential target for anti-inflammatory therapy. In this study we have constructed mouse-human chimeric antibodies by genetic engineering in order to circumvent the potential problems involved in using murine antibodies in man. Our chimeric anti-VAP-1 antibodies, which were designed to lack Fc-dependent effector functions, bound specifically to cell surface-expressed recombinant human VAP-1 and recognized VAP-1 in different cell types in tonsil. Furthermore, the chimeric antibodies prevented leukocyte adhesion and transmigration in vitro and in vivo. Hence, these chimeric antibodies have the potential to be used as a new anti-inflammatory therapy.

Clindamycin phosphate 1.2% and tretinoin 0.025% gel for rosacea: summary of a placebo-controlled, double-blind trial.

PubMed

Freeman, Scott A; Moon, Summer D; Spencer, James M

2012-12-01

Rosacea is a common, chronic, and poorly understood dermatological condition characterized by an inflammatory component composed of papules and pustules and a vascular component composed of flushing and erythema. Current treatment options include topical, systemic, and light-based methods, each of which focuses on either the inflammatory or the vascular component. Retinoids are not routinely indicated as treatment because of the common conception that they would be too inflammatory for the sensitive rosacea patient. However, photodamage may play a role in rosacea and tretinoin is well-known to repair photodamage. Thirty rosacea subjects were enrolled to assess their response to the use of clindamycin phosphate 1.2% and tretinoin 0.025% gel (ZIANA; Medicis Pharmaceutical Corporation, Scottsdale, AZ) for a period of 12 weeks. The results showed a dramatic decrease in pustules and papules without any significant inflammation or overall intolerance. No improvement in facial redness was achieved. Based on our results, more investigation of topical retinoids for rosacea treatment is prudent.

HETEROTYPIC INTERACTIONS ENABLED BY POLARIZED NEUTROPHIL MICRODOMAINS MEDIATE THROMBO-INFLAMMATORY INJURY

PubMed Central

Hidalgo, Andrés; Chang, Jungshan; Jang, Jung-Eun; Peired, Anna J.; Chiang, Elaine Y.; Frenette, Paul S.

2009-01-01

Selectins and their ligands mediate leukocyte rolling allowing interactions with chemokines that lead to integrin activation and arrest. Here, we demonstrate that E-selectin is critical to induce a secondary wave of activating signals transduced specifically by E-selectin ligand-1, that induces polarized, activated αMβ2 integrin clusters at the leading edge of crawling neutrophils, allowing the capture of circulating erythrocytes or platelets. In a humanized model of sickle cell disease (SCD), the capture of erythrocytes by αMβ2 microdomains leads to acute lethal vascular occlusions. In a model of transfusion-related acute lung injury, polarized neutrophils capture circulating platelets, resulting in the generation of oxidative species that produces vascular damage and lung injury. Inactivation of E-selectin or αMβ2 prevented tissue injury in both inflammatory models, suggesting broad implications of this paradigm in thrombo-inflammatory diseases. These results indicate that endothelial selectins can influence neutrophil behavior beyond its canonical rolling step through delayed, organ-damaging, polarized activation. PMID:19305412

Caveolae: a regulatory platform for nutritional modulation of inflammatory diseases

PubMed Central

Layne, Joseph; Majkova, Zuzana; Smart, Eric J.; Toborek, Michal; Hennig, Bernhard

2010-01-01

Dietary intervention strategies have proven to be an effective means of decreasing several risk factors associated with the development of atherosclerosis. Endothelial cell dysfunction influences vascular inflammation and is involved in promoting the earliest stages of lesion formation. Caveolae are lipid raft microdomains abundant within the plasma membrane of endothelial cells and are responsible for mediating receptor-mediated signal transduction. Caveolae have been implicated in the regulation of enzymes associated with several key signaling pathways capable of determining intracellular redox status. Diet and plasma-derived nutrients may modulate an inflammatory outcome by interacting with and altering caveolae-associated cellular signaling. For example, omega-3 fatty acids and several polyphenolics have been shown to improve endothelial cell function by decreasing the formation of ROS and increasing NO bioavailability, events associated with altered caveolae composition. Thus, nutritional modulation of caveolae-mediated signaling events may provide an opportunity to ameliorate inflammatory signaling pathways capable of promoting the formation of vascular diseases, including atherosclerosis. PMID:21292468

Protective effects of friedelin isolated from Azima tetracantha Lam. against ethanol-induced gastric ulcer in rats and possible underlying mechanisms.

PubMed

Antonisamy, Paulrayer; Duraipandiyan, Veeramuthu; Aravinthan, Adithan; Al-Dhabi, Naif Abdullah; Ignacimuthu, Savarimuthu; Choi, Ki Choon; Kim, Jong-Hoon

2015-03-05

The current study was aimed to investigate the gastroprotective effects of friedelin isolated from the hexane extract of leaves of Azima tetracantha. Ethanol-induced gastric ulcer model was used to investigate the gastroprotective effects of friedelin. Antioxidant enzymes, lipid peroxidation, nitric oxide, gastric vascular permeability, pro and anti-inflammatory cytokines and apoptosis level have been investigated. Ethanol caused severe gastric damage and friedelin pretreatment protected against its deleterious role. Antioxidant enzyme activities, anti-inflammatory cytokines, prostaglandin E2 (PGE2), constitutive nitric oxide synthase (cNOS) and mucus weight have been increased significantly. However, the vascular permeability, pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS), caspase-3 and apoptosis level have significantly been decreased after friedelin ingestion. The present study has clearly demonstrated the anti-ulcer potential of friedelin, these findings suggested that friedelin could be a new useful natural gastroprotective tool against gastric ulcer. Copyright © 2015 Elsevier B.V. All rights reserved.

Eicosapentaenoic Acid Versus Docosahexaenoic Acid as Options for Vascular Risk Prevention: A Fish Story.

PubMed

Singh, Sarabjeet; Arora, Rohit R; Singh, Mukesh; Khosla, Sandeep

2016-01-01

Vascular inflammation is a key component involved in the process of arthrosclerosis, which in turn increases the risk for cardiovascular injury. In the last 10 years, there have been many trials that looked at omega-3 fatty acids as a way to reduce cardiovascular risk. These trials observed the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the traditional lipid panel and found that both EPA and DHA reduce triglyceride (TG) level and increase high-density lipoprotein cholesterol (HDL-C) levels but also increase the low-density lipoprotein cholesterol (LDL-C) levels. In the 2 more recent trials, the MARINE and ANCHOR, EPA was given as an adjunct therapy to high-risk patients and not only was the traditional lipids measured but also examined the vascular inflammatory biomarkers. The results of these 2 trials not only showed reduction in cardiovascular risk because of reduction in vascular inflammation and reduction in the lipid panel but also showed that one of the MARINE-derived omega-3 fatty acid is superior to the other. Data search for omega-3 fatty acids and cardiovascular risk was performed, and articles were selected for review from 2006 to date. The research studies were all double-blind randomized trials except for one, which was a single-blind and focused on the effects of omega-3 fatty acids on the entire lipid panel. The participants received DHA/EPA and compared with a placebo group on the effect seen in the lipid panel. The first 7 studies looked at the effects of omega-3 fatty acids on TG, LDL-C, and HDL-C; of the 7, 1 directly compared DHA and EPA, 2 focused on EPA, and 4 were directed towards DHA alone. The MARINE and ANCHOR trials were more recent and also looked at the same parameter but also monitored vascular inflammatory biomarkers and how they were affected by omega-3 fatty acids. A second data search was performed for vascular biomarkers and cardiovascular risk, and articles that focused on high-sensitivity C-reactive protein and oxidized low-density lipoprotein were selected for review. Omega-3 fatty acids have shown to decrease TG level in multiple trials, but they have also shown to increase LDL and HDL levels, likely because omega-3 fatty acids promote TG conversion into HDL/LDL. The older data suggested that the benefits of omega-3 fatty acids are nullified by their effects on LDL levels. The data from the MARINE and ANCHOR trials have shown that EPA alone at 4 g per day has shown to decrease TG and total cholesterol without affecting the LDL levels. The earlier data showed that both EPA and DHA decreased TG level and increased levels of HDL-C, but that the DHA alone and direct comparison of DHA/EPA showed that DHA has more undesirable effects on LDL. Furthermore, the MARINE and ANCHOR trials have both shown that not only does EPA improve the lipid panel but also helps to decrease the levels of the vascular inflammatory biomarkers, thus further helping to decrease cardiovascular risk. The use of EPA as an adjunct therapy for high-risk patient has shown to help decrease cardiovascular risk. The reduction in risk is performed not only by decreasing TG but also by reducing vascular inflammation. Although because there are no randomized double-blind study looking at this, the research is inconclusive and requires further investigation.

Identification of Mature Atherosclerotic Plaque Proteome Signatures Using Data-Independent Acquisition Mass Spectrometry.

PubMed

Hansmeier, Nicole; Buttigieg, Josef; Kumar, Pankaj; Pelle, Shaneen; Choi, Kyoo Yoon; Kopriva, David; Chao, Tzu-Chiao

2018-01-05

Atherosclerosis is a chronic inflammatory disease with complex pathobiology and one of the most common causes of cardiovascular events. The process is characterized by complex vascular remodeling processes that require the actions of numerous proteins. The composition of atherosclerotic plaque is increasingly recognized as a major factor governing the occurrence of cardiovascular or neurological symptoms. To gain deeper insights into the composition of atherosclerotic plaques, we created quantitative proteome profiles of advanced plaque tissues of six male patients undergoing carotid endarterectomy for stroke prevention. Using a quantitative, data-independent proteome approach, we identified 4181 proteins with an average protein coverage of 45%. An analysis of the quantitative composition of the tissue revealed key players of vascular remodeling processes. Moreover, compared with proximal arterial tissue, 20 proteins in mature plaques were enriched, whereas 52 proteins were found in lower quantities. Among the proteins with increased abundance were prominent extracellular matrix proteins such as biglycan and lumican, whereas cytoskeletal markers for contractile smooth muscle cells (SMCs) were decreased. Taken together, this study provides the most comprehensive quantitative assessment of mature human plaque tissue to date, which indicates a central role of SMCs in the structure of advanced atherosclerotic plaques.

Binswanger's disease: biomarkers in the inflammatory form of vascular cognitive impairment and dementia.

PubMed

Rosenberg, Gary A

2018-03-01

Vascular cognitive impairment and dementia (VCID) is a major public health concern because of the increased incidence of vascular disease in the aging population and the impact of vascular disease on Alzheimer's disease. VCID is a heterogeneous group of diseases for which there are no proven treatments. Biomarkers can be used to select more homogeneous populations. Small vessel disease is the most prevalent form of VCID and is the optimal form for treatment trials because there is a progressive course with characteristic pathological changes. Subcortical ischemic vascular disease of the Binswanger type (SIVD-BD) has a characteristic set of features that can be used both to identify patients and to follow treatment. SIVD-BD patients have clinical, neuropsychological, cerebrospinal fluid (CSF) and imaging features that can be used as biomarkers. No one feature is diagnostic, but a multimodal approach defines the SIVD-BD spectrum disorder. The most important features are large white matter lesions with axonal damage, blood-brain barrier disruption as shown by magnetic resonance imaging and CSF, and neuropsychological evidence of executive dysfunction. We have used these features to create a Binswanger Disease Scale and a probability of SIVD-BD, using a machine-learning algorithm. The patients discussed in this review are derived from published studies. Biomarkers not only aid in early diagnosis before the disease process has progressed too far for treatment, but also can indicate response to treatment. Refining the use of biomarkers will allow dementia treatment to enter the era of precision medicine. This article is part of the Special Issue "Vascular Dementia". © 2017 International Society for Neurochemistry.

Effect of uric acid on inflammatory COX-2 and ROS pathways in vascular smooth muscle cells.

PubMed

Oğuz, Nurgül; Kırça, Mustafa; Çetin, Arzu; Yeşilkaya, Akın

2017-10-01

Hyperuricemia is thought to play a role in cardiovascular diseases (CVD), including hypertension, coronary artery disease and atherosclerosis. However, exactly how uric acid contributes to these pathologies is unknown. An underlying mechanism of inflammatory diseases, such as atherosclerosis, includes enhanced production of cyclooxygenase-2 (COX-2) and superoxide anion. Here, we aimed to examine the effect of uric acid on inflammatory COX-2 and superoxide anion production and to determine the role of losartan. Primarily cultured vascular smooth muscle cells (VSMCs) were time and dose-dependently induced by uric acid and COX-2 and superoxide anion levels were measured. COX-2 levels were determined by ELISA, and superoxide anion was measured by the superoxide dismutase (SOD)-inhibitable reduction of ferricytochrome c method. Uric acid elevated COX-2 levels in a time-dependent manner. Angiotensin-II receptor blocker, losartan, diminished uric-acid-induced COX-2 elevation. Uric acid also increased superoxide anion level in VSMCs. Uric acid plays an important role in CVD pathogenesis by inducing inflammatory COX-2 and ROS pathways. This is the first study demonstrating losartan's ability to reduce uric-acid-induced COX-2 elevation.

Underlying chronic inflammation alters the profile and mechanisms of acute neutrophil recruitment.

PubMed

Ma, Bin; Whiteford, James R; Nourshargh, Sussan; Woodfin, Abigail

2016-11-01

Chronically inflamed tissues show altered characteristics that include persistent populations of inflammatory leukocytes and remodelling of the vascular network. As the majority of studies on leukocyte recruitment have been carried out in normal healthy tissues, the impact of underlying chronic inflammation on ongoing leukocyte recruitment is largely unknown. Here, we investigate the profile and mechanisms of acute inflammatory responses in chronically inflamed and angiogenic tissues, and consider the implications for chronic inflammatory disorders. We have developed a novel model of chronic ischaemia of the mouse cremaster muscle that is characterized by a persistent population of monocyte-derived cells (MDCs), and capillary angiogenesis. These tissues also show elevated acute neutrophil recruitment in response to locally administered inflammatory stimuli. We determined that Gr1 low MDCs, which are widely considered to have anti-inflammatory and reparative functions, amplified acute inflammatory reactions via the generation of additional proinflammatory signals, changing both the profile and magnitude of the tissue response. Similar vascular and inflammatory responses, including activation of MDCs by transient ischaemia-reperfusion, were observed in mouse hindlimbs subjected to chronic ischaemia. This response demonstrates the relevance of the findings to peripheral arterial disease, in which patients experience transient exercise-induced ischaemia known as claudication.These findings demonstrate that chronically inflamed tissues show an altered profile and altered mechanisms of acute inflammatory responses, and identify tissue-resident MDCs as potential therapeutic targets. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Intraocular inflammation in autoimmune diseases.

PubMed

Pras, Eran; Neumann, Ron; Zandman-Goddard, Gisele; Levy, Yair; Assia, Ehud I; Shoenfeld, Yehuda; Langevitz, Pnina

2004-12-01

The uveal tract represents the vascular organ of the eye. In addition to providing most of the blood supply to the intraocular structures, it acts as a conduit for immune cells, particularly lymphocytes, to enter the eye. Consequently, the uveal tract is represented in many intraocular inflammatory processes. Uveitis is probably a misnomer unless antigens within the uvea are the direct targets of the inflammatory process. A better term of the condition is "intraocular inflammation" (IOI). To review the presence of IOI in autoimmune diseases, the immunopathogenic mechanisms leading to disease, and treatment. We reviewed the English medical literature by using MEDLINE (1984-2003) employing the terms "uveitis," "intraocular inflammation," and "autoimmune diseases." An underlying autoimmune disease was identified in up to 40% of patients with IOI, and included spondyloarthropathies, Behcets disease, sarcoidosis, juvenile chronic arthritis, Vogt-Koyanagi-Harada syndrome (an inflammatory syndrome including uveitis with dermatologic and neurologic manifestations), immune recovery syndrome, and uveitis with tubulointerstitial disease. The immunopathogenesis of IOI involves enhanced T-cell response. Recently, guidelines for the use of immunosuppressive drugs for inflammatory eye disease were established and include: corticosteroids, azathioprine, methotrexate, mycophenolate mofetil, cyclosporine, tacrolimus, cyclophosphamide, and chlorambucil. New therapies with limited experience include the tumor necrosis factor alpha inhibitors, interferon alfa, monoclonal antibodies against lymphocyte surface antigens, intravenous immunoglobulin (IVIG), and the intraocular delivery of immunosuppressive agents. An underlying autoimmune disease was identified in up to 40% of patients with IOI. Immunosuppressive drugs, biologic agents, and IVIG are employed for the treatment of IOI in autoimmune diseases.

Davallia bilabiata inhibits TNF-α-induced adhesion molecules and chemokines by suppressing IKK/NF-kappa B pathway in vascular endothelial cells.

PubMed

Yang, Rong-Chi; Chang, Cheng-Chieh; Sheen, Jer-Ming; Wu, Hsiao-Ting; Pang, Jong-Hwei S; Huang, Sheng-Teng

2014-01-01

Davallia bilabiata (D. bilabiata) is also called GuSuiBu in Taiwan and is used as a substitute for Drynaria fortunei J. Sm. It is often used for trauma and bone repair. The inhibitory effect of D. bilabiata on inflammatory activity has not been reported. In the present study, we aimed to study the mechanism of anti-inflammation of D. bilabiata on the adhesion of leukocytes to vascular endothelial cells. The results showed that D. bilabiata, at concentrations without cytotoxic effect, inhibited the adhesion of monocytes (THP-1) to the TNF-α-stimulated human umbilical vascular endothelial cells (HUVECs). D. bilabiata suppressed the expression of the adhesion molecules ICAM, VCAM, and E-selectin at both the mRNA and protein level. In addition, both of the TNF-α-induced mRNA and protein expression of chemokines including fractalkine/CX3CL1, MCP-1 and RANTES as well as the level of secreted soluble fractalkine were decreased by D. bilabiata. We also verified that D. bilabiata inhibited the TNF-α-induced nuclear translocation of NF-κB through the inhibitory process on the TNF-α-activated phosphorylation of IKKα, IKKβ, IκB and NF-κB. All together, we concluded that the D. bilabiata affected the canonical pathway of TNF-α-induced NF-κB activation and down-regulated cell adhesion molecules and chemokine expression through inhibition of the NF-κB/IκBα/IKK signaling pathway. These findings strongly indicated that D. bilabiata might be a promising alternative/adjunct treatment for inflammatory diseases, such as rheumatoid arthritis and osteoarthritis.

The Production of Nitric Oxide, IL-6, and TNF-Alpha in Palmitate-Stimulated PBMNCs Is Enhanced through Hyperglycemia in Diabetes

PubMed Central

Volpe, Caroline Maria Oliveira; Abreu, Luana Farnese Machado; Gomes, Pollyanna Stephanie; Gonzaga, Raquel Miranda; Veloso, Clara Araújo; Nogueira-Machado, José Augusto

2014-01-01

We examined nitric oxide (NO), IL-6, and TNF-α secretion from cultured palmitate-stimulated PBMNCs or in the plasma from type 2 diabetes mellitus (T2MD) patients or nondiabetic (ND) controls. Free fatty acids (FFA) have been suggested to induce chronic low-grade inflammation, activate the innate immune system, and cause deleterious effects on vascular cells and other tissues through inflammatory processes. The levels of NO, IL-6, TNF-α, and MDA were higher in supernatant of palmitate stimulated blood cells (PBMNC) or from plasma from patients. The results obtained in the present study demonstrated that hyperglycemia in diabetes exacerbates in vitro inflammatory responses in PBMNCs stimulated with high levels of SFA (palmitate). These results suggest that hyperglycemia primes PBMNCs for NO, IL-6, and TNF-alpha secretion under in vitro FFA stimulation are associated with the secretion of inflammatory biomarkers in diabetes. A combined therapy targeting signaling pathways activated by hyperglycemia in conjunction with simultaneous control of hyperglycemia and hypertriglyceridemia would be suggested for controlling the progress of diabetic complications. PMID:24803982

Pathophysiological Approaches of Acute Respiratory Distress syndrome: Novel Bases for Study of Lung Injury

PubMed Central

Castillo, R.L; Carrasco Loza, R; Romero-Dapueto, C

2015-01-01

Experimental approaches have been implemented to research the lung damage related-mechanism. These models show in animals pathophysiological events for acute respiratory distress syndrome (ARDS), such as neutrophil activation, reactive oxygen species burst, pulmonary vascular hypertension, exudative edema, and other events associated with organ dysfunction. Moreover, these approaches have not reproduced the clinical features of lung damage. Lung inflammation is a relevant event in the develop of ARDS as component of the host immune response to various stimuli, such as cytokines, antigens and endotoxins. In patients surviving at the local inflammatory states, transition from injury to resolution is an active mechanism regulated by the immuno-inflammatory signaling pathways. Indeed, inflammatory process is regulated by the dynamics of cell populations that migrate to the lung, such as neutrophils and on the other hand, the role of the modulation of transcription factors and reactive oxygen species (ROS) sources, such as nuclear factor kappaB and NADPH oxidase. These experimental animal models reproduce key components of the injury and resolution phases of human ALI/ARDS and provide a methodology to explore mechanisms and potential new therapies. PMID:26312099

Critical role of sphingosine-1-phosphate receptor 2 (S1PR2) in acute vascular inflammation.

PubMed

Zhang, Guoqi; Yang, Li; Kim, Gab Seok; Ryan, Kieran; Lu, Shulin; O'Donnell, Rebekah K; Spokes, Katherine; Shapiro, Nathan; Aird, William C; Kluk, Michael J; Yano, Kiichiro; Sanchez, Teresa

2013-07-18

The endothelium, as the interface between blood and all tissues, plays a critical role in inflammation. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid, highly abundant in plasma, that potently regulates endothelial responses through interaction with its receptors (S1PRs). Here, we studied the role of S1PR2 in the regulation of the proadhesion and proinflammatory phenotype of the endothelium. By using genetic approaches and a S1PR2-specific antagonist (JTE013), we found that S1PR2 plays a key role in the permeability and inflammatory responses of the vascular endothelium during endotoxemia. Experiments with bone marrow chimeras (S1pr2(+/+) → S1pr2(+/+), S1pr2(+/+) → S1pr2(-/-), and S1pr2(-/-) → S1pr2(+/+)) indicate the critical role of S1PR2 in the stromal compartment, in the regulation of vascular permeability and vascular inflammation. In vitro, JTE013 potently inhibited tumor necrosis factor α-induced endothelial inflammation. Finally, we provide detailed mechanisms on the downstream signaling of S1PR2 in vascular inflammation that include the activation of the stress-activated protein kinase pathway that, together with the Rho-kinase nuclear factor kappa B pathway (NF-kB), are required for S1PR2-mediated endothelial inflammatory responses. Taken together, our data indicate that S1PR2 is a key regulator of the proinflammatory phenotype of the endothelium and identify S1PR2 as a novel therapeutic target for vascular disorders.

Hass avocado modulates postprandial vascular reactivity and postprandial inflammatory responses to a hamburger meal in healthy volunteers.

PubMed

Li, Zhaoping; Wong, Angela; Henning, Susanne M; Zhang, Yanjun; Jones, Alexis; Zerlin, Alona; Thames, Gail; Bowerman, Susan; Tseng, Chi-Hong; Heber, David

2013-02-26

Hass avocados are rich in monounsaturated fatty acids (oleic acid) and antioxidants (carotenoids, tocopherols, polyphenols) and are often eaten as a slice in a sandwich containing hamburger or other meats. Hamburger meat forms lipid peroxides during cooking. After ingestion, the stomach functions as a bioreactor generating additional lipid peroxides and this process can be inhibited when antioxidants are ingested together with the meat. The present pilot study was conducted to investigate the postprandial effect of the addition of 68 g of avocado to a hamburger on vasodilation and inflammation. Eleven healthy subjects on two separate occasions consumed either a 250 g hamburger patty alone (ca. 436 cal and 25 g fat) or together with 68 grams of avocado flesh (an additional 114 cal and 11 g of fat for a total of 550 cal and 36 g fat), a common culinary combination, to assess effects on vascular health. Using the standard peripheral arterial tonometry (PAT) method to calculate the PAT index, we observed significant vasoconstriction 2 hours following hamburger ingestion (2.19 ± 0.36 vs. 1.56 ± 0.21, p = 0.0007), which did not occur when the avocado flesh was ingested together with the burger (2.17 ± 0.57 vs. 2.08 ± 0.51, NS p = 0.68). Peripheral blood mononuclear cells were isolated from postprandial blood samples and the Ikappa-B alpha (IκBα) protein concentration was determined to assess effects on inflammation. At 3 hours, there was a significant preservation of IκBα (131% vs. 58%, p = 0.03) when avocado was consumed with the meat compared to meat alone, consistent with reduced activation of the NF-kappa B (NFκB) inflammatory pathway. IL-6 increased significantly at 4 hours in postprandial serum after consumption of the hamburger, but no change was observed when avocado was added. Postprandial serum triglyceride concentration increased, but did not further increase when avocado was ingested with the burger compared to burger alone despite the added fat and calories from the avocado. These observations are suggestive of beneficial anti-inflammatory and vascular health effects of ingesting added Hass avocado with a hamburger patty.

Efficacy and safety of vedolizumab in the treatment of ulcerative colitis.

PubMed

Domènech, Eugeni; Gisbert, Javier P

2016-12-01

Integrins play a crucial role in the development and maintenance of the inflammatory process in patients with inflammatory bowel disease. Vedolizumab is a humanized monoclonal antibody with a predominantly gastrointestinal effect. It specifically inhibits leukocyte integrin α 4 β 7 , thus preventing its interaction with mucosal vascular addressin cell adhesion molecule 1(MAdCAM-1), which is involved in the migration of lymphocytes from the blood stream to the intestinal tissue. Vedolizumab is indicated in the treatment of moderate to severe active Crohn's disease and ulcerative colitis in adult patients with poor response, loss of response, or intolerance to conventional treatment or to tumour necrosis factor alpha (TNF-α) antagonists. This review presents the most relevant clinical outcomes of vedolizumab in the treatment of patients with ulcerative colitis. Copyright © 2016 Elsevier España, S.L.U., AEEH y AEG. All rights reserved.

Redox-dependent impairment of vascular function in sickle cell disease.

PubMed

Aslan, Mutay; Freeman, Bruce A

2007-12-01

The vascular pathophysiology of sickle cell disease (SCD) is influenced by many factors, including adhesiveness of red and white blood cells to endothelium, increased coagulation, and homeostatic perturbation. The vascular endothelium is central to disease pathogenesis because it displays adhesion molecules for blood cells, balances procoagulant and anticoagulant properties of the vessel wall, and regulates vascular homeostasis by synthesizing vasoconstricting and vasodilating substances. The occurrence of intermittent vascular occlusion in SCD leads to reperfusion injury associated with granulocyte accumulation and enhanced production of reactive oxygen species. The participation of nitric oxide (NO) in oxidative reactions causes a reduction in NO bioavailability and contributes to vascular dysfunction in SCD. Therapeutic strategies designed to counteract endothelial, inflammatory, and oxidative abnormalities may reduce the frequency of hospitalization and blood transfusion, the incidence of pain, and the occurrence of acute chest syndrome and pulmonary hypertension in patients with SCD.

Connexin-Based Therapeutics and Tissue Engineering Approaches to the Amelioration of Chronic Pancreatitis and Type I Diabetes: Construction and Characterization of a Novel Prevascularized Bioartificial Pancreas.

PubMed

Rhett, J Matthew; Wang, Hongjun; Bainbridge, Heather; Song, Lili; Yost, Michael J

2016-01-01

Total pancreatectomy and islet autotransplantation is a cutting-edge technique to treat chronic pancreatitis and postoperative diabetes. A major obstacle has been low islet cell survival due largely to the innate inflammatory response. Connexin43 (Cx43) channels play a key role in early inflammation and have proven to be viable therapeutic targets. Even if cell death due to early inflammation is avoided, insufficient vascularization is a primary obstacle to maintaining the viability of implanted cells. We have invented technologies targeting the inflammatory response and poor vascularization: a Cx43 mimetic peptide that inhibits inflammation and a novel prevascularized tissue engineered construct. We combined these technologies with isolated islets to create a prevascularized bioartificial pancreas that is resistant to the innate inflammatory response. Immunoconfocal microscopy showed that constructs containing islets express insulin and possess a vascular network similar to constructs without islets. Glucose stimulated islet-containing constructs displayed reduced insulin secretion compared to islets alone. However, labeling for insulin post-glucose stimulation revealed that the constructs expressed abundant levels of insulin. This discrepancy was found to be due to the expression of insulin degrading enzyme. These results suggest that the prevascularized bioartificial pancreas is potentially a tool for improving long-term islet cell survival in vivo.

Vasculoprotective effects of heme oxygenase-1 in a murine model of hyperoxia-induced bronchopulmonary dysplasia

PubMed Central

Fernandez-Gonzalez, Angeles; Alex Mitsialis, S.; Liu, Xianlan

2012-01-01

Bronchopulmonary dysplasia (BPD) is characterized by simplified alveolarization and arrested vascular development of the lung with associated evidence of endothelial dysfunction, inflammation, increased oxidative damage, and iron deposition. Heme oxygenase-1 (HO-1) has been reported to be protective in the pathogenesis of diseases of inflammatory and oxidative etiology. Because HO-1 is involved in the response to oxidative stress produced by hyperoxia and is critical for cellular heme and iron homeostasis, it could play a protective role in BPD. Therefore, we investigated the effect of HO-1 in hyperoxia-induced lung injury using a neonatal transgenic mouse model with constitutive lung-specific HO-1 overexpression. Hyperoxia triggered an increase in pulmonary inflammation, arterial remodeling, and right ventricular hypertrophy that was attenuated by HO-1 overexpression. In addition, hyperoxia led to pulmonary edema, hemosiderosis, and a decrease in blood vessel number, all of which were markedly improved in HO-1 overexpressing mice. The protective vascular response may be mediated at least in part by carbon monoxide, due to its anti-inflammatory, antiproliferative, and antiapoptotic properties. HO-1 overexpression, however, did not prevent alveolar simplification nor altered the levels of ferritin and lactoferrin, proteins involved in iron binding and transport. Thus the protective mechanisms elicited by HO-1 overexpression primarily preserve vascular growth and barrier function through iron-independent, antioxidant, and anti-inflammatory pathways. PMID:22287607

Type I IFNs Are Required to Promote Central Nervous System Immune Surveillance through the Recruitment of Inflammatory Monocytes upon Systemic Inflammation

PubMed Central

Peralta Ramos, Javier María; Bussi, Claudio; Gaviglio, Emilia Andrea; Arroyo, Daniela Soledad; Baez, Natalia Soledad; Rodriguez-Galan, Maria Cecilia; Iribarren, Pablo

2017-01-01

Brain-resident microglia and peripheral migratory leukocytes play essential roles in shaping the immune response in the central nervous system. These cells activate and migrate in response to chemokines produced during active immune responses and may contribute to the progression of neuroinflammation. Herein, we addressed the participation of type I–II interferons in the response displayed by microglia and inflammatory monocytes to comprehend the contribution of these cytokines in the establishment and development of a neuroinflammatory process. Following systemic lipopolysaccharide (LPS) challenge, we found glial reactivity and an active recruitment of CD45hi leukocytes close to CD31+ vascular endothelial cells in circumventricular organs. Isolated CD11b+ CD45hi Ly6Chi Ly6G−-primed inflammatory monocytes were able to induce T cell proliferation, unlike CD11b+ CD45lo microglia. Moreover, ex vivo re-stimulation with LPS exhibited an enhancement of T cell proliferative response promoted by inflammatory monocytes. These myeloid cells also proved to be recruited in a type I interferon-dependent fashion as opposed to neutrophils, unveiling a role of these cytokines in their trafficking. Together, our results compares the phenotypic and functional features between tissue-resident vs peripheral recruited cells in an inflamed microenvironment, identifying inflammatory monocytes as key sentinels in a LPS-induced murine model of neuroinflammation. PMID:29255461

The influence of occupational chronic lead exposure on the levels of selected pro-inflammatory cytokines and angiogenic factors.

PubMed

Machoń-Grecka, A; Dobrakowski, M; Boroń, M; Lisowska, G; Kasperczyk, A; Kasperczyk, S

2017-05-01

The aim of the study was to determine the effect of occupational exposure to lead on the blood levels of pro-inflammatory cytokines and selected factors that influence angiogenesis. The study population was divided into two groups. The first group consisted of 56 male workers chronically exposed to lead. The second group (control) was comprised of 24 male administrative workers. The serum levels of interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) were significantly higher in the group of workers chronically exposed to lead compared to control values by 38%, 68%, and 57%, respectively. Similarly, the values of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and fibroblast growth factor-basic (FGF-basic) were higher by 19% and 63%, respectively. In the group of workers chronically exposed to lead, there were positive correlations between the levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and angiogenic factors (VEGF, FGF-basic, sVEGFR-1, and soluble angiopoietin receptor). In the control group, there were no correlations between the levels of the abovementioned parameters. Results of the present study indicate that chronic occupational lead exposure promotes inflammatory processes via induction of pro-inflammatory cytokines, modulates angiogenesis, and elicits interdependencies between the immune response and angiogenic factors.

The hexane fraction of Ardisia crispa Thunb. A. DC. roots inhibits inflammation-induced angiogenesis

PubMed Central

2013-01-01

Background Ardisia crispa (Myrsinaceae) is used in traditional Malay medicine to treat various ailments associated with inflammation, including rheumatism. The plant’s hexane fraction was previously shown to inhibit several diseases associated with inflammation. As there is a strong correlation between inflammation and angiogenesis, we conducted the present study to investigate the anti-angiogenic effects of the plant’s roots in animal models of inflammation-induced angiogenesis. Methods We first performed phytochemical screening and high-performance liquid chromatography (HPLC) fingerprinting of the hexane fraction of Ardisia crispa roots ethanolic extract (ACRH) and its quinone-rich fraction (QRF). The anti-inflammatory properties of ACRH and QRF were tested using the Miles vascular permeability assay and the murine air pouch granuloma model following oral administration at various doses. Results Preliminary phytochemical screening of ACRH revealed the presence of flavonoids, triterpenes, and tannins. The QRF was separated from ACRH (38.38% w/w) by column chromatography, and was isolated to yield a benzoquinonoid compound. The ACRH and QRF were quantified by HPLC. The LD50 value of ACRH was 617.02 mg/kg. In the Miles vascular permeability assay, the lowest dose of ACRH (10 mg/kg) and all doses of QRF significantly reduced vascular endothelial growth factor (VEGF)-induced hyperpermeability, when compared with the vehicle control. In the murine air pouch granuloma model, ACRH and QRF both displayed significant and dose-dependent anti-inflammatory effects, without granuloma weight. ACRH and QRF significantly reduced the vascular index, but not granuloma tissue weight. Conclusions In conclusion, both ACRH and QRF showed potential anti-inflammatory properties in a model of inflammation-induced angiogenesis model, demonstrating their potential anti-angiogenic properties. PMID:23298265

PET Study of Sphingosine-1-Phosphate Receptor 1 Expression in Response to Vascular Inflammation in a Rat Model of Carotid Injury

DOE PAGES

Liu, Hui; Jin, Hongjun; Yue, Xuyi; ...

2017-01-30

Sphingosine-1-phosphate receptor (S1PR) activation plays a key role in vascular inflammatory response. Here, we report in vivo validation of [ 11C]TZ3321, a potent S1PR1 radioligand, for imaging vascular inflammation in a rat model of carotid injury. The right common carotid artery of male adult Sprague-Dawley rats was injured by balloon overinflation that denuded the endothelium and distended the vessel wall. Animals received a 60-minute micro-positron emission tomography (micro PET) scan with [ 11C]TZ3321 at 72 hours after injury. Ex vivo autoradiography was also conducted. The expression and cellular location of S1PR1 were examined by immunohistological analysis. Three-dimensional (3D) reconstruction ofmore » the first 100-second microPET/computed tomography (CT) image indicated the location of bilateral common carotid arteries. [ 11C]TZ3321 displayed significantly higher accumulation (standardized uptake values: 0.93 ± 0.07 vs 0.78 ± 0.09, n = 6, P = .001) in the injured carotid artery than in the contralateral side. Increased tracer uptake in the injured artery was confirmed by autoradiography (photostimulated luminescence measures: 85.5 ± 0.93 vs 71.48 ± 6.22, n = 2). Concordantly, high S1PR1expression was observed in infiltrated inflammatory cells in the injured artery. Our studies demonstrate [ 11C]TZ3321 microPET is able to detect the acute upregulation of S1PR1 expression in inflamed carotid artery. Therefore, [ 11C]TZ3321 has potential to be a PET radiotracer for detecting early inflammatory response and monitoring therapeutic efficacy of vascular inflammation.« less

Targeting Tumor Necrosis Factor-α with Adalimumab: Effects on Endothelial Activation and Monocyte Adhesion

PubMed Central

Oberoi, Raghav; Schuett, Jutta; Schuett, Harald; Koch, Ann-Kathrin; Luchtefeld, Maren

2016-01-01

Objective It is well known that atherosclerotic inflammatory vascular disease is critically driven by oxidized lipids and cytokines. In this regard, tumor necrosis factor (TNF)-α is known as a crucial mediator of early pro-atherosclerotic events. Epidemiologic data suggest that blockade of TNF-α has beneficial effects on vascular outcomes in patients with rheumatoid arthritis, however, detailed mechanistic studies are still lacking. This study aims to elucidate effects of TNF-α blockade by adalimumab–which is approved for several inflammatory disorders–on endothelial activation and monocyte adhesion under pro-atherosclerotic conditions. Methods and Results Phorbol myristate acetate (PMA) differentiated THP-1 macrophages were stimulated with oxidized low density lipoprotein and subsequent analysis of this conditioned media (oxLDL CM) revealed a strong release of TNF-α. The TNF-α rich supernatant led to activation of human umbilical vein endothelial cells (HUVEC) as shown by enhanced expression of major adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin which was suppressed by the TNF-α inhibitor adalimumab. Accordingly, adalimumab effectively prevented THP-1 monocyte adhesion to endothelial cells under static as well as under flow conditions. Furthermore, adalimumab suppressed endothelial leakage as shown by Evan's blue diffusion across a confluent endothelial monolayer. Of note, after intraperitoneal injection we detected abundant deposition of fluorophore-labelled adalimumab in atherosclerotic plaques of hypercholesterolemic mice. Conclusion Our results show that adalimumab prevents major inflammatory effects of TNF-α on endothelial activation, endothelial monocyte adhesion, endothelial leakage and therefore extends the therapeutic options of adalimumab to limit vascular inflammation. PMID:27467817

Interleukin-35 Inhibits Endothelial Cell Activation by Suppressing MAPK-AP-1 Pathway.

PubMed

Sha, Xiaojin; Meng, Shu; Li, Xinyuan; Xi, Hang; Maddaloni, Massimo; Pascual, David W; Shan, Huimin; Jiang, Xiaohua; Wang, Hong; Yang, Xiao-feng

2015-07-31

Vascular response is an essential pathological mechanism underlying various inflammatory diseases. This study determines whether IL-35, a novel responsive anti-inflammatory cytokine, inhibits vascular response in acute inflammation. Using a mouse model of LPS-induced acute inflammation and plasma samples from sepsis patients, we found that IL-35 was induced in the plasma of mice after LPS injection as well as in the plasma of sepsis patients. In addition, IL-35 decreased LPS-induced proinflammatory cytokines and chemokines in the plasma of mice. Furthermore, IL-35 inhibited leukocyte adhesion to the endothelium in the vessels of lung and cremaster muscle and decreased the numbers of inflammatory cells in bronchoalveolar lavage fluid. Mechanistically, IL-35 inhibited the LPS-induced up-regulation of endothelial cell (EC) adhesion molecule VCAM-1 through IL-35 receptors gp130 and IL-12Rβ2 via inhibition of the MAPK-activator protein-1 (AP-1) signaling pathway. We also found that IL-27, which shares the EBI3 subunit with IL-35, promoted LPS-induced VCAM-1 in human aortic ECs and that EBI3-deficient mice had similar vascular response to LPS when compared with that of WT mice. These results demonstrated for the first time that inflammation-induced IL-35 inhibits LPS-induced EC activation by suppressing MAPK-AP1-mediated VCAM-1 expression and attenuates LPS-induced secretion of proinflammatory cytokines/chemokines. Our results provide insight into the control of vascular inflammation by IL-35 and suggest that IL-35 is an attractive novel therapeutic reagent for sepsis and cardiovascular diseases. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Titanium dioxide nanoparticles increase inflammatory responses in vascular endothelial cells

PubMed Central

Han, Sung Gu; Newsome, Bradley; Hennig, Bernhard

2013-01-01

Atherosclerosis is a chronic inflammatory disease that remains the leading cause of death in the United States. Numerous risk factors for endothelial cell inflammation and the development of atherosclerosis have been identified, including inhalation of ultrafine particles. Recently, engineered nanoparticles (NPs) such as titanium (TiO2) NPs have attracted much attention due to their wide range of applications. However, there are also great concerns surrounding potential adverse health effects in vascular systems. Although TiO2 NPs are known to induce oxidative stress and inflammation, the associated signaling pathways have not been well studied. The focus of this work, therefore, deals with examination of the cellular signaling pathways responsible for TiO2 NP-induced endothelial oxidative stress and inflammation. In this study, primary vascular endothelial cells were treated with TiO2 NPs for 2–16 h at concentrations of 0–50 µg/mL. TiO2 NP exposure increased cellular oxidative stress and DNA binding of NF-κB. Further, phosphorylation of Akt, ERK, JNK and p38 was increased in cells exposed to TiO2 NPs. TiO2 NPs also significantly increased induction of mRNA and protein levels of vascular cell adhesion molecule-1 (VCAM-1) and mRNA levels of monocyte chemoattractant protein-1 (MCP-1). Pretreatment with inhibitors for NF-κB (pyrrolidine dithiocarbamate), oxidative stress (epigallocatechin gallate and apocynin), Akt (LY294002), ERK (PD98059), JNK (SP600125) and p38 (SB203580) significantly attenuated TiO2 NP-induced MCP-1 and VCAM-1 gene expression, as well as activation of NF-κB. These data indicate that TiO2 NPs can induce endothelial inflammatory responses via redox-sensitive cellular signaling pathways. PMID:23380242

PET Study of Sphingosine-1-Phosphate Receptor 1 Expression in Response to Vascular Inflammation in a Rat Model of Carotid Injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Hui; Jin, Hongjun; Yue, Xuyi

Sphingosine-1-phosphate receptor (S1PR) activation plays a key role in vascular inflammatory response. Here, we report in vivo validation of [ 11C]TZ3321, a potent S1PR1 radioligand, for imaging vascular inflammation in a rat model of carotid injury. The right common carotid artery of male adult Sprague-Dawley rats was injured by balloon overinflation that denuded the endothelium and distended the vessel wall. Animals received a 60-minute micro-positron emission tomography (micro PET) scan with [ 11C]TZ3321 at 72 hours after injury. Ex vivo autoradiography was also conducted. The expression and cellular location of S1PR1 were examined by immunohistological analysis. Three-dimensional (3D) reconstruction ofmore » the first 100-second microPET/computed tomography (CT) image indicated the location of bilateral common carotid arteries. [ 11C]TZ3321 displayed significantly higher accumulation (standardized uptake values: 0.93 ± 0.07 vs 0.78 ± 0.09, n = 6, P = .001) in the injured carotid artery than in the contralateral side. Increased tracer uptake in the injured artery was confirmed by autoradiography (photostimulated luminescence measures: 85.5 ± 0.93 vs 71.48 ± 6.22, n = 2). Concordantly, high S1PR1expression was observed in infiltrated inflammatory cells in the injured artery. Our studies demonstrate [ 11C]TZ3321 microPET is able to detect the acute upregulation of S1PR1 expression in inflamed carotid artery. Therefore, [ 11C]TZ3321 has potential to be a PET radiotracer for detecting early inflammatory response and monitoring therapeutic efficacy of vascular inflammation.« less

Modulation of early functional recovery of Achilles tendon to bone unit after transection by BPC 157 and methylprednisolone.

PubMed

Krivic, A; Majerovic, M; Jelic, I; Seiwerth, S; Sikiric, P

2008-05-01

In the presented study we compared the effect of stable peptide BPC 157 and methylprednisolone on early functional recovery after Achilles tendon to bone transection in a rat model before collagen healing started. Surgical transection of the right Achilles tendon to bone area was performed in seventy two Wistar Albino male rats. Healing Achilles tendon edges were harvested at days 1-4 following the transection. Using Achilles functional index (AFI), myeloperoxidase activity, histological inflammatory cell influx and vascular index early functional recovery was evaluated. Agents (stable peptide BPC 157 10 microg methylprednisolone 5 mg, normal saline 5 ml) were given alone (/kg b.w., intraperitoneally, once daily, first 30 min after surgery, last 24 h before analysis). Control group received normal saline 5 ml/kg. BPC 157 improved functional recovery (AFI values increased at all time points, p <0.05) by anti-inflammatory (decreased myeloperoxidase (MPO) activity and histological inflammatory cell influx, p <0.05) and increased new blood vessel formation (increased vascular index, p <0.05). Methyprednisolone decreased MPO activity and histological inflammatory cell influx, (p <0.05) but also decreased new blood vessel formation and did not affect early functional recovery. Stable peptide BPC 157 with combined anti-inflammatory action and induction of early new blood vessel formation facilitates early functional recovery in Achilles tendon to bone healing.

Adiponectin attenuates LPS-induced acute lung injury through suppression of endothelial cell activation1

PubMed Central

Konter, Jason M; Parker, Jennifer L; Baez, Elizabeth; Li, Stephanie Z; Ranscht, Barbara; Denzel, Martin; Little, Frederic F; Nakamura, Kazuto; Ouchi, Noriyuki; Fine, Alan; Walsh, Kenneth; Summer, Ross S

2011-01-01

Adiponectin (APN) is an adipose tissue-derived factor with anti-inflammatory and vascular protective properties whose levels paradoxically decrease with increasing body fat. In this study, APN’s role in the early development of ALI to lipopolysaccharide (LPS) was investigated. Intra-tracheal (i.t.) LPS elicited an exaggerated systemic inflammatory response in APN-deficient (APN−/−) mice compared to wild-type (wt) littermates. Increased lung injury and inflammation were observed in APN−/− mice as early as 4 hours after delivery of LPS. Targeted gene expression profiling performed on immune and endothelial cells isolated from lung digests 4 hours after LPS administration showed increased pro-inflammatory gene expression (e.g. IL-6) only in endothelial cells of APN−/− mice when compared to wt mice. Direct effects on lung endothelium were demonstrated by APN’s ability to inhibit LPS-induced IL-6 production in primary human endothelial cells in culture. Furthermore, T-cadherin-deficient (T-cad−/−) mice that have significantly reduced lung airspace APN but high serum APN levels had pulmonary inflammatory responses after i.t. LPS that were similar to those of wt mice. These findings indicate the importance of serum APN in modulating LPS-induced ALI and suggest that conditions leading to hypoadiponectinemia (e.g. obesity) predispose to development of ALI through exaggerated inflammatory response in pulmonary vascular endothelium. PMID:22156343

Induced Pluripotent Stem Cell‐Derived Endothelial Cells Overexpressing Interleukin‐8 Receptors A/B and/or C‐C Chemokine Receptors 2/5 Inhibit Vascular Injury Response

PubMed Central

Giordano, Samantha; Zhao, Xiangmin; Chen, Yiu‐Fai; Litovsky, Silvio H.; Hage, Fadi G.; Townes, Tim M.; Sun, Chiao‐Wang; Wu, Li‐Chen; Oparil, Suzanne

2017-01-01

Abstract Recruitment of neutrophils and monocytes/macrophages to the site of vascular injury is mediated by binding of chemoattractants to interleukin (IL) 8 receptors RA and RB (IL8RA/B) C‐C chemokine receptors (CCR) 2 and 5 expressed on neutrophil and monocyte/macrophage membranes. Endothelial cells (ECs) derived from rat‐induced pluripotent stem cells (RiPS) were transduced with adenovirus containing cDNA of IL8RA/B and/or CCR2/5. We hypothesized that RiPS‐ECs overexpressing IL8RA/B (RiPS‐IL8RA/B‐ECs), CCR2/5 (RiPS‐CCR2/5‐ECs), or both receptors (RiPS‐IL8RA/B+CCR2/5‐ECs) will inhibit inflammatory responses and neointima formation in balloon‐injured rat carotid artery. Twelve‐week‐old male Sprague‐Dawley rats underwent balloon injury of the right carotid artery and intravenous infusion of (a) saline vehicle, (b) control RiPS‐Null‐ECs (ECs transduced with empty virus), (c) RiPS‐IL8RA/B‐ECs, (d) RiPS‐CCR2/5‐ECs, or (e) RiPS‐IL8RA/B+CCR2/5‐ECs. Inflammatory mediator expression and leukocyte infiltration were measured in injured and uninjured arteries at 24 hours postinjury by enzyme‐linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. Neointima formation was assessed at 14 days postinjury. RiPS‐ECs expressing the IL8RA/B or CCR2/5 homing device targeted the injured arteries and decreased injury‐induced inflammatory cytokine expression, neutrophil/macrophage infiltration, and neointima formation. Transfused RiPS‐ECs overexpressing IL8RA/B and/or CCR2/5 prevented inflammatory responses and neointima formation after vascular injury. Targeted delivery of iPS‐ECs with a homing device to inflammatory mediators in injured arteries provides a novel strategy for the treatment of cardiovascular diseases. Stem Cells Translational Medicine 2017;6:1168–1177 PMID:28233474

Herbal remedy magnolol suppresses IL-6-induced STAT3 activation and gene expression in endothelial cells

PubMed Central

Chen, Shih-Chung; Chang, Ying-Ling; Wang, Danny Ling; Cheng, Jing-Jy

2006-01-01

Magnolol (Mag), an active constituent isolated from the Chinese herb Hou p'u (Magnolia officinalis) has long been used to suppress inflammatory processes. Chronic inflammation is well known to be involved in vascular injuries such as atherosclerosis in which interleukin (IL)-6 may participate. Signal transducer and activator of transcription protein 3 (STAT3), a transcription factor involved in inflammation and the cell cycle, is activated by IL-6. In this study, we evaluated whether Mag can serve as an anti-inflammatory agent during endothelial injuries. The effects of Mag on IL-6-induced STAT3 activation and downstream target gene induction in endothelial cells (ECs) were examined. Pretreatment of ECs with Mag dose dependently inhibited IL-6-induced Tyr705 and Ser727 phosphorylation in STAT3 without affecting the phosphorylation of JAK1, JAK2, and ERK1/2. Mag pretreatment of these ECs dose dependently suppressed IL-6-induced promoter activity of intracellular cell adhesion molecule (ICAM)-1 that contains functional IL-6 response elements (IREs). An electrophoretic mobility shift assay (EMSA) revealed that Mag treatment significantly reduced STAT3 binding to the IRE region. Consistently, Mag treatment markedly inhibited ICAM-1 expression on the endothelial surface. As a result, reduced monocyte adhesion to IL-6-activated ECs was observed. Furthermore, Mag suppressed IL-6-induced promoter activity of cyclin D1 and monocyte chemotactic protein (MCP)-1 for which STAT3 activation plays a role. In conclusion, our results indicate that Mag inhibits IL-6-induced STAT3 activation and subsequently results in the suppression of downstream target gene expression in ECs. These results provide a therapeutic basis for the development of Mag as an anti-inflammatory agent for vascular disorders including atherosclerosis. PMID:16520748

Changes in the vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and c-reactive protein following administration of aqueous extract of piper sarmentosum on experimental rabbits fed with cholesterol diet

PubMed Central

2011-01-01

Background Inflammation process plays an important role in the development of atherosclerosis. Hypercholesterolemia is one of the major risk factors for atherosclerosis. The present study aimed to evaluate the effect of aqueous extract of Piper sarmentosum (P.s) on inflammatory markers like vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and C-reactive protein (CRP). Methods Forty two male New Zealand white rabbits were divided equally into seven groups; (i) C- control group fed normal rabbit chow (ii) CH- cholesterol diet (1%cholesterol) (iii) X1- 1% cholesterol with water extract of P.s (62.5 mg/kg) (iv) X2- 1% cholesterol with water extract of P.s (125 mg/kg (v) X3- 1% cholesterol with water extract of P.s (250 mg/kg) (vi) X4- 1% cholesterol with water extract of P.s (500 mg/kg) and (vii) SMV group fed with 1% cholesterol supplemented with simvistatin drug (1.2 mg/kg). All animals were treated for 10 weeks. Blood serum was taken for observing the inflammatory markers at the beginning and end of the experiment. Results Rabbits fed with 1% cholesterol diet (CH) showed significant increase in the level of VCAM-1, ICAM-1 and CRP compared to the C group. The levels of VCAM-1, ICAM-1 and CRP in the 1% cholesterol group and supplemented with P.s (500 mg/kg) were significantly reduced compared to the cholesterol group. Similar results were also reported with simvistatin group. Conclusion These results suggest that the supplementation of Piper sarmentosum extract could inhibit inflammatory markers which in turn could prevent atherosclerosis. PMID:21214952

Activation of GPR4 by Acidosis Increases Endothelial Cell Adhesion through the cAMP/Epac Pathway

PubMed Central

Leffler, Nancy R.; Asch, Adam S.; Witte, Owen N.; Yang, Li V.

2011-01-01

Endothelium-leukocyte interaction is critical for inflammatory responses. Whereas the tissue microenvironments are often acidic at inflammatory sites, the mechanisms by which cells respond to acidosis are not well understood. Using molecular, cellular and biochemical approaches, we demonstrate that activation of GPR4, a proton-sensing G protein-coupled receptor, by isocapnic acidosis increases the adhesiveness of human umbilical vein endothelial cells (HUVECs) that express GPR4 endogenously. Acidosis in combination with GPR4 overexpression further augments HUVEC adhesion with U937 monocytes. In contrast, overexpression of a G protein signaling-defective DRY motif mutant (R115A) of GPR4 does not elicit any increase of HUVEC adhesion, indicating the requirement of G protein signaling. Downregulation of GPR4 expression by RNA interference reduces the acidosis-induced HUVEC adhesion. To delineate downstream pathways, we show that inhibition of adenylate cyclase by inhibitors, 2′,5′-dideoxyadenosine (DDA) or SQ 22536, attenuates acidosis/GPR4-induced HUVEC adhesion. Consistently, treatment with a cAMP analog or a Gi signaling inhibitor increases HUVEC adhesiveness, suggesting a role of the Gs/cAMP signaling in this process. We further show that the cAMP downstream effector Epac is important for acidosis/GPR4-induced cell adhesion. Moreover, activation of GPR4 by acidosis increases the expression of vascular adhesion molecules E-selectin, VCAM-1 and ICAM-1, which are functionally involved in acidosis/GPR4-mediated HUVEC adhesion. Similarly, hypercapnic acidosis can also activate GPR4 to stimulate HUVEC adhesion molecule expression and adhesiveness. These results suggest that acidosis/GPR4 signaling regulates endothelial cell adhesion mainly through the Gs/cAMP/Epac pathway and may play a role in the inflammatory response of vascular endothelial cells. PMID:22110680

The protective role of melatonin on L-arginine-induced acute pancreatitis in adult male albino rats.

PubMed

Sadek, A S; Khattab, R T

2017-01-01

Acute pancreatitis (AP) is an inflammatory disease that has an increasing incidence worldwide. AP is associated with high morbidity and mortality rates ranging 15-40% in its severe form. Oxidative stress plays an important role in pancreatic acinar cell injury in case of AP. Melatonin (Mel) is proven to have both antioxidant and anti-inflammatory effects. The aim of the work was to investigate the protective role of Mel against L-arginine (L-arg)-induced AP in adult male albino rats. Thirty-six adult male albino rats were used in this study. Animals were divided into four groups; Control group (Group A; n = 6), Mel group (Group B; n = 6), L-arg group (Group C; n = 12) receiving two doses of L-arg injection with 1 h interval in-between, and L-arg+Mel group (Group D; n = 12) receiving Mel 1 h after each L-arg injection. 24 h after the second L-arg injection, the serum levels of amylase (AM), lipase (LP), interleukin-6 (IL-6) and tumour necrotic factor-alpha (TNF-α) were determined. Then, pancreatic specimens were processed for histological and immunohistochemical staining with vascular endothelial growth factor (VEGF) and the area percentage of VEGF and collagen content were measured by digital image analysis. Microscopic examination revealed that animals received L-arg only (Group C) showed loss of the pancreatic lobular architecture with marked fibrosis, acinar degeneration, inflammatory reaction and marked oedema with vascular congestion. Also, L-arg-induced AP caused a significant elevation of the serum levels of AM, LP, IL-6. All these histo-pathological and serological parameters were markedly improved by Mel administration. Melatonin exhibits strong therapeutic effects in the course of AP. Hence, the use of Mel as adjuvant treatment in AP is recommended.

Differential Regulatory Role of Pituitary Adenylate Cyclase–Activating Polypeptide in the Serum-Transfer Arthritis Model

PubMed Central

Botz, Bálint; Bölcskei, Kata; Kereskai, László; Kovács, Miklós; Németh, Tamás; Szigeti, Krisztián; Horváth, Ildikó; Máthé, Domokos; Kovács, Noémi; Hashimoto, Hitoshi; Reglődi, Dóra; Szolcsányi, János; Pintér, Erika; Mócsai, Attila; Helyes, Zsuzsanna

2014-01-01

Objective Pituitary adenylate cyclase–activating polypeptide (PACAP) expressed in capsaicin-sensitive sensory neurons and immune cells has divergent functions in inflammatory and pain processes. This study was undertaken to investigate the involvement of PACAP in a mouse model of rheumatoid arthritis. Methods Arthritis was induced in PACAP−/− and wild-type (PACAP+/+) mice by K/BxN serum transfer. General features of the disease were investigated by semiquantitative scoring, plethysmometry, and histopathologic analysis. Mechano- and thermonociceptive thresholds and motor functions were also evaluated. Metabolic activity was assessed by positron emission tomography. Bone morphology was measured by in vivo micro–computed tomography, myeloperoxidase activity and superoxide production by bioluminescence imaging with luminol and lucigenin, respectively, and vascular permeability by fluorescent indocyanine green dye study. Results PACAP+/+ mice developed notable joint swelling, reduced grasping ability, and mechanical (but not thermal) hyperalgesia after K/BxN serum transfer. In PACAP−/− mice clinical scores and edema were significantly reduced, and mechanical hyperalgesia and motor impairment were absent, throughout the 2-week period of observation. Metabolic activity and superoxide production increased in the tibiotarsal joints of wild-type mice but were significantly lower in PACAP−/− animals. Myeloperoxidase activity in the ankle joints of PACAP−/− mice was significantly reduced in the early phase of arthritis, but increased in the late phase. Synovial hyperplasia was also significantly increased, and progressive bone spur formation was observed in PACAP-deficient mice only. Conclusion In PACAP-deficient mice with serum-transfer arthritis, joint swelling, vascular leakage, hyperalgesia, and early inflammatory cell accumulation are reduced; in the later phase of the disease, immune cell function and bone neoformation are increased. Elucidation of the underlying pathways of PACAP activity may open promising new avenues for development of therapy in inflammatory arthritis. PMID:25048575

Genetically Engineered Autologous Cells for Antiangiogenic Therapy of Breast Cancer

DTIC Science & Technology

2004-07-01

consisted of a large, fragmented avascular center surrounded by a thin band of vascularized matrix material, itself covered by a capsule of connective tissue...contained dead cells that showed features of coagulation necrosis . The minimal inflammatory response consisted of neutrophils scattered within the...vascularize most likely contributed to the death (coagulation necrosis ) of implanted MSCs localized in the implant core and to the fragmentation of the

NF1 Signal Transduction and Vascular Dysfunction

DTIC Science & Technology

2015-05-01

microenvironment that promotes much of the pathology associated with the disease . Moreover we hypothesize that a mechanistic consequence of the loss...obliteration of the normal red pulp architecture. In addition, we found significant peri-aveolar and peri-vascular inflammatory infiltrates in the lung...the mouse model of NF1 disease in the endothelium we proposed and have done experiments investigating the loss of endothelial NF1 in the adult

Heme Oxygenase in the Regulation of Vascular Biology: From Molecular Mechanisms to Therapeutic Opportunities

PubMed Central

Kim, Young-Myeong; Pae, Hyun-Ock; Park, Jeong Euy; Lee, Yong Chul; Woo, Je Moon; Kim, Nam-Ho; Choi, Yoon Kyung; Lee, Bok-Soo; Kim, So Ri

2011-01-01

Abstract Heme oxygenases (HOs) are the rate-limiting enzymes in the catabolism of heme into biliverdin, free iron, and carbon monoxide. Two genetically distinct isoforms of HO have been characterized: an inducible form, HO-1, and a constitutively expressed form, HO-2. HO-1 is a kind of stress protein, and thus regarded as a sensitive and reliable indicator of cellular oxidative stress. The HO system acts as potent antioxidants, protects endothelial cells from apoptosis, is involved in regulating vascular tone, attenuates inflammatory response in the vessel wall, and participates in angiogenesis and vasculogenesis. Endothelial integrity and activity are thought to occupy the central position in the pathogenesis of cardiovascular diseases. Cardiovascular disease risk conditions converge in the contribution to oxidative stress. The oxidative stress leads to endothelial and vascular smooth muscle cell dysfunction with increases in vessel tone, cell growth, and gene expression that create a pro-thrombotic/pro-inflammatory environment. Subsequent formation, progression, and obstruction of atherosclerotic plaque may result in myocardial infarction, stroke, and cardiovascular death. This background provides the rationale for exploring the potential therapeutic role for HO system in the amelioration of vascular inflammation and prevention of adverse cardiovascular outcomes. Antioxid. Redox Signal. 14, 137–167. PMID:20624029

Omega-3 Fatty acids and inflammation: novel interactions reveal a new step in neutrophil recruitment.

PubMed

Tull, Samantha P; Yates, Clara M; Maskrey, Benjamin H; O'Donnell, Valerie B; Madden, Jackie; Grimble, Robert F; Calder, Philip C; Nash, Gerard B; Rainger, G Ed

2009-08-01

Inflammation is a physiological response to tissue trauma or infection, but leukocytes, which are the effector cells of the inflammatory process, have powerful tissue remodelling capabilities. Thus, to ensure their precise localisation, passage of leukocytes from the blood into inflamed tissue is tightly regulated. Recruitment of blood borne neutrophils to the tissue stroma occurs during early inflammation. In this process, peptide agonists of the chemokine family are assumed to provide a chemotactic stimulus capable of supporting the migration of neutrophils across vascular endothelial cells, through the basement membrane of the vessel wall, and out into the tissue stroma. Here, we show that, although an initial chemokine stimulus is essential for the recruitment of flowing neutrophils by endothelial cells stimulated with the inflammatory cytokine tumour necrosis factor-alpha, transit of the endothelial monolayer is regulated by an additional and downstream stimulus. This signal is supplied by the metabolism of the omega-6-polyunsaturated fatty acid (n-6-PUFA), arachidonic acid, into the eicosanoid prostaglandin-D(2) (PGD(2)) by cyclooxygenase (COX) enzymes. This new step in the neutrophil recruitment process was revealed when the dietary n-3-PUFA, eicosapentaenoic acid (EPA), was utilised as an alternative substrate for COX enzymes, leading to the generation of PGD(3). This alternative series eicosanoid inhibited the migration of neutrophils across endothelial cells by antagonising the PGD(2) receptor. Here, we describe a new step in the neutrophil recruitment process that relies upon a lipid-mediated signal to regulate the migration of neutrophils across endothelial cells. PGD(2) signalling is subordinate to the chemokine-mediated activation of neutrophils, but without the sequential delivery of this signal, neutrophils fail to penetrate the endothelial cell monolayer. Importantly, the ability of the dietary n-3-PUFA, EPA, to inhibit this process not only revealed an unsuspected level of regulation in the migration of inflammatory leukocytes, it also contributes to our understanding of the interactions of this bioactive lipid with the inflammatory system. Moreover, it indicates the potential for novel therapeutics that target the inflammatory system with greater affinity and/or specificity than supplementing the diet with n-3-PUFAs.

Enhanced endothelial cell density on NiTi surfaces with sub-micron to nanometer roughness

PubMed Central

Samaroo, Harry D; Lu, Jing; Webster, Thomas J

2008-01-01

The shape memory effect and superelastic properties of NiTi (or Nitinol, a nickel-titanium alloy) have already attracted much attention for various biomedical applications (such as vascular stents, orthodontic wires, orthopedic implants, etc). However, for vascular stents, conventional approaches have required coating NiTi with anti-thrombogenic or anti-inflammatory drug-eluting polymers which as of late have proven problematic for healing atherosclerotic blood vessels. Instead of focusing on the use of drug-eluting anti-thrombogenic or anti-inflammatory proteins, this study focused on promoting the formation of a natural anti-thrombogenic and anti-inflammatory surface on metallic stents: the endothelium. In this study, we synthesized various NiTi substrates with different micron to nanometer surface roughness by using dissimilar dimensions of constituent NiTi powder. Endothelial cell adhesion on these compacts was compared with conventional commercially pure (cp) titanium (Ti) samples. The results after 5 hrs showed that endothelial cells adhered much better on fine grain (<60 μm) compared with coarse grain NiTi compacts (<100 μm). Coarse grain NiTi compacts and conventional Ti promoted similar levels of endothelial cell adhesion. In addition, cells proliferated more after 5 days on NiTi with greater sub-micron and nanoscale surface roughness compared with coarse grain NiTi. In this manner, this study emphasized the positive pole that NiTi with sub-micron to nanometer surface features can play in promoting a natural anti-thrombogenic and anti-inflammatory surface (the endothelium) on a vascular stent and, thus, suggests that more studies should be conducted on NiTi with sub-micron to nanometer surface features. PMID:18488418

Chronic periaortitis with thoracic aorta and epiaortic artery involvement: a systemic large vessel vasculitis?

PubMed

Palmisano, Alessandra; Urban, Maria L; Corradi, Domenico; Cobelli, Rocco; Alberici, Federico; Maritati, Federica; Versari, Annibale; Pipitone, Nicolò; Salvarani, Carlo; Buzio, Carlo; Vaglio, Augusto

2015-11-01

Chronic periaortitis (CP) is a rare disease characterized by fibro-inflammatory tissue surrounding the abdominal aorta and the iliac arteries. Anecdotal reports have shown that CP may also involve other vascular districts, particularly the thoracic aorta. The aim of this study was to investigate the thoracic aorta and epiaortic artery involvement in CP. Patients were eligible if they had undergone imaging studies assessing inflammatory involvement of the thoracic aorta and its major branches (e.g. contrast CT, MRI or PET-CT). We explored the patterns of thoracic vessel involvement and compared the clinical characteristics of patients with and without thoracic disease. Where available, we also reviewed the thoracic vascular/perivascular tissue biopsies. Of 153 CP patients seen between 1999 and 2012, 77 were eligible. Of these, 28 (36%) had thoracic involvement: 15 (54%) had thoracic periaortitis, with 7 also showing epiaortic artery involvement; 6 (21%) had periaortitis surrounding a thoracic aortic aneurysm, 2 of them with epiaortic artery involvement; 7 (25%) had a thoracic aortic aneurysm without periaortitis. Patients with thoracic disease were more frequently female (P = 0.01), were older (P = 0.001) and had a higher frequency of pain and constitutional symptoms (P = 0.02). Thoracic (peri)vascular biopsies revealed adventitial and peri-adventitial fibro-inflammatory patterns similar to those observed in abdominal CP. In about one-third of patients, CP also involves the thoracic aorta and the epiaortic arteries, which supports the hypothesis of a systemic inflammatory disease of the large arteries. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Estrogen Effects on Vascular Inflammation are Age-Dependent: Role of Estrogen Receptors

PubMed Central

Kapadia, Akash; Chen, Yiu-Fai; Szalai, Alexander J.; Oparil, Suzanne; Hage, Fadi G.

2014-01-01

Objective 17β-Estradiol (E2) offers cardiovascular protection in young female animals and postmenopausal women. In contrast, randomized trials of menopausal hormones carried out in older women have shown harm or no cardiovascular benefit. We hypothesize that E2 effects on vascular inflammation are age-dependent. Approach and Results Young (10-wk) and aged (52-wk) female C57BL/6 mice were used as source for primary cultures of bone marrow-derived macrophages (BMMs) and vascular smooth muscle cells (VSMCs). E2 pre-treatment of cells derived from young mice attenuated C-reactive protein (CRP)-induced expression of inflammatory mediators. In contrast, E2 pre-treatment of cells from aged mice did not alter (BMMs) or paradoxically exaggerated (VSMCs) inflammatory mediator response to CRP. Using E2 receptor (ER)-knockout mice, we demonstrated that E2 regulates inflammatory response to CRP in BMMs via ERα and in VSMCs via ERβ. BMMs derived from aged (vs. young) mice expressed significantly less ERα mRNA and protein. A selective ligand of the novel ER GPR30 reproduced the E2 effects in BMMs and VSMCs. Unlike in young mice, E2 did not reduce neointima formation in ligated carotid arteries of aged CRP transgenic mice. Conclusions E2 attenuates inflammatory response to CRP in BMMs and VSMCs derived from young but not aged mice and reduces neointima formation in injured carotid arteries of young but not aged CRP transgenic mice. ERα expression in BMMs is greatly diminished with aging. These data suggest that vasoprotective effects of E2 are age-dependent and may explain the vasotoxic effects of E2 seen in clinical trials of postmenopausal women. PMID:24876352

Relationship of C-reactive protein, metabolic syndrome and diabetes mellitus: potential role of statins.

PubMed Central

Nash, David T.

2005-01-01

Atherosclerosis and the metabolic derangements of insulin resistance, metabolic syndrome and diabetes mellitus are all associated with underlying inflammatory processes. C-reactive protein (CRP), a marker of inflammation, has been shown to be a strong independent predictor of vascular events. It adds to cardiovascular disease risk at all levels of low-density-lipoprotein cholesterol and Framingham risk scores, and elevated levels are also associated with increasing severity of the metabolic syndrome. The development of a simple, stable, noninvasive test to measure high-sensitivity CRP has provided a clinical tool that may have an important role in the identification and assessment of individuals likely to develop cardiovascular or metabolic disease. The role of CRP in predicting cardiovascular risk is less clear in African Americans, however, than in white populations. Statins and thiazolidinediones are being investigated for their potential role in the prevention and treatment of the inflammatory processes involved in the metabolic syndrome and cardiovascular disease. In the future, assessment of CRP levels may contribute importantly to clinical decision-making in reducing cardiovascular risk. PMID:16396052

Relationship of C-reactive protein, metabolic syndrome and diabetes mellitus: potential role of statins.

PubMed

Nash, David T

2005-12-01

Atherosclerosis and the metabolic derangements of insulin resistance, metabolic syndrome and diabetes mellitus are all associated with underlying inflammatory processes. C-reactive protein (CRP), a marker of inflammation, has been shown to be a strong independent predictor of vascular events. It adds to cardiovascular disease risk at all levels of low-density-lipoprotein cholesterol and Framingham risk scores, and elevated levels are also associated with increasing severity of the metabolic syndrome. The development of a simple, stable, noninvasive test to measure high-sensitivity CRP has provided a clinical tool that may have an important role in the identification and assessment of individuals likely to develop cardiovascular or metabolic disease. The role of CRP in predicting cardiovascular risk is less clear in African Americans, however, than in white populations. Statins and thiazolidinediones are being investigated for their potential role in the prevention and treatment of the inflammatory processes involved in the metabolic syndrome and cardiovascular disease. In the future, assessment of CRP levels may contribute importantly to clinical decision-making in reducing cardiovascular risk.

Increased Levels of Txa₂ Induced by Dengue Virus Infection in IgM Positive Individuals Is Related to the Mild Symptoms of Dengue.

PubMed

Oliveira, Eneida S; Colombarolli, Stella G; Nascimento, Camila S; Batista, Izabella C A; Ferreira, Jorge G G; Alvarenga, Daniele L R; de Sousa, Laís O B; Assis, Rafael R; Rocha, Marcele N; Alves, Érica A R; Calzavara-Silva, Carlos E

2018-02-28

The inflammatory process plays a major role in the prognosis of dengue. In this context, the eicosanoids may have considerable influence on the regulation of the Dengue virus -induced inflammatory process. To quantify the molecules involved in the cyclooxygenase and lipoxygenase pathways during Dengue virus infection, plasma levels of thromboxane A2, prostaglandin E2 and leukotriene B4; mRNA levels of thromboxane A2 synthase, prostaglandin E2 synthase, leukotriene A4 hydrolase, cyclooxygenase-2 and 5-lipoxygenase; and the levels of lipid bodies in peripheral blood leukocytes collected from IgM-positive and IgM-negative volunteers with mild dengue, and non-infected volunteers, were evaluated. Dengue virus infection increases the levels of thromboxane A2 in IgM-positive individuals as well as the amount of lipid bodies in monocytes in IgM-negative individuals. We suggest that increased levels of thromboxane A2 in IgM-positive individuals plays a protective role against the development of severe symptoms of dengue, such as vascular leakage.

Increased Levels of Txa2 Induced by Dengue Virus Infection in IgM Positive Individuals Is Related to the Mild Symptoms of Dengue

PubMed Central

Oliveira, Eneida S.; Colombarolli, Stella G.; Nascimento, Camila S.; Batista, Izabella C. A.; Ferreira, Jorge G. G.; Alvarenga, Daniele L. R.; de Sousa, Laís O. B.; Assis, Rafael R.; Rocha, Marcele N.; Alves, Érica A. R.; Calzavara-Silva, Carlos E.

2018-01-01

The inflammatory process plays a major role in the prognosis of dengue. In this context, the eicosanoids may have considerable influence on the regulation of the Dengue virus-induced inflammatory process. To quantify the molecules involved in the cyclooxygenase and lipoxygenase pathways during Dengue virus infection, plasma levels of thromboxane A2, prostaglandin E2 and leukotriene B4; mRNA levels of thromboxane A2 synthase, prostaglandin E2 synthase, leukotriene A4 hydrolase, cyclooxygenase-2 and 5-lipoxygenase; and the levels of lipid bodies in peripheral blood leukocytes collected from IgM-positive and IgM-negative volunteers with mild dengue, and non-infected volunteers, were evaluated. Dengue virus infection increases the levels of thromboxane A2 in IgM-positive individuals as well as the amount of lipid bodies in monocytes in IgM-negative individuals. We suggest that increased levels of thromboxane A2 in IgM-positive individuals plays a protective role against the development of severe symptoms of dengue, such as vascular leakage. PMID:29495587

Green Tea Extracts Epigallocatechin-3-gallate for Different Treatments

PubMed Central

Chu, Chenyu; Deng, Jia

2017-01-01

Epigallocatechin-3-gallate (EGCG), a component extracted from green tea, has been proved to have multiple effects on human pathological and physiological processes, and its mechanisms are discrepant in cancer, vascularity, bone regeneration, and nervous system. Although there are multiple benefits associated with EGCG, more and more challenges are still needed to get through. For example, EGCG shows low bioactivity via oral administration. This review focuses on effects of EGCG, including anti-cancer, antioxidant, anti-inflammatory, anticollagenase, and antifibrosis effects, to express the potential of EGCG and necessity of further studies in this field. PMID:28884125

Glycolipids from spinach suppress LPS-induced vascular inflammation through eNOS and NK-κB signaling.

PubMed

Ishii, Masakazu; Nakahara, Tatsuo; Araho, Daisuke; Murakami, Juri; Nishimura, Masahiro

2017-07-01

Glycolipids are the major constituent of the thylakoid membrane of higher plants and have a variety of biological and pharmacological activities. However, anti-inflammatory effects of glycolipids on vascular endothelial cells have not been elucidated. Here, we investigated the effect of glycolipids extracted from spinach on lipopolysaccharides (LPS)-induced endothelial inflammation and evaluated the underlying molecular mechanisms. Treatment with glycolipids from spinach had no cytotoxic effects on cultured human umbilical vein endothelial cells (HUVECs) and significantly blocked the expression of LPS-induced interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and intracellular adhesion molecule-1 (ICAM-1) in them. Glycolipids treatment also effectively suppressed monocyte adhesion to HUVECs. Treatment with glycolipids inhibited LPS-induced NF-κB phosphorylation and nuclear translocation. In addition, glycolipids treatment significantly promoted endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production in HUVECs. Furthermore, glycolipids treatment blocked LPS-induced inducible NOS (iNOS) expression in HUVECs. Pretreatment with a NOS inhibitor attenuated glycolipids-induced suppression of NF-κB activation and adhesion molecule expression, and abolished the glycolipids-mediated suppression of monocyte adhesion to HUVECs. These results indicate that glycolipids suppress LPS-induced vascular inflammation through attenuation of the NF-κB pathway by increasing NO production in endothelial cells. These findings suggest that glycolipids from spinach may have a potential therapeutic use for inflammatory vascular diseases. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Tofacitinib ameliorates murine lupus and its associated vascular dysfunction

PubMed Central

Furumoto, Yasuko; Smith, Carolyne K.; Blanco, Luz; Zhao, Wenpu; Brooks, Stephen R.; Thacker, Seth G; Abdalrahman, Zarzour; Sciumè, Giuseppe; Tsai, Wanxia L.; Trier, Anna M.; Nunez, Leti; Mast, Laurel; Hoffmann, Victoria; Remaley, Alan T.; O'Shea, John J.

2016-01-01

Objectives Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. To date, no drug targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a Janus kinase (JAK) inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis. While clinical trials have shown that tofacitinib exhibits significant clinical efficacy in various autoimmune diseases, its role in SLE and on its associated vascular pathology remains to be characterized. Methods MRL/lpr lupus-prone mice received tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm). Nephritis, skin inflammation, serum autoantibody levels and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular trap (NET) release, endothelium-dependent vasorelaxation and endothelial differentiation were compared in treated and untreated mice. Results Treatment with tofacitinib led to significant improvement in measures of disease activity including nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment reduced serum levels of pro-inflammatory cytokines and interferon responses in splenocytes and kidney tissue. Tofacitinib also modulated NET formation and significantly increased endothelium-dependent vasorelaxation and endothelial differentiation. The drug was effective as both preventive and therapeutic strategies. Conclusions Tofacitinib modulates the innate and adaptive immune responses, ameliorates murine lupus and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage. PMID:27429362

Effects of Olive Oil Phenolic Compounds on Inflammation in the Prevention and Treatment of Coronary Artery Disease

PubMed Central

de Souza, Priscilla Azambuja Lopes; Marcadenti, Aline; Portal, Vera Lúcia

2017-01-01

Coronary artery disease (CAD) is responsible for more than 7 million deaths worldwide. In the early stages of the development of atherosclerotic plaques, cardiovascular risk factors stimulate vascular endothelial cells, initiating an inflammatory process, fundamental in the pathogenesis of CAD. The inclusion of potentially cardioprotective foods, such as olive oil, to the diet, may aid in the control of these risk factors, and in the reduction of cytokines and inflammatory markers. The present review aims to address the interaction between phenolic compounds present in olive oil, and inflammation, in the prevention and treatment of CAD. In vitro and in vivo studies suggest that phenolic compounds, such as hydroxytyrosol, tyrosol, and their secoiridoid derivatives, may reduce the expression of adhesion molecules and consequent migration of immune cells, modify the signaling cascade and the transcription network (blocking the signal and expression of the nuclear factor kappa B), inhibit the action of enzymes responsible for the production of eicosanoids, and consequently, decrease circulating levels of inflammatory markers. Daily consumption of olive oil seems to modulate cytokines and inflammatory markers related to CAD in individuals at risk for cardiovascular diseases. However, clinical studies that have evaluated the effects of olive oil and its phenolic compounds on individuals with CAD are still scarce. PMID:28973999

Mitochondria-targeted antioxidant SkQ1 improves impaired dermal wound healing in old mice.

PubMed

Demyanenko, Ilya A; Popova, Ekaterina N; Zakharova, Vlada V; Ilyinskaya, Olga P; Vasilieva, Tamara V; Romashchenko, Valeria P; Fedorov, Artem V; Manskikh, Vasily N; Skulachev, Maxim V; Zinovkin, Roman A; Pletjushkina, Olga Yu; Skulachev, Vladimir P; Chernyak, Boris V

2015-07-01

The process of skin wound healing is delayed or impaired in aging animals. To investigate the possible role of mitochondrial reactive oxygen species (mtROS) in cutaneous wound healing of aged mice, we have applied the mitochondria-targeted antioxidant SkQ1. The SkQ1 treatment resulted in accelerated resolution of the inflammatory phase, formation of granulation tissue, vascularization and epithelization of the wounds. The wounds of SkQ1-treated mice contained increased amount of myofibroblasts which produce extracellular matrix proteins and growth factors mediating granulation tissue formation. This effect resembled SkQ1-induced differentiation of fibroblasts to myofibroblast, observed earlierin vitro. The Transforming Growth Factor beta (TGFb) produced by SkQ1-treated fibroblasts was found to stimulated motility of endothelial cells in vitro, an effect which may underlie pro-angiogenic action of SkQ1 in the wounds. In vitro experiments showed that SkQ1 prevented decomposition of VE-cadherin containing contacts and following increase in permeability of endothelial cells monolayer, induced by pro-inflammatory cytokine TNF. Prevention of excessive reaction of endothelium to the pro-inflammatory cytokine(s) might account for anti-inflammatory effect of SkQ1. Our findings point to an important role of mtROS in pathogenesis of age-related chronic wounds.

Mitochondria-targeted antioxidant SkQ1 improves impaired dermal wound healing in old mice

PubMed Central

Zakharova, Vlada V.; Ilyinskaya, Olga P.; Vasilieva, Tamara V.; Romashchenko, Valeria P.; Fedorov, Artem V.; Manskikh, Vasily N.; Skulachev, Maxim V.; Zinovkin, Roman A.; Pletjushkina, Olga Yu.; Skulachev, Vladimir P.; Chernyak, Boris V.

2015-01-01

The process of skin wound healing is delayed or impaired in aging animals. To investigate the possible role of mitochondrial reactive oxygen species (mtROS) in cutaneous wound healing of aged mice, we have applied the mitochondria-targeted antioxidant SkQ1. The SkQ1 treatment resulted in accelerated resolution of the inflammatory phase, formation of granulation tissue, vascularization and epithelization of the wounds. The wounds of SkQ1-treated mice contained increased amount of myofibroblasts which produce extracellular matrix proteins and growth factors mediating granulation tissue formation. This effect resembled SkQ1-induced differentiation of fibroblasts to myofibroblast, observed earlier in vitro. The Transforming Growth Factor beta (TGFβ)produced by SkQ1-treated fibroblasts was found to stimulated motility of endothelial cells in vitro, an effect which may underlie pro-angiogenic action of SkQ1 in the wounds. In vitro experiments showed that SkQ1 prevented decomposition of VE-cadherin containing contacts and following increase in permeability of endothelial cells monolayer, induced by pro-inflammatory cytokine TNF. Prevention of excessive reaction of endothelium to the pro-inflammatory cytokine(s) might account for anti-inflammatory effect of SkQ1. Our findings point to an important role of mtROS in pathogenesis of age-related chronic wounds. PMID:26187706

PDGF-BB Promotes Type I IFN-Dependent Vascular Alterations and Monocyte Recruitment in a Model of Dermal Fibrosis.

PubMed

Cho, John S; Fang, Terry C; Reynolds, Taylor L; Sofia, Daniel J; Hamann, Stefan; Burkly, Linda C

2016-01-01

Systemic sclerosis (SSc) is a chronic autoimmune disorder that can result in extensive tissue damage in the skin and, in advanced cases, internal organs. Vasculopathy, aberrant immune activation, and tissue fibrosis are three hallmarks of the disease that have been identified, with vasculopathy and aberrant immunity being amongst the earliest events. However, a mechanistic link between these processes has not been established. Here, we have identified a novel role of platelet derived growth factor-BB (PDGF-BB)/PDGFRβ activation in combination with dermal injury induced by bleomycin as a driver of early, aberrant expression of interferon stimulatory genes (ISGs) and inflammatory monocyte infiltration. Activation of PDGFRβ in combination with bleomycin-induced dermal injury resulted in increased dermal thickness, vascular density, monocyte/macrophage infiltration, and exacerbation of tissue injury. Many of these features were dependent on IFNAR-signaling, and an increase in the number of interferon-beta (IFN-β) producing monocytes cells was found in the skin lesions. Taken together, these results identify a novel link between PDGFRβ activation, and Type I IFN-driven vascular maintenance and monocyte/macrophage cell recruitment, and provide a potential explanation linking key features of SSc that were previously thought to be unrelated.

Antioxidant and anti-inflammatory medicinal plants have potential role in the treatment of cardiovascular disease: a review.

PubMed

Adegbola, Peter; Aderibigbe, Ifewumi; Hammed, Wasiu; Omotayo, Tolulope

2017-01-01

Cardiovascular disease is a compound name for clusters of disorders afflicting the heart and blood vessels; it is assuming an increasing role as a major cause of morbidity and mortality. Unhealthy practices such as smoking, high intake of saturated fat and cholesterol, diabetes and physical inactivity are predisposing factors. The risk factors cause alteration in vascular integrity, compromised membrane integrity, increase free radical generation and reduced endogenous antioxidant system resulting in oxidative stress. Substance with ability to maintain vascular integrity, prevent, or reduce radical formation are able to treat cardiovascular disease. Conventional drugs in use to this effect are with side effect and as alternative, medicinal plants are increasingly gaining acceptance from the public and medical professionals. Reports have shown that bioactive compounds in plants with antioxidant, anti-inflammatory, ability to protect vascular endothelium, prevent lipid oxidation, and augment endogenous antioxidant system are cardioprotective. Phenolics and flavonoids in medicinal plants have been widely reported to play these major roles. This study reviewed the role of bioactive compounds in medicinal plants using a wide range database search.

Antioxidant and anti-inflammatory medicinal plants have potential role in the treatment of cardiovascular disease: a review

PubMed Central

Adegbola, Peter; Aderibigbe, Ifewumi; Hammed, Wasiu; Omotayo, Tolulope

2017-01-01

Cardiovascular disease is a compound name for clusters of disorders afflicting the heart and blood vessels; it is assuming an increasing role as a major cause of morbidity and mortality. Unhealthy practices such as smoking, high intake of saturated fat and cholesterol, diabetes and physical inactivity are predisposing factors. The risk factors cause alteration in vascular integrity, compromised membrane integrity, increase free radical generation and reduced endogenous antioxidant system resulting in oxidative stress. Substance with ability to maintain vascular integrity, prevent, or reduce radical formation are able to treat cardiovascular disease. Conventional drugs in use to this effect are with side effect and as alternative, medicinal plants are increasingly gaining acceptance from the public and medical professionals. Reports have shown that bioactive compounds in plants with antioxidant, anti-inflammatory, ability to protect vascular endothelium, prevent lipid oxidation, and augment endogenous antioxidant system are cardioprotective. Phenolics and flavonoids in medicinal plants have been widely reported to play these major roles. This study reviewed the role of bioactive compounds in medicinal plants using a wide range database search. PMID:28533927

Occlusion of retinal capillaries caused by glial cell proliferation in chronic ocular inflammation.

PubMed

Bianchi, E; Ripandelli, G; Feher, J; Plateroti, A M; Plateroti, R; Kovacs, I; Plateroti, P; Taurone, S; Artico, M

2015-01-01

The inner blood-retinal barrier is a gliovascular unit in which glial cells surround capillary endothelial cells and regulate retinal capillaries by paracrine interactions. During chronic ocular inflammation, microvascular complications can give rise to vascular proliferative lesions, which compromise visual acuity. This pathologic remodelling caused by proliferating Müller cells determines occlusion of retinal capillaries. The aim of the present study was to identify qualitative and quantitative alterations in the retinal capillaries in patients with post-traumatic chronic ocular inflammation or post-thrombotic vascular glaucoma. Moreover, we investigated the potential role of vascular endothelial growth factor (VEGF) and pro-inflammatory cytokines in retinal inflammation. Our electron microscopy findings demonstrated that during chronic ocular inflammation, thickening of the basement membrane, loss of pericytes and endothelial cells and proliferation of Müller cells occur with irreversible occlusion of retinal capillaries. Angiogenesis takes place as part of a regenerative reaction that results in fibrosis. We believe that VEGF and pro-inflammatory cytokines may be potential therapeutic targets in the treatment of this disease although further studies are required to confirm these findings.

Glycolaldehyde-derived advanced glycation end products (glycol-AGEs)-induced vascular smooth muscle cell dysfunction is regulated by the AGES-receptor (RAGE) axis in endothelium.

PubMed

Nam, Mi-Hyun; Son, Won-Rak; Lee, Young Sik; Lee, Kwang-Won

Advanced glycation end-products (AGEs) are involved in the development of vascular smooth muscle cell (VSMC) dysfunction and the progression of atherosclerosis. However, AGEs may indirectly affect VSMCs via AGEs-induced signal transduction between monocytes and human umbilical endothelial cells (HUVECs), rather than having a direct influence. This study was designed to elucidate the signaling pathway underlying AGEs-RAGE axis influence on VSMC dysfunction using a co-culture system with monocytes, HUVECs and VSMCs. AGEs stimulated production of reactive oxygen species and pro-inflammatory mediators such as tumor necrosis factor-α and interleukin-1β via extracellular-signal-regulated kinases phosphorylation and nuclear factor-κB activation in HUVECs. It was observed that AGEs-induced pro-inflammatory cytokines increase VSMC proliferation, inflammation and vascular remodeling in the co-culture system. This result implies that RAGE plays a role in AGEs-induced VSMC dysfunction. We suggest that the regulation of signal transduction via the AGEs-RAGE axis in the endothelium can be a therapeutic target for preventing atherosclerosis.

Arginase-I enhances vascular endothelial inflammation and senescence through eNOS-uncoupling.

PubMed

Zhu, Cuicui; Yu, Yi; Montani, Jean-Pierre; Ming, Xiu-Fen; Yang, Zhihong

2017-02-02

Augmented arginase-II (Arg-II) is implicated in endothelial senescence and inflammation through a mutual positive regulatory circuit with S6K1. This study was conducted to investigate whether Arg-I, another isoform of arginase that has been also reported to play a role in vascular endothelial dysfunction, promotes endothelial senescence through similar mechanisms. The non-senescent human endothelial cells from umbilical veins (passage 2 to 4) were transduced with empty recombinant adenovirus vector (rAd/CMV) as control or rAd/CMV-Arg-I to overexpress Arg-I. Overexpressing Arg-I promoted eNOS-uncoupling, enhanced senescence markers including p53-S15, p21 and senescence-associated β-galactosidase (SA-β-gal) staining, and increased inflammatory vascular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) as well as monocyte adhesion to endothelial cells without activating S6K1. All the effects of Arg-I were inhibited by the anti-oxidant N-acetylcysteine (NAC). Our study demonstrates that Arg-I promotes endothelial senescence and inflammatory responses through eNOS-uncoupling unrelated to activation of the S6K1 pathway.

VESGEN Mapping of Bioactive Protection against Intestinal Inflammation: Application to Human Spaceflight and ISS Experiments

NASA Technical Reports Server (NTRS)

Parsons-Wingerter, P. A.; Chen, X.; Kelly, C. P.; Reinecker, H. C.

2011-01-01

Challenges to successful space exploration and colonization include adverse physiological reactions to micro gravity and space radiation factors. Constant remodeling of the microvasculature is critical for tissue preservation, wound healing, and recovery after ischemia. Regulation of the vascular system in the intestine is particularly important to enable nutrient absorption while maintaining barrier function and mucosal defense against micro biota. Although tremendous progress has been made in understanding the molecular circuits regulating neovascularization, our knowledge of the adaptations of the vascular system to environmental challenges in the intestine remains incomplete. This is in part because of the lack of methods to observe and quantify the complex processes associated with vascular responses in vivo. Developed by GRC as a mature beta version, pre-release research software, VESsel GENeration Analysis (VESGEN) maps and quantifies the fractal-based complexity of vascular branching for novel insights into the cytokine, transgenic and therapeutic regulation of angiogenesis, lymphangiogenesis and microvascular remodeling. Here we demonstrate that VESGEN can be used to characterize the dynamic vascular responses to acute intestinal inflammation and mucosal recovery from in vivo confocal microscopic 3D image series. We induced transient intestinal inflammation in mice by DSS treatment and investigated whether the ability of the pro biotic yeast Saccharomyces boulardii (Sb) to protect against intestinal inflammation was due to regulation of vascular remodeling. A primary characteristic of inflammation is excessive neovascularization (angiogenesis) resulting in fragile vessels prone to bleeding. Morphological parameters for triplicate specimens revealed that Sb treatment greatly reduced the inflammatory response of vascular networks by an average of 78%. This resulted from Sb inhibition of vascular endothelial growth factor receptor signaling, a major angiogenesis signaling pathway. It needs to be determined whether pro biotic yeast represents a promising approach to GI protection in space. GRC performed only the VESGEN post-testing analysis.

Oral Administration of Linoleic Acid Induces New Vessel Formation and Improves Skin Wound Healing in Diabetic Rats.

PubMed

Rodrigues, Hosana G; Vinolo, Marco A R; Sato, Fabio T; Magdalon, Juliana; Kuhl, Carolina M C; Yamagata, Ana S; Pessoa, Ana Flávia M; Malheiros, Gabriella; Dos Santos, Marinilce F; Lima, Camila; Farsky, Sandra H; Camara, Niels O S; Williner, Maria R; Bernal, Claudio A; Calder, Philip C; Curi, Rui

2016-01-01

Impaired wound healing has been widely reported in diabetes. Linoleic acid (LA) accelerates the skin wound healing process in non-diabetic rats. However, LA has not been tested in diabetic animals. We investigated whether oral administration of pure LA improves wound healing in streptozotocin-induced diabetic rats. Dorsal wounds were induced in streptozotocin-induced type-1 diabetic rats treated or not with LA (0.22 g/kg b.w.) for 10 days. Wound closure was daily assessed for two weeks. Wound tissues were collected at specific time-points and used to measure fatty acid composition, and contents of cytokines, growth factors and eicosanoids. Histological and qPCR analyses were employed to examine the dynamics of cell migration during the healing process. LA reduced the wound area 14 days after wound induction. LA also increased the concentrations of cytokine-induced neutrophil chemotaxis (CINC-2αβ), tumor necrosis factor-α (TNF-α) and leukotriene B4 (LTB4), and reduced the expression of macrophage chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1). These results together with the histological analysis, which showed accumulation of leukocytes in the wound early in the healing process, indicate that LA brought forward the inflammatory phase and improved wound healing in diabetic rats. Angiogenesis was induced by LA through elevation in tissue content of key mediators of this process: vascular-endothelial growth factor (VEGF) and angiopoietin-2 (ANGPT-2). Oral administration of LA hastened wound closure in diabetic rats by improving the inflammatory phase and angiogenesis.

Vascular repair strategies in type 2 diabetes: novel insights

PubMed Central

Kuschnerus, Kira; Landmesser, Ulf

2015-01-01

Impaired functions of vascular cells are responsible for the majority of complications in patients with type 2 diabetes (T2D). Recently a better understanding of mechanisms contributing to development of vascular dysfunction and the role of systemic inflammatory activation and functional alterations of several secretory organs, of which adipose tissue has more recently been investigated, has been achieved. Notably, the progression of vascular disease within the context of T2D appears to be driven by a multitude of incremental signaling shifts. Hence, successful therapies need to target several mechanisms in parallel, and over a long time period. This review will summarize the latest molecular strategies and translational developments of cardiovascular therapy in patients with T2D. PMID:26543824

Hyaluronic Acid in Vascular and Immune Homeostasis during Normal Pregnancy and Preeclampsia

PubMed Central

Ziganshina, M. M.; Pavlovich, S. V.; Bovin, N. V.; Sukhikh, G. T.

2016-01-01

Preeclampsia (PE) is a multisystem pathologic state that clinically manifests itself after the 20th week of pregnancy. It is characterized by high maternal and perinatal morbidity and mortality. According to modern concepts, the impairment of trophoblast invasion into maternal spiral arteries, leading to the development of ischemia in placenta, is considered to be the major pathogenetic factor of PE development. Ischemic lesions initiate the development of a systemic inflammatory response (SIR) and endothelial dysfunction, which is the main cause of the multiple organ failure in PE. Some data has appear indicating the importance of a glycans-forming endothelial glycocalyx and extracellular matrix (ECM) for placenta morphogenesis, as well as their role in the regulation of vascular permeability and vascular tone in hypertension disorders and, in particular, PE. Since intact glycocalyx and ECM are considered to be the major factors that maintain the physiological vascular tone and adequate intercellular interactions, their value in PE pathogenesis is underestimated. This review is focused on hyaluronic acid (HA) as the key glycan providing the organization and stabilization of the ECM and glycocalyx, its distribution in tissues in the case of presence or absence of placental pathology, as well as on the regulatory function of hyaluronic acids of various molecular weights in different physiological and pathophysiological processes. The summarized data will provide a better understanding of the PE pathogenesis, with the main focus on glycopathology. PMID:27795844

Anti-inflammatory effects of methylthiouracil in vitro and in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ku, Sae-Kwang; Baek, Moon-Chang, E-mail: mcbaek@knu.ac.kr; Bae, Jong-Sup, E-mail: baejs@knu.ac.kr

The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases. Here, methylthiouracil (MTU), an antithyroid drug, was examined for its effects on lipopolysaccharide (LPS)-mediated vascular inflammatory responses. The anti-inflammatory activities of MTU were determined by measuring permeability, human neutrophil adhesion and migration, and activation of pro-inflammatory proteins in LPS-activated human umbilical vein endothelial cells and mice. We found that post-treatment with MTU inhibited LPS-induced barrier disruption, expression of cell adhesion molecules (CAMs), and adhesion/transendothelial migration of human neutrophils to human endothelial cells. MTU induced potent inhibition of LPS-inducedmore » endothelial cell protein C receptor (EPCR) shedding. It also suppressed LPS-induced hyperpermeability and neutrophil migration in vivo. Furthermore, MTU suppressed the production of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, and the activation of nuclear factor-κB (NF-κB) and extracellular regulated kinases (ERK) 1/2 by LPS. Moreover, post-treatment with MTU resulted in reduced LPS-induced lethal endotoxemia. These results suggest that MTU exerts anti-inflammatory effects by inhibiting hyperpermeability, expression of CAMs, and adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases. - Highlights: • MTU reduced LPS-mediated hyperpermeability in vitro and in vivo. • MTU inhibited LPS-mediated leukocyte adhesion and migration. • MTU inhibited LPS-mediated production of IL-6 and TNF-α. • MTU reduced LPS-mediated mortality and lung injury.« less

Vascular Hyperpermeability Response in Animals Systemically Exposed to Arsenic.

PubMed

Chen, Shih-Chieh; Chang, Chao-Yuah; Lin, Ming-Lu

2018-01-01

The mechanisms underlying cardiovascular diseases induced by chronic exposure to arsenic remain unclarified. The objectives of this study were to investigate whether increased vascular leakage is induced by inflammatory mustard oil in mice systemically exposed to various doses of arsenic and whether an increased vascular leakage response is still present in arsenic-fed mice after arsenic discontinuation for 2 or 6 months. ICR mice were fed water or various doses of sodium arsenite (10, 15, or 20 mg/kg/day; 5 days/week) for 8 weeks. In separate experiments, the mice were treated with sodium arsenite (20 mg/kg) for 2 or 8 weeks, followed by arsenic discontinuation for 2 or 6 months. Vascular permeability to inflammatory mustard oil was quantified using Evans blue (EB) techniques. Both arsenic-exposed and water-fed (control) mice displayed similar basal levels of EB leakage in the ears brushed with mineral oil, a vehicle of mustard oil. The levels of EB leakage induced by mustard oil in the arsenic groups fed with sodium arsenite (10 or 15 mg/kg) were similar to those of water-fed mice. However, increased levels of EB leakage in response to mustard oil stimulation were significantly higher in mice treated with sodium arsenite (20 mg/kg; high dose) than in arsenic-fed (10 or 15 mg/kg; low and middle doses) or control mice. After arsenic discontinuation for 2 or 6 months, mustard oil-induced vascular EB leakage in arsenic-fed (20 mg/kg) mice was similar to that in control mice. Dramatic increases in mustard oil-induced vascular leakage were only present in mice systemically exposed to the high arsenic dose, indicating the synergistic effects of the high arsenic dose and mustard oil.

VEGF-A expression by HSV-1–infected cells drives corneal lymphangiogenesis

PubMed Central

Wuest, Todd R.

2010-01-01

Inflammatory lymphangiogenesis plays a crucial role in the development of inflammation and transplant rejection. The mechanisms of inflammatory lymphangiogenesis during bacterial infection, toll-like receptor ligand administration, and wound healing are well characterized and depend on ligands for the vascular endothelial grow factor receptor (VEGFR) 3 that are produced by infiltrating macrophages. But inflammatory lymphangiogenesis in nonlymphoid tissues during chronic viral infection is unstudied. Herpes simplex virus 1 (HSV-1) infection of the cornea is a leading cause of blindness and depends on aberrant host immune responses to antigen within the normally immunologically privileged cornea. We report that corneal HSV-1 infection drives lymphangiogenesis and that corneal lymphatics persist past the resolution of infection. The mechanism of HSV-1–induced lymphangiogenesis was distinct from the described mechanisms of inflammatory lymphangiogenesis. HSV-1–elicited lymphangiogenesis was strictly dependent on VEGF-A/VEGFR-2 signaling but not on VEGFR-3 ligands. Macrophages played no role in the induction of lymphangiogenesis and were not a detectable source of VEGF-A. Rather, using VEGF-A reporter transgenic mice, we have identified infected epithelial cells as the primary source of VEGF-A during HSV-1 infection. Our results indicate that HSV-1 directly induces vascularization of the cornea through up-regulation of VEGF-A expression. PMID:20026662

Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease

PubMed Central

Jison, Maria L.; Munson, Peter J.; Barb, Jennifer J.; Suffredini, Anthony F.; Talwar, Shefali; Logun, Carolea; Raghavachari, Nalini; Beigel, John H.; Shelhamer, James H.; Danner, Robert L.; Gladwin, Mark T.

2016-01-01

In sickle cell disease, deoxygenation of intra-erythrocytic hemoglobin S leads to hemoglobin polymerization, erythrocyte rigidity, hemolysis, and microvascular occlusion. Ischemia-reperfusion injury, plasma hemoglobin-mediated nitric oxide consumption, and free radical generation activate systemic inflammatory responses. To characterize the role of circulating leukocytes in sickle cell pathogenesis we performed global transcriptional analysis of blood mononuclear cells from 27 patients in steady-state sickle cell disease (10 patients treated and 17 patients untreated with hydroxyurea) compared with 13 control subjects. We used gender-specific gene expression to validate human microarray experiments. Patients with sickle cell disease demonstrated differential gene expression of 112 genes involved in heme metabolism, cell-cycle regulation, antioxidant and stress responses, inflammation, and angiogenesis. Inducible heme oxygenase-1 and downstream proteins biliverdin reductase and p21, a cyclin-dependent kinase, were up-regulated, potentially contributing to phenotypic heterogeneity and absence of atherosclerosis in patients with sickle cell disease despite endothelial dysfunction and vascular inflammation. Hydroxyurea therapy did not significantly affect leukocyte gene expression, suggesting that such therapy has limited direct anti-inflammatory activity beyond leukoreduction. Global transcriptional analysis of circulating leukocytes highlights the intense oxidant and inflammatory nature of steady-state sickle cell disease and provides insight into the broad compensatory responses to vascular injury. PMID:15031206

Involvement of the different lung compartments in the pathogenesis of pH1N1 influenza virus infection in ferrets.

PubMed

Vidaña, Beatriz; Martínez, Jorge; Martorell, Jaime; Montoya, María; Córdoba, Lorena; Pérez, Mónica; Majó, Natàlia

2016-11-08

Severe cases after pH1N1 infection are consequence of interstitial pneumonia triggered by alveolar viral replication and an exacerbated host immune response, characterized by the up-regulation of pro-inflammatory cytokines and the influx of inflammatory leukocytes to the lungs. Different lung cell populations have been suggested as culprits in the unregulated innate immune responses observed in these cases. This study aims to clarify this question by studying the different induction of innate immune molecules by the distinct lung anatomic compartments (vascular, alveolar and bronchiolar) of ferrets intratracheally infected with a human pH1N1 viral isolate, by means of laser microdissection techniques. The obtained results were then analysed in relation to viral quantification in the different anatomic areas and the histopathological lesions observed. More severe lung lesions were observed at 24 h post infection (hpi) correlating with viral antigen detection in bronchiolar and alveolar epithelial cells. However, high levels of viral RNA were detected in all anatomic compartments throughout infection. Bronchiolar areas were the first source of IFN-α and most pro-inflammatory cytokines, through the activation of RIG-I. In contrast, vascular areas contributed with the highest induction of CCL2 and other pro-inflammatory cytokines, through the activation of TLR3.

A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation.

PubMed

Massberg, Steffen; Brand, Korbinian; Grüner, Sabine; Page, Sharon; Müller, Elke; Müller, Iris; Bergmeier, Wolfgang; Richter, Thomas; Lorenz, Michael; Konrad, Ildiko; Nieswandt, Bernhard; Gawaz, Meinrad

2002-10-07

The contribution of platelets to the process of atherosclerosis remains unclear. Here, we show in vivo that platelets adhere to the vascular endothelium of the carotid artery in ApoE(-)(/)(-) mice before the development of manifest atherosclerotic lesions. Platelet-endothelial cell interaction involved both platelet glycoprotein (GP)Ibalpha and GPIIb-IIIa. Platelet adhesion to the endothelium coincides with inflammatory gene expression and preceded atherosclerotic plaque invasion by leukocytes. Prolonged blockade of platelet adhesion in ApoE(-)(/)(-) mice profoundly reduced leukocyte accumulation in the arterial intima and attenuated atherosclerotic lesion formation in the carotid artery bifurcation, the aortic sinus, and the coronary arteries. These findings establish the platelet as a major player in initiation of the atherogenetic process.

Caffeoyl glucosides from Nandina domestica inhibit LPS-induced endothelial inflammatory responses.

PubMed

Kulkarni, Roshan R; Lee, Wonhwa; Jang, Tae Su; Lee, JungIn; Kwak, Soyoung; Park, Mi Seon; Lee, Hyun-Shik; Bae, Jong-Sup; Na, MinKyun

2015-11-15

Endothelial dysfunction is a key pathological feature of many inflammatory diseases, including sepsis. In the present study, a new caffeoyl glucoside (1) and two known caffeoylated compounds (2 and 3) were isolated from the fruits of Nandina domestica Thunb. (Berberidaceae). The compounds were investigated for their effects against lipopolysaccharide (LPS)-mediated endothelial inflammatory responses. At 20 μM, 1 and 2 inhibited LPS-induced hyperpermeability, adhesion, and migration of leukocytes across a human endothelial cell monolayer in a dose-dependent manner suggesting that 1 and 2 may serve as potential scaffolds for the development of therapeutic agents to treat vascular inflammatory disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.

Primary vascularization of allografts governs their immunogenicity and susceptibility to tolerogenesis

PubMed Central

Kant, Cavit D.; Akiyama, Yoshinobu; Tanaka, Katsunori; Shea, Susan; Connolly, Sarah E; Germana, Sharon; Winn, Henry J.; LeGuern, Christian; Tocco, Georges; Benichou, Gilles

2013-01-01

We investigated the influence of allograft primary vascularization on alloimmunity, rejection and tolerance in mice. First, we showed that fully allogeneic primarily vascularized and conventional skin transplants were rejected at the same pace. Remarkably, however, short-term treatment of mice with anti-CD40L antibodies achieved long-term survival of vascularized skin and cardiac transplants but not conventional skin grafts. Non-vascularized skin transplants triggered vigorous direct and indirect pro-inflammatory type 1 T cell responses (IL-2 and γIFN) while primarily-vascularized skin allografts failed to trigger a significant indirect alloresponse. Similar lack of indirect alloreactivity was also observed after placement of different vascularized organ transplants including hearts and kidneys while hearts placed under the skin (non-vascularized) triggers potent indirect alloresponses. Altogether, these results suggest that primary vascularization of allografts is associated with lack of indirect T cell alloreactivity. Finally, we show that long-term survival of vascularized skin allografts induced by anti-CD40L antibodies was associated with a combined lack of indirect alloresponse and a shift of the direct alloresponse towards a type 2 cytokine (IL-4, IL-10) secretion pattern but no activation/expansion of regulatory T cells. Therefore, primary vascularization of allografts governs their immunogenicity and tolerogenicity. PMID:23833234

Mechanism of the protective effects of the combined treatment with rhynchophylla total alkaloids and sinapine thiocyanate against a prothrombotic state caused by vascular endothelial cell inflammatory damage

PubMed Central

Li, Yunlun; Zhang, Xinya; Yang, Wenqing; Li, Chao; Chu, Yanjun; Jiang, Haiqiang; Shen, Zhenzhen

2017-01-01

The aim of the present study was to investigate the effect and the underlying mechanism of the combined treatment of rhynchophylla total alkaloids (RTA) and sinapine thiocyanate for protection against a prothrombotic state (PTS) associated with the tumor necrosis factor-alpha (TNF-α)-induced inflammatory injury of vascular endothelial cells (VECs). A TNF-α-induced VEC inflammatory injury model was established, and cell morphology of VECs was evaluated using scanning electron microscopy. In addition, reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to examine the mRNA and protein expression of coagulation-related factors, including nuclear factor-κB (NF-κB), transforming growth factor-β1 (TGF-β1), tissue factor (TF), plasminogen activator inhibitor (PAI-1), protease-activation receptors (PAR-1) and protein kinase C (PKC-α) in VECs. Combined treatment with RTA and sinapine thiocyanate was demonstrated to reduce, to a varying extent, the mRNA and protein expression of NF-κB, TGF-β1, TF, PAR-1, PKC-α and PAI-1. Furthermore, combined treatment with RTA and sinapine thiocyanate was able to downregulate the expression of coagulation-related factors in injured VECs, thereby inhibiting the PTS induced by vascular endothelial injury. The underlying mechanism is partially associated with the TF-mediated activation of the thrombin-receptor signaling pathway that suppresses coagulation during inflammation and balances fibrinolysis in order to inhibit fibrin generation and deposition. PMID:28587383

Red Grape Skin Polyphenols Blunt Matrix Metalloproteinase-2 and -9 Activity and Expression in Cell Models of Vascular Inflammation: Protective Role in Degenerative and Inflammatory Diseases.

PubMed

Calabriso, Nadia; Massaro, Marika; Scoditti, Egeria; Pellegrino, Mariangela; Ingrosso, Ilaria; Giovinazzo, Giovanna; Carluccio, Maria Annunziata

2016-08-29

Matrix metalloproteinases (MMPs) are endopeptidases responsible for the hydrolysis of various components of extracellular matrix. MMPs, namely gelatinases MMP-2 and MMP-9, contribute to the progression of chronic and degenerative diseases. Since gelatinases' activity and expression are regulated by oxidative stress, we sought to evaluate whether supplementation with polyphenol-rich red grape skin extracts modulated the matrix-degrading capacity in cell models of vascular inflammation. Human endothelial and monocytic cells were incubated with increasing concentrations (0.5-25 μg/mL) of Negroamaro and Primitivo red grape skin polyphenolic extracts (NSPE and PSPE, respectively) or their specific components (0.5-25 μmol/L), before stimulation with inflammatory challenge. NSPE and PSPE inhibited, in a concentration-dependent manner, endothelial invasion as well as the MMP-9 and MMP-2 release in stimulated endothelial cells, and MMP-9 production in inflamed monocytes, without affecting tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2. The matrix degrading inhibitory capacity was the same for both NSPE and PSPE, despite their different polyphenolic profiles. Among the main polyphenols of grape skin extracts, trans-resveratrol, trans-piceid, kaempferol and quercetin exhibited the most significant inhibitory effects on matrix-degrading enzyme activities. Our findings appreciate the grape skins as rich source of polyphenols able to prevent the dysregulation of vascular remodelling affecting degenerative and inflammatory diseases.

Inhibitive Effects of Quercetin on Myeloperoxidase-Dependent Hypochlorous Acid Formation and Vascular Endothelial Injury.

PubMed

Lu, Naihao; Sui, Yinhua; Tian, Rong; Peng, Yi-Yuan

2018-05-16

Myeloperoxidase (MPO) from activated neutrophils plays important roles in multiple human inflammatory diseases by catalyzing the formation of powerful oxidant hypochlorous acid (HOCl). As a major flavonoid in the human diet, quercetin has been suggested to act as antioxidant and anti-inflammatory agent in vitro and in vivo. In this study, we showed that quercetin inhibited MPO-mediated HOCl formation (75.0 ± 6.2% for 10 μM quercetin versus 100 ± 5.2% for control group, P < 0.01) and cytotoxicity to endothelial cells in vitro, while this flavonoid was nontoxic to endothelial cell cultures ( P > 0.05, all cases). Moreover, quercetin inhibited HOCl generation by stimulated neutrophils (a rich source of MPO) and protected endothelial cells from neutrophils-induced injury. Furthermore, quercetin could inhibit HOCl-induced endothelial dysfunction such as loss of cell viability, and decrease of nitric oxide formation in endothelial cells ( P < 0.05, all cases). Consistent with these in vitro data, quercetin attenuated lipopolysaccharide-induced endothelial dysfunction and increase of MPO activity in mouse aortas, while this flavonoid could protect against HOCl-mediated endothelial dysfunction in isolated aortas ( P < 0.05). Therefore, it was proposed that quercetin attenuated endothelial injury in inflammatory vasculature via inhibition of vascular-bound MPO-mediated HOCl formation or scavenging of HOCl. These data indicate that quercetin is a nontoxic inhibitor of MPO activity and MPO/neutrophils-induced cytotoxicity in endothelial cells and may be useful for targeting MPO-dependent vascular disease and inflammation.

Combinatorial Therapy with Acetylation and Methylation Modifiers Attenuates Lung Vascular Hyperpermeability in Endotoxemia-Induced Mouse Inflammatory Lung Injury

PubMed Central

Thangavel, Jayakumar; Malik, Asrar B.; Elias, Harold K.; Rajasingh, Sheeja; Simpson, Andrew D.; Sundivakkam, Premanand K.; Vogel, Stephen M.; Xuan, Yu-Ting; Dawn, Buddhadeb; Rajasingh, Johnson

2015-01-01

Impairment of tissue fluid homeostasis and migration of inflammatory cells across the vascular endothelial barrier are crucial factors in the pathogenesis of acute lung injury (ALI). The goal for treatment of ALI is to target pathways that lead to profound dysregulation of the lung endothelial barrier. Although studies have shown that chemical epigenetic modifiers can limit lung inflammation in experimental ALI models, studies to date have not examined efficacy of a combination of DNA methyl transferase inhibitor 5-Aza 2-deoxycytidine and histone deacetylase inhibitor trichostatin A (herein referred to as Aza+TSA) after endotoxemia-induced mouse lung injury. We tested the hypothesis that treatment with Aza+TSA after lipopolysaccharide induction of ALI through epigenetic modification of lung endothelial cells prevents inflammatory lung injury. Combinatorial treatment with Aza+TSA mitigated the increased endothelial permeability response after lipopolysaccharide challenge. In addition, we observed reduced lung inflammation and lung injury. Aza+TSA also significantly reduced mortality in the ALI model. The protection was ascribed to inhibition of the eNOS-Cav1-MLC2 signaling pathway and enhanced acetylation of histone markers on the vascular endothelial-cadherin promoter. In summary, these data show for the first time the efficacy of combinatorial Aza+TSA therapy in preventing ALI in lipopolysaccharide-induced endotoxemia and raise the possibility of an essential role of DNA methyl transferase and histone deacetylase in the mechanism of ALI. PMID:24929240

Mechanism of the protective effects of the combined treatment with rhynchophylla total alkaloids and sinapine thiocyanate against a prothrombotic state caused by vascular endothelial cell inflammatory damage.

PubMed

Li, Yunlun; Zhang, Xinya; Yang, Wenqing; Li, Chao; Chu, Yanjun; Jiang, Haiqiang; Shen, Zhenzhen

2017-06-01

The aim of the present study was to investigate the effect and the underlying mechanism of the combined treatment of rhynchophylla total alkaloids (RTA) and sinapine thiocyanate for protection against a prothrombotic state (PTS) associated with the tumor necrosis factor-alpha (TNF-α)-induced inflammatory injury of vascular endothelial cells (VECs). A TNF-α-induced VEC inflammatory injury model was established, and cell morphology of VECs was evaluated using scanning electron microscopy. In addition, reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to examine the mRNA and protein expression of coagulation-related factors, including nuclear factor-κB (NF-κB), transforming growth factor-β1 (TGF-β1), tissue factor (TF), plasminogen activator inhibitor (PAI-1), protease-activation receptors (PAR-1) and protein kinase C (PKC-α) in VECs. Combined treatment with RTA and sinapine thiocyanate was demonstrated to reduce, to a varying extent, the mRNA and protein expression of NF-κB, TGF-β1, TF, PAR-1, PKC-α and PAI-1. Furthermore, combined treatment with RTA and sinapine thiocyanate was able to downregulate the expression of coagulation-related factors in injured VECs, thereby inhibiting the PTS induced by vascular endothelial injury. The underlying mechanism is partially associated with the TF-mediated activation of the thrombin-receptor signaling pathway that suppresses coagulation during inflammation and balances fibrinolysis in order to inhibit fibrin generation and deposition.

Role of parnaparin in atherosclerosis.

PubMed

Bonomini, Francesca; Taurone, Samanta; Parnigotto, Pierpaolo; Zamai, Loris; Rodella, Luigi F; Artico, Marco; Rezzani, Rita

2016-12-01

Atherosclerosis is characterized by a proliferation of vascular smooth muscle cells (VSMCs) and their migration to the intima, which induces thickening of the intima itself, but the mechanism remains poorly understood. Low molecular weight heparin (LMWH) inhibits the proliferation of VSMCs. Previous studies have shown that a LMWH, parnaparin (PNP), acts on the processes of atherogenesis and atheroprogression in experimental animal models. The aim of this study was to investigate the involvement of oxidative stress, inflammation and VSMCs in the regulation of vascular wall homeostasis. We also considered the possibility of restoring vascular pathological changes using PNP treatment. In order to evaluate vascular remodelling in this study we have analysed the morphological changes in aortas of an animal model of atherosclerosis, apolipoprotein E-deficient mice (ApoE-/-) fed with a normal or a western diet without treatment or treated with PNP. We also analysed, by immunohistochemistry, the expression of proteins linked to atherogenesis and atheroprogression - an enzyme involved in oxidative stress, iNOS, examples of inflammatory mediators, such as tumour necrosis factor alpha (TNF-α), interleukins 1 and 6 (IL-1 and IL-6), and markers of VSMC changes, in particular plasminogen activator inhibitor-1 and thrombospondin-1 (PAI-1 and TSP-1). Our results could suggest that PNP downregulates VSMC proliferation and migration, mediated by PAI-1 and TSP-1, and reduces inflammation and oxidative stress in vessels. These data suggested that LMWH, in particular PNP, could be a theoretically practical tool in the prevention of atherosclerotic vascular modification. © 2017 The Authors. International Journal of Experimental Pathology © 2017 International Journal of Experimental Pathology.

Role of reactive oxygen and nitrogen species in the vascular responses to inflammation

PubMed Central

Kvietys, Peter R.; Granger, D. Neil

2012-01-01

Inflammation is a complex and potentially life-threatening condition that involves the participation of a variety of chemical mediators, signaling pathways, and cell types. The microcirculation, which is critical for the initiation and perpetuation of an inflammatory response, exhibits several characteristic functional and structural changes in response to inflammation. These include vasomotor dysfunction (impaired vessel dilation and constriction), the adhesion and transendothelial migration of leukocytes, endothelial barrier dysfunction (increased vascular permeability), blood vessel proliferation (angiogenesis), and enhanced thrombus formation. These diverse responses of the microvasculature largely reflect the endothelial cell dysfunction that accompanies inflammation and the central role of these cells in modulating processes as varied as blood flow regulation, angiogenesis, and thrombogenesis. The importance of endothelial cells in inflammation-induced vascular dysfunction is also predicated on the ability of these cells to produce and respond to reactive oxygen and nitrogen species. Inflammation seems to upset the balance between nitric oxide and superoxide within (and surrounding) endothelial cells, which is necessary for normal vessel function. This review is focused on defining the molecular targets in the vessel wall that interact with reactive oxygen species and nitric oxide to produce the characteristic functional and structural changes that occur in response to inflammation. This analysis of the literature is consistent with the view that reactive oxygen and nitrogen species contribute significantly to the diverse vascular responses in inflammation and supports efforts that are directed at targeting these highly reactive species to maintain normal vascular health in pathological conditions that are associated with acute or chronic inflammation. PMID:22154653

The WOMED model of benign thyroid disease: Acquired magnesium deficiency due to physical and psychological stressors relates to dysfunction of oxidative phosphorylation

PubMed Central

Moncayo, Roy; Moncayo, Helga

2014-01-01

Background The aim of this study was to discern whether a relation between biochemical parameters, sonography and musculoskeletal data exists in cases of hyperthyroidism and whether they are modifiable through supplementation with selenomethionine and magnesium citrate as well as by acupuncture and manual medicine methods. Results A direct correlation between whole blood selenium and serum magnesium was found in subjects without thyroid disease and in menopausal women while it was reversed in cases of thyroid diseases as well as in patients with depression, infection, and in infertile women. Vascularization indices were elevated in cases of newly diagnosed benign thyroid diseases. Musculoskeletal changes i.e. lateral tension and idiopathic moving toes, as well as situations of physical and psychological stress and minor trauma and infection led to an increase of vascularization. Magnesium levels correlated negatively with these two conditions. The supplementation brought a reduction of the vascularization indices and reduced the incidence of idiopathic moving toes. Treatment of lateral tension required manual medicine methods and acupuncture (gastrocnemius). A small subgroup of patients showed a further reduction of hyper-vascularization after receiving coenzyme Q10. Conclusions We interpret the elevated thyroid vascularization and low magnesium levels as signs of an inflammatory process related to the musculoskeletal changes. Improvement of thyroid function and morphology can be achieved after correcting the influence of stressors together with the supplementation regime. We hypothesize that the central biochemical event in thyroid disease is that of an acquired, altered mitochondrial function due to deficiency of magnesium, selenium, and coenzyme Q10. PMID:26675817

Decursin and decursinol angelate: molecular mechanism and therapeutic potential in inflammatory diseases.

PubMed

Shehzad, Adeeb; Parveen, Sajida; Qureshi, Munibah; Subhan, Fazli; Lee, Young Sup

2018-03-01

Epidemiological studies have shown that inflammation plays a critical role in the development and progression of various chronic diseases, including cancers, neurological diseases, hepatic fibrosis, diabetic retinopathy, and vascular diseases. Decursin and decursinol angelate (DA) are pyranocoumarin compounds obtained from the roots of Angelica gigas. Several studies have described the anti-inflammatory effects of decursin and DA. Decursin and DA have shown potential anti-inflammatory activity by modulating growth factors such as vascular endothelial growth factor, transcription factors such as signal transducer and activator of transcription 3 and nuclear factor kappa-light-chain-enhancer of activated B cells, cellular enzymes including matrix metalloproteinases cyclooxygenase, and protein kinases such as extracellular receptor kinase, phosphatidylinositol-3-kinase, and protein kinase C. These compounds have the ability to induce apoptosis by activating pro-apoptotic proteins and the caspase cascade, and reduced the expression of anti-apoptotic proteins such as B-cell lymphoma 2 and B-cell lymphoma-extra-large. Interaction with multiple molecular targets and cytotoxic effects, these two compounds are favorable candidates for treating various chronic inflammatory diseases such as cancers (prostate, breast, leukemia, cervical, and myeloma), rheumatoid arthritis, diabetic retinopathy, hepatic fibrosis, osteoclastogenesis, allergy, and Alzheimer's disease. We have summarized the preliminary studies regarding the biological effects of decursin and DA. In this review, we will also highlight the functions of coumarin compounds that can be translated to a clinical practice for the treatment and prevention of various inflammatory ailments.

Identification and pharmacological characterization of the anti-inflammatory principal of the leaves of dwarf elder (Sambucus ebulus L.)

PubMed Central

Schwaiger, Stefan; Zeller, Iris; Pölzelbauer, Petra; Frotschnig, Sandra; Laufer, Günther; Messner, Barbara; Pieri, Valerio; Stuppner, Hermann; Bernhard, David

2011-01-01

Aim of the study The performed investigations aimed on the identification of the anti-inflammatory principal of extracts of leaves of Sambucus ebulus L. (dwarf elder) in order to rationalize the traditional use of this plant for the treatment of chronically inflammatory diseases. Materials and methods Dwarf elder leaf extract was subjected to activity guided fractionation using inhibition of TNFα induced expression of vascular cell adhesion molecule 1 (VCAM-1) on the surface of human umbilical vein endothelial cells (HUVECs) as monitoring tool (positive control: parthenolide 10 μM, VCAM-1 expression (% of control): 5.35 ± 0.38%). Results Bio-guided isolation resulted in identification of ursolic acid as anti-inflammatory principal. Besides its inhibitory effects against TNFα induced expression of VCAM-1 (IC50 6.25 μM), ursolic acid inhibits also TNFα induced expression of ICAM-1 (IC50 value between 3.13 and 6.25 μM) (positive control: parthenolide 10 μM, ICAM-1 expression (% of control): 38.89 ± 16.6%). Toxic effects of ursolic acid on HUVECs can be drastically reduced using an enriched extract instead of the pure compound. Conclusions Our findings suggest an additional mechanism of the anti-inflammatory activity of ursolic acid by demonstrating its ability to inhibit TNFα-stimulated expression of VCAM-1 and ICAM-1 and support the traditional use of extracts and preparations of Sambucus ebulus L., rich in ursolic acid, for the treatment of chronically inflammatory processes. PMID:21040770

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) enhances vascular and renal damage induced by hyperlipidemic diet in ApoE-knockout mice.

PubMed

Muñoz-García, Begoña; Moreno, Juan Antonio; López-Franco, Oscar; Sanz, Ana Belén; Martín-Ventura, José Luis; Blanco, Julia; Jakubowski, Aniela; Burkly, Linda C; Ortiz, Alberto; Egido, Jesús; Blanco-Colio, Luis Miguel

2009-12-01

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily of cytokines. TWEAK binds and activates the Fn14 receptor, and may regulate apoptosis, inflammation, and angiogenesis, in different pathological conditions. We have evaluated the effect of exogenous TWEAK administration as well as the role of endogenous TWEAK on proinflammatory cytokine expression and vascular and renal injury severity in hyperlipidemic ApoE-knockout mice. ApoE(-/-) mice were fed with hyperlipidemic diet for 4 to 10 weeks, then randomized and treated with saline (controls), TWEAK (10 microg/kg/d), anti-TWEAK neutralizing mAb (1000 microg/kg/d), TWEAK plus anti-TWEAK antibody (10 microg TWEAK +1000 microg anti-TWEAK/kg/d), or nonspecific IgG (1000 microg/kg/d) daily for 9 days. In ApoE(-/-) mice, exogenous TWEAK administration in ApoE(-/-) mice induced activation of NF-kappaB, a key transcription factor implicated in the regulation of the inflammatory response, in vascular and renal lesions. Furthermore, TWEAK treatment increased chemokine expression (RANTES and MCP-1), as well as macrophage infiltration in atherosclerotic plaques and renal lesions. These effects were associated with exacerbation of vascular and renal damage. Conversely, treatment of ApoE(-/-) mice with an anti-TWEAK blocking mAb decreased NF-kappaB activation, proinflammatory cytokine expression, macrophage infiltration, and vascular and renal injury severity, indicating a pathological role for endogenous TWEAK. Finally, in murine vascular smooth muscle cells or tubular cells, either ox-LDL or TWEAK treatment increased expression and secretion of both RANTES and MCP-1. Furthermore, ox-LDL and TWEAK synergized for induction of MCP-1 and RANTES expression and secretion. Our results suggest that TWEAK exacerbates the inflammatory response associated with a high lipid-rich diet. TWEAK may be a novel therapeutic target to prevent vascular and renal damage associated with hyperlipidemia.

Regulation and function of endothelial glycocalyx layer in vascular diseases.

PubMed

Sieve, Irina; Münster-Kühnel, Anja K; Hilfiker-Kleiner, Denise

2018-01-01

In the vascular system, the endothelial surface layer (ESL) as the inner surface of blood vessels affects mechanotransduction, vascular permeability, rheology, thrombogenesis, and leukocyte adhesion. It creates barriers between endothelial cells and blood and neighbouring cells. The glycocalyx, composed of glycoconjugates and proteoglycans, is an integral component of the ESL and a key element in inter- and intracellular communication and tissue homeostasis. In pathophysiological conditions (atherosclerosis, infection, ischemia/reperfusion injury, diabetes, trauma and acute lung injury) glycocalyx-degrading factors, i.e. reactive oxygen and nitrogen species, matrix metalloproteinases, heparanase and sialidases, damage the ESL, thereby impairing endothelial functions. This leads to increased capillary permeability, leucocyte-endothelium interactions, thrombosis and vascular inflammation, the latter further driving glycocalyx destruction. The present review highlights current knowledge on the vasculoprotective role of the ESL, with specific emphasis on its remodelling in inflammatory vascular diseases and discusses its potential as a novel therapeutic target to treat vascular pathologies. Copyright © 2017 Elsevier Inc. All rights reserved.

Neuroprotective effect of formononetin in ameliorating learning and memory impairment in mouse model of Alzheimer's disease.

PubMed

Fei, Hong-Xin; Zhang, Ying-Bo; Liu, Ting; Zhang, Xiao-Jie; Wu, Shu-Liang

2018-01-01

Alzheimer's disease (AD) is the most common cause of dementia among elderly population. Deranged β-amyloid (Aβ) trafficking across the blood-brain barrier is known to be a critical element in the pathogenesis of AD. In the vascular endothelial cells of hippocampus, Aβ transport is mainly mediated by low-density lipoprotein-associated protein 1 (LRP1) and the receptor for advanced glycation end (RAGE) products; therefore, LRP1 and RAGE endothelial cells are potential therapeutic targets for AD. In this study, we explored the effects of Formononetin (FMN) on learning and memory improvement in APP/PS1 mice and the related mechanisms. We found that FMN significantly improved learning and memory ability by suppressing Aβ production from APP processing, RAGE-dependent inflammatory signaling and promoted LRP1-dependent cerebral Aβ clearance pathway. Moreover, FMN treatment alleviated ultrastructural changes in hippocampal vascular endothelial cells. In conclusion, we believe that FMN may be an efficacious and promising treatment for AD.

Subcutaneous haemangiosarcoma in a cockatiel (Nymphicus hollandicus).

PubMed

Sledge, D G; Radi, Z A; Miller, D L; Lynn, B S

2006-08-01

An ulcerated, 1 x 0.5 cm, subcutaneous mass on the craniolateral aspect of the right tibiotarsus of a 4-year-old male cockatiel was removed. Histologically, the neoplasm was non-encapsulated, infiltrative and composed of irregular vascular channels lined by branching and variably sized spindle-shaped cells with large vesicular nuclei, prominent nucleoli and rare mitoses. Surrounding these vascular channels were fibroblasts and mixed inflammatory cells. Neoplastic cells had diffuse immunoreactivity to factor VIII supporting a diagnosis of haemangiosarcoma.

Interleukin-6 overexpression induces pulmonary hypertension.

PubMed

Steiner, M Kathryn; Syrkina, Olga L; Kolliputi, Narasaish; Mark, Eugene J; Hales, Charles A; Waxman, Aaron B

2009-01-30

Inflammatory cytokine interleukin (IL)-6 is elevated in the serum and lungs of patients with pulmonary artery hypertension (PAH). Several animal models of PAH cite the potential role of inflammatory mediators. We investigated role of IL-6 in the pathogenesis of pulmonary vascular disease. Indices of pulmonary vascular remodeling were measured in lung-specific IL-6-overexpressing transgenic mice (Tg(+)) and compared to wild-type (Tg(-)) controls in both normoxic and chronic hypoxic conditions. The Tg(+) mice exhibited elevated right ventricular systolic pressures and right ventricular hypertrophy with corresponding pulmonary vasculopathic changes, all of which were exacerbated by chronic hypoxia. IL-6 overexpression increased muscularization of the proximal arterial tree, and hypoxia enhanced this effect. It also reproduced the muscularization and proliferative arteriopathy seen in the distal arteriolar vessels of PAH patients. The latter was characterized by the formation of occlusive neointimal angioproliferative lesions that worsened with hypoxia and were composed of endothelial cells and T-lymphocytes. IL-6-induced arteriopathic changes were accompanied by activation of proangiogenic factor, vascular endothelial growth factor, the proproliferative kinase extracellular signal-regulated kinase, proproliferative transcription factors c-MYC and MAX, and the antiapoptotic proteins survivin and Bcl-2 and downregulation of the growth inhibitor transforming growth factor-beta and proapoptotic kinases JNK and p38. These findings suggest that IL-6 promotes the development and progression of pulmonary vascular remodeling and PAH through proproliferative antiapoptotic mechanisms.

Genetic framework for GATA factor function in vascular biology.

PubMed

Linnemann, Amelia K; O'Geen, Henriette; Keles, Sunduz; Farnham, Peggy J; Bresnick, Emery H

2011-08-16

Vascular endothelial dysfunction underlies the genesis and progression of numerous diseases. Although the GATA transcription factor GATA-2 is expressed in endothelial cells and is implicated in coronary heart disease, it has been studied predominantly as a master regulator of hematopoiesis. Because many questions regarding GATA-2 function in the vascular biology realm remain unanswered, we used ChIP sequencing and loss-of-function strategies to define the GATA-2-instigated genetic network in human endothelial cells. In contrast to erythroid cells, GATA-2 occupied a unique target gene ensemble consisting of genes encoding key determinants of endothelial cell identity and inflammation. GATA-2-occupied sites characteristically contained motifs that bind activator protein-1 (AP-1), a pivotal regulator of inflammatory genes. GATA-2 frequently occupied the same chromatin sites as c-JUN and c-FOS, heterodimeric components of AP-1. Although all three components were required for maximal AP-1 target gene expression, GATA-2 was not required for AP-1 chromatin occupancy. GATA-2 conferred maximal phosphorylation of chromatin-bound c-JUN at Ser-73, which stimulates AP-1-dependent transactivation, in a chromosomal context-dependent manner. This work establishes a link between a GATA factor and inflammatory genes, mechanistic insights underlying GATA-2-AP-1 cooperativity and a rigorous genetic framework for understanding GATA-2 function in normal and pathophysiological vascular states.

Simvastatin attenuates the cerebral vascular endothelial inflammatory response in a rat traumatic brain injury.

PubMed

Wang, Kuo-Wei; Chen, Han-Jung; Lu, Kang; Liliang, Po-Chou; Liang, Cheng-Loong; Tsai, Yu-Duan; Cho, Chung-Lung

2014-01-01

Traumatic brain injury (TBI) leads to important and deleterious inflammation, as evidenced by edema, cytokine production, induction of nitric oxide synthase, and leukocyte infiltration. After TBI, the activation of cerebral vascular endothelial cells plays a crucial role in the pathogenesis of inflammation. In this study, we hypothesized that the activation of cerebral vascular endothelial cells plays a crucial role in the pathogenesis of inflammation and outcome after TBI. It may represent a key cellular target for statin therapy. In our study, cortical contusions were induced, and the effect of continuous treatment of simvastatin on behavior and inflammation in adult rats following experimental TBI was evaluated. The treatment group received 15 mg/kg of simvastatin daily for 3 days. Neurological function was assessed with the grip test. The results showed that the non-treatment control group had a significantly greater increase in ICAM-1 expression from pre-injury to the post-injury 72 h time point as compared to the expression in treatment group. The treatment group had better neurological function as evidenced in a grip test performed from baseline to 72 h. The analysis of a western blot test and pathology also demonstrated reduced ICAM-1 expression and a smaller area of damage and tissue loss. Our findings suggest that simvastatin could attenuate the activation of cerebral vascular endothelial inflammatory response and decrease the loss of neurological function and brain tissue.

Glatiramer acetate (GA) prevents TNF-α-induced monocyte adhesion to primary endothelial cells through interfering with the NF-κB pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wei, Guoqian; Zhang, Xueyan; Su, Zhendong

2015-01-30

Highlights: • GA inhibited TNF-α-induced binding of monocytes to endothelial cells. • GA inhibited the induction of adhesion molecules MCP-1, VCAM-1 and E-selectin. • GA inhibits NF-κB p65 nuclear translocation and transcriptional activity. • GA inhibits TNF-α-induced IκBα degradation. - Abstract: Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) is considered to be the major one contributing to the process of development of endothelial dysfunction. Exposure to TNF-α induces the expression of a number of proinflammatory chemokines, such as monocyte chemotactic protein-1 (MCP-1), and adhesion molecules, including vascular adhesion molecule-1 (VCAM-1) and E-selectin, which mediate the interaction of invading monocytesmore » with vascular endothelial cells. Glatiramer acetate (GA) is a licensed clinical drug for treating patients suffering from multiple sclerosis (MS). The effects of GA in vascular disease have not shown before. In this study, we found that GA significantly inhibited TNF-α-induced binding of monocytes to endothelial cells. Mechanistically, we found that GA ameliorated the upregulation of MCP-1, VCAM-1, and E-selectin induced by TNF-α. Notably, this process is mediated by inhibiting the nuclear translocation and activation of NF-κB. Our results also indicate that GA pretreatment attenuates the up-regulation of COX-2 and iNOS. These data suggest that GA might have a potential benefit in therapeutic endothelial dysfunction related diseases.« less

Hemorheological changes in ischemia-reperfusion: an overview on our experimental surgical data.

PubMed

Nemeth, Norbert; Furka, Istvan; Miko, Iren

2014-01-01

Blood vessel occlusions of various origin, depending on the duration and extension, result in tissue damage, causing ischemic or ischemia-reperfusion injuries. Necessary surgical clamping of vessels in vascular-, gastrointestinal or parenchymal organ surgery, flap preparation-transplantation in reconstructive surgery, as well as traumatological vascular occlusions, all present special aspects. Ischemia and reperfusion have effects on hemorheological state by numerous ways: besides the local metabolic and micro-environmental changes, by hemodynamic alterations, free-radical and inflammatory pathways, acute phase reactions and coagulation changes. These processes may be harmful for red blood cells, impairing their deformability and influencing their aggregation behavior. However, there are still many unsolved or non-completely answered questions on relation of hemorheology and ischemia-reperfusion. How do various organ (liver, kidney, small intestine) or limb ischemic-reperfusionic processes of different duration and temperature affect the hemorheological factors? What is the expected magnitude and dynamics of these alterations? Where is the border of irreversibility? How can hemorheological investigations be applied to experimental models using laboratory animals in respect of inter-species differences? This paper gives a summary on some of our research data on organ/tissue ischemia-reperfusion, hemorheology and microcirculation, related to surgical research and experimental microsurgery.

P2X receptor characterization and IL-1/IL-1Ra release from human endothelial cells.

PubMed

Wilson, H L; Varcoe, R W; Stokes, L; Holland, K L; Francis, S E; Dower, S K; Surprenant, A; Crossman, D C

2007-05-01

The pro-inflammatory cytokine, interleukin-1beta (IL-1beta), has been implicated in the pathogenesis of atherosclerosis, potentially via its release from vascular endothelium. Endothelial cells (EC) synthesize IL-1beta in response to inflammatory stimuli, but the demonstration and mechanism of release of IL-1 from ECs remains unclear. In activated monocytes, efficient release of bioactive IL-1beta occurred via activation of ATP-gated P2X(7) receptors (P2X(7)Rs). Activation of P2X(7)R in ECs from human umbilical vein (HUVECs) released IL-1 receptor antagonist (IL-1Ra). The purpose of this study was to provide a quantitative investigation of P2XR expression and function, in parallel with IL-1beta and IL-1Ra synthesis, processing and release, in HUVECs under pro-inflammatory conditions. Quantitative RT-PCR, immunoblotting, ELISA, flow cytometry, and whole-cell patch clamp recordings were used to determine protein expression and receptor function. IL-8-luciferase-reporter was used as an IL-1 sensitive bioassay. HUVECs expressed P2X(4)R and P2X(7)R subtypes and both were significantly up-regulated under inflammatory conditions. P2X(7)R currents were increased 3-fold by inflammatory stimuli, whereas no P2X(4)R-mediated currents were detected. Caspase-1, but not IL-1beta, was present intracellularly under basal conditions; inflammatory stimuli activated the synthesis of intracellular pro-IL-1beta and increased caspase-1 levels. Activation of P2X(7)Rs resulted in low-level release of bioactive IL-1beta and simultaneous release of IL-1Ra. The net biological effect of release was anti-inflammatory. Endothelial P2X(7)Rs induced secretion of both pro- and anti-inflammatory IL-1 receptor ligands, the balance of which may provide a means for altering the inflammatory state of the arterial vessel wall.

Protecting the BBB Endothelium against Cigarette Smoke-Induced Oxidative Stress Using Popular Antioxidants: Are they really beneficial?

PubMed Central

Kaisar, Mohammad Abul; Prasad, Shikha; Cucullo, Luca

2015-01-01

Blood Brain Barrier (BBB) exposed to realistic concentrations (comparable to a chronic heavy smoker) of Cigarette Smoke Extract (CSE) triggers a strong endothelial inflammatory which can lead to the onset of neurological disorders. The involvement of Reactive Oxygen Species (ROS) in this inflammatory cascade is evident from the up-regulation of nuclear factor erythroid 2 related factor 2 (Nrf-2), a transcription factor involved in anti-oxidant response signaling in CSE exposed endothelial cells. We have shown that pre-treatment with α-tocopherol and/or ascorbic acid is highly protective for the BBB, thus suggesting that, prophylactic administration of antioxidants can reduce CSE and/or inflammatory-dependent BBB damage. We have assessed and ranked the protective effects of 5 popular OTC antioxidants (Coenzyme Q10, Melatonin, Glutathione, Lipoic acid and Resveratrol) against CSE-induced BBB endothelial damage using hCMEC/D3 cells. The analysis of pro-inflammatory cytokines release by ELISA revealed that, resveratrol, lipoic acid melatonin and Co-Q10 inhibited the BBB endothelial release of pro-inflammatory cytokines IL-6 & IL-8, reduced (not Co-Q10) CSE-induced up-regulation of Platelet Endothelial Cell Adhesion Molecule -1 (PECAM-1), Vascular Endothelial Cell Adhesion Molecule-1 (VCAM-1) & E-selectin and inhibited monocytes-endothelial cell adhesion. The anti-inflammatory effects correlated with the anti-oxidative protection endowed by these compounds as evidenced by upregulation of NADPH: Quinone Oxidoreductase 1 (NQO1) and reduced cellular oxidative stress. CSE-induced release of Vascular Endothelial Growth Factor (VEGF) was inhibited by all tested compounds although the effect was not strictly dose-dependent. Further in vivo studies are required to validate our results and expand our current study to include combinatorial treatments. PMID:26410779

Anti-edematogenic and anti-inflammatory activity of the essential oil from Croton rhamnifolioides leaves and its major constituent 1,8-cineole (eucalyptol).

PubMed

Martins, Anita Oliveira Brito Pereira Bezerra; Rodrigues, Lindaiane Bezerra; Cesário, Francisco Rafael Alves Santana; de Oliveira, Maria Rayane Correia; Tintino, Cicera Datiane Morais; Castro, Fyama Ferreira E; Alcântara, Isabel Sousa; Fernandes, Maria Neyze Martins; de Albuquerque, Thaís Rodrigues; da Silva, Maria Sanadia Alexandre; de Sousa Araújo, Adriano Antunes; Júniur, Lucindo José Quintans; da Costa, José Galberto Martins; de Menezes, Irwin Rose Alencar; Wanderley, Almir Gonçalves

2017-12-01

The species Croton rhamnifolioides, belonging to the Croton genus, is known in ethnomedicine as "quebra faca" and is used in the treatment of stomach pain, vomiting and fever. This study aims to evaluate the anti-edematogenic and anti-inflammatory effect of Croton rhamnifolioides leaf essential oil (OEFC) and its major constituent: 1,8-cineole (eucalyptol). The essential oil was extracted from fresh leaves through a hydrodistillation system. The chemical analysis was determined by gas chromatography-mass spectrometry (GC-MS). The acute anti-inflammatory activity was determined from the models of: ear edema by the single application of croton oil, paw edema induced by: carrageenan, dextran, histamine and arachidonic acid, while vascular permeability was determined by Evans blue extravasation and chronic anti-inflammatory activity by granuloma induction using the implantation of cotton pellets. The GC-MS results identified and quantified 11 constituents, with the major component being 1,8-cineole (41.33%). The OEFC (20mg/mL) and 1,8-cineole (8.26mg/mL) significantly reduced the edema induced by croton oil by 42.1 and 34.9%, respectively. The OEFC (25, 50, 100 and 200mg/kg) and 1,8-cineole (10.33, 20.66, 41.33 and 82.66mg/kg) statistically reduced paw edema induced by carrageenan, dextran as well as vascular permeability (protein extravasation). The OEFC (25mg/kg) and 1,8-cineole (10.33mg/kg) demonstrated efficacy in reducing edema induced by histamine and arachidonic acid and granuloma. In conclusion, the OEFC and 1,8-cineole have anti-inflammatory activity in the acute and chronic phase, suggesting therapeutic potential as a source for the development of new anti-inflammatory agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Exploring the anti-inflammatory activity of a novel 2-phenylquinazoline analog with protection against inflammatory injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chatterjee, Nabanita; Das, Subhadip; Bose, Dipayan

Inflammation is a protective immune response against harmful stimuli whose long time continuation results in host disease. Quinazolinones are nitrogen containing heterocyclic compounds with wide spectrum of biological activities. The anticancer effect of a 3-(arylideneamino)‐phenylquinazoline-4(3H)-one derivative was reported earlier. The anti-inflammatory effect of these quinazolinone derivatives has now been examined in endotoxin stimulated macrophages and in different in vivo models of inflammation by measuring the proinflammatory cytokines (TNF-α, IL-1β and IL-6), mediators NO and NF-κB (by ELISA and western blot), and translocation of the nuclear factor kB (by immunocytochemical analysis). To elucidate the in vivo effect, mice endotoxin model wasmore » and the various levels of edema, inflammatory pain and vascular permeability were studied. One of the quinazolinone derivatives showed significant anti-inflammatory activity in stimulated macrophage cells by inhibiting the expression of TNF-α, IL-1β, IL-6, iNOS, COX-2, p-IκB and NF-κBp65. Significant (P < 0.01) improvement was observed in the mortality of endotoxemic mice. The carrageenan and formalin-induced paw edema thicknesses were found to be reduced significantly (P < 0.01) along with the reduction of pain, vascular permeability and edema induced by complete Freund's adjuvant (P < 0.01). These findings indicate that 3-(arylideneamino)‐phenylquinazoline-4(3H)-one derivative as a potential anti-inflammatory agent. -- Highlights: ► 2-phenylquinazoline analog suppresses the cytokines in stimulated macrophages. ► 2-phenylquinazoline analog down regulated NF-kB P65 translocation. ► Role of 2-phenylquinazoline analog in endotoximia and peripheral inflammations.« less

Biomarkers for Adverse Pregnancy Outcomes in Rheumatic Diseases.

PubMed

Soh, May Ching; Nelson-Piercy, Catherine

2017-05-01

Pregnancy is a delicate balance of angiogenic factors. Adverse pregnancy outcomes in the form of placental insufficiency occur when antiangiogenic factors predominate, which manifests as maternal-placental syndrome (MPS). Women with rheumatic disease are at increased risk of MPS. Endothelial damage from circulating antiangiogenic factors and other inflammatory molecules in combination with preexisting maternal vascular risk factors is the likely underlying pathophysiological process for MPS. It is likely that these changes persist, and additional "insults" from ongoing inflammation, medications, and disease damage contribute to the development of accelerated cardiovascular disease seen in young women with rheumatic disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Hepatoprotective effect of Caesalpinia gilliesii and Cajanus cajan proteins against acetoaminophen overdose-induced hepatic damage.

PubMed

Rizk, Maha Z; Aly, Hanan F; Abo-Elmatty, Dina M; Desoky, M M; Ibrahim, N; Younis, Eman A

2016-05-01

This study aims to evaluate two proteins derived from the seeds of the plants Cajanus cajan (Leguminosae) and Caesalpinia gilliesii (Leguminosae) for their abilities to ameliorate the toxic effects of chronic doses of acetoaminphen (APAP) through the determination of certain biochemical parameters including liver marker enzymes: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin. Also, total protein content and hepatic marker enzyme, lactate dehydrogenase were studied. Moreover, liver antioxidants, glutathione (GSH), nitric oxide, and lipid peroxides were determined in this study. Hepatic adenosine triphosphatase (ATPase), adenylate energy charge (ATP, adenosine diphosphate, adenosine monophosphate, and inorganic phosphate), and phosphate potential, serum interleukin-6, tumor necrosis factor-α, and myeloperoxidase were also examined in the present study. On the other hand, histopathological examination of intoxicated and liver treated with both proteins was taken into consideration. The present results show disturbances in all biochemical parameters and hepatic toxicity signs including mild vascular congestion, moderate inflammatory changes with moderate congested sinusoids, moderate nuclear changes (pyknosis), moderate centrilobular necrosis, fatty changes, nuclear pyknosis vascular congestion, and change in fatty centrilobular necrosis liver. Improvement in all biochemical parameters studied was noticed as a result of treatment intoxicated liver with C. gilliesii and C. cajan proteins either paracetamol with or post paracetamol treatment. These results were documented by the amelioration signs in rat's hepatic architecture. Thus, both plant protein extracts can upregulate and counteract the inflammatory process, minimize damage of the liver, delay disease progression, and reduce its complications. © The Author(s) 2014.

Diabetic foot syndrome: Immune-inflammatory features as possible cardiovascular markers in diabetes

PubMed Central

Tuttolomondo, Antonino; Maida, Carlo; Pinto, Antonio

2015-01-01

Diabetic foot ulcerations have been extensively reported as vascular complications of diabetes mellitus associated with a high degree of morbidity and mortality. Diabetic foot syndrome (DFS), as defined by the World Health Organization, is an “ulceration of the foot (distally from the ankle and including the ankle) associated with neuropathy and different grades of ischemia and infection”. Pathogenic events able to cause diabetic foot ulcers are multifactorial. Among the commonest causes of this pathogenic pathway it’s possible to consider peripheral neuropathy, foot deformity, abnormal foot pressures, abnormal joint mobility, trauma, peripheral artery disease. Several studies reported how diabetic patients show a higher mortality rate compared to patients without diabetes and in particular these studies under filled how cardiovascular mortality and morbidity is 2-4 times higher among patients affected by type 2 diabetes mellitus. This higher degree of cardiovascular morbidity has been explained as due to the observed higher prevalence of major cardiovascular risk factor, of asymptomatic findings of cardiovascular diseases, and of prevalence and incidence of cardiovascular and cerebrovascular events in diabetic patients with foot complications. In diabetes a fundamental pathogenic pathway of most of vascular complications has been reported as linked to a complex interplay of inflammatory, metabolic and procoagulant variables. These pathogenetic aspects have a direct interplay with an insulin resistance, subsequent obesity, diabetes, hypertension, prothrombotic state and blood lipid disorder. Involvement of inflammatory markers such as IL-6 plasma levels and resistin in diabetic subjects as reported by Tuttolomondo et al confirmed the pathogenetic issue of the a “adipo-vascular” axis that may contribute to cardiovascular risk in patients with type 2 diabetes. This “adipo-vascular axis” in patients with type 2 diabetes has been reported as characterized by lower plasma levels of adiponectin and higher plasma levels of interleukin-6 thus linking foot ulcers pathogenesis to microvascular and inflammatory events. The purpose of this review is to highlight the immune inflammatory features of DFS and its possible role as a marker of cardiovascular risk in diabetes patients and to focus the management of major complications related to diabetes such as infections and peripheral arteriopathy. PMID:25621212

Measuring Leukocyte Adhesion to (Primary) Endothelial Cells after Photon and Charged Particle Exposure with a Dedicated Laminar Flow Chamber

PubMed Central

Erbeldinger, Nadine; Rapp, Felicitas; Ktitareva, Svetlana; Wendel, Philipp; Bothe, Anna S.; Dettmering, Till; Durante, Marco; Friedrich, Thomas; Bertulat, Bianca; Meyer, Stephanie; Cardoso, M. C.; Hehlgans, Stephanie; Rödel, Franz; Fournier, Claudia

2017-01-01

The vascular endothelium interacts with all types of blood cells and is a key modulator of local and systemic inflammatory processes, for example, in the adhesion of blood leukocytes to endothelial cells (EC) and the following extravasation into the injured tissue. The endothelium is constantly exposed to mechanical forces caused by blood flow, and the resulting shear stress is essential for the maintenance of endothelial function. Changes in local hemodynamics are sensed by EC, leading to acute or persistent changes. Therefore, in vitro assessment of EC functionality should include shear stress as an essential parameter. Parallel-plate flow chambers with adjustable shear stress can be used to study EC properties. However, commercially available systems are not suitable for radiation experiments, especially with charged particles, which are increasingly used in radiotherapy of tumors. Therefore, research on charged-particle-induced vascular side effects is needed. In addition, α-particle emitters (e.g., radon) are used to treat inflammatory diseases at low doses. In the present study, we established a flow chamber system, applicable for the investigation of radiation induced changes in the adhesion of lymphocytes to EC as readout for the onset of an inflammatory reaction or the modification of a pre-existing inflammatory state. In this system, primary human EC are cultured under physiological laminar shear stress, subjected to a proinflammatory treatment and/or irradiation with X-rays or charged particles, followed by a coincubation with primary human lymphocytes (peripheral blood lymphocytes (PBL)). Analysis is performed by semiautomated quantification of fluorescent staining in microscopic pictures. First results obtained after irradiation with X-rays or helium ions indicate decreased adhesion of PBL to EC under laminar conditions for both radiation qualities, whereas adhesion of PBL under static conditions is not clearly affected by irradiation. Under static conditions, no radiation-induced changes in surface expression of adhesion molecules and activation of nuclear factor kappa B (NF-κB) signaling were observed after single cell-based high-throughput analysis. In subsequent studies, these investigations will be extended to laminar conditions. PMID:28620384

Specialized proresolving mediator targets for RvE1 and RvD1 in peripheral blood and mechanisms of resolution

PubMed Central

Fredman, Gabrielle; Serhan, Charles N.

2011-01-01

Inflammation when unchecked is associated with many prevalent disorders such as the classic inflammatory diseases arthritis and periodontal disease, as well as the more recent additions that include diabetes and cardiovascular maladies. Hence mechanisms to curtail the inflammatory response and promote catabasis are of immense interest. In recent years, evidence has prompted a paradigm shift whereby the resolution of acute inflammation is a biochemically active process regulated in part by endogenous PUFA (polyunsaturated fatty acid)-derived autacoids. Among these are a novel genus of SPMs (specialized proresolving mediators) that comprise novel families of mediators including lipoxins, resolvins, protectins and maresins. SPMs have distinct structures and act via specific G-protein seven transmembrane receptors that signal intracellular events on selective cellular targets activating proresolving programmes while countering pro-inflammatory signals. An appreciation of these endogenous pathways and mediators that control timely resolution opened a new terrain for therapeutic approaches targeted at stimulating resolution of local inflammation. In the present review, we provide an overview of the biosynthesis and actions of resolvin E1, underscoring its protective role in vascular systems and regulating platelet responses. We also give an overview of newly described resolution circuitry whereby resolvins govern miRNAs (microRNAs), and transcription factors that counter-regulate pro-inflammatory chemokines, cytokines and lipid mediators. PMID:21711247

Glucocorticoids and estrogens modulate the NF-κB pathway differently in the micro- and macrovasculature.

PubMed

Edgar, Abarca-Rojano; Judith, Pacheco-Yépez; Elisa, Drago-Serrano Maria; Rafael, Campos-Rodríguez

2013-12-01

Estrogens and glucocorticoids have synergistic effects in the micro and macrovasculature of endothelial cells (ECs), having pro-inflammatory effects in the former and inhibiting the expression of adhesion molecules in the latter. The molecular basis of these effects in the endothelium has not yet been clarified. We postulate that the ECs of the micro- and macrovasculature have different non-genomic mechanisms that regulate levels of preexisting complexes of glucocorticoids and estrogens with their respective receptors. Since these receptors are regulated by NF-κB, their expression could be critical to the activation of a pro- or anti-inflammatory response. In the macrovasculature the synergistic effects of estrogens and glucocorticoids on ECs may be through the inhibition of NF-κB, leading to the inhibition of the expression of inflammatory molecules. It seems likely that glucocorticoid-receptor and estrogen-receptor complexes directly bind to NF-κB proteins in the macrovasculature, resulting in the inhibition of an excessive proinflammatory response. Further insights into these processes may help clarify the role of the endothelial cells of different vascular beds during the inflammatory response and chronic inflammation, and thus contribute to the design of more effective therapeutic strategies for the prevention of diseases related to inflammation, including atherosclerosis, systemic lupus erythematosus and rheumatoid arthritis. Copyright © 2013 Elsevier Ltd. All rights reserved.

TWEAK: A New Player in Obesity and Diabetes

PubMed Central

Vendrell, Joan; Chacón, Matilde R.

2013-01-01

Obesity and type 2 diabetes (T2D) are associated with chronic low-grade inflammation. Mounting evidence suggests the involvement of an inflammatory switch in adipose tissue, both in mature adipocytes and immune-competent cells from the stromal vascular compartment, in the progression of obesity and insulin resistance. Several inflammatory cytokines secreted by obese adipose tissue, including TNFα and IL-6 have been described as hallmark molecules involved in this process, impairing insulin signaling in insulin-responsive organs. An increasing number of new molecules affecting the local and systemic inflammatory imbalance in obesity and T2D have been identified. In this complex condition, some molecules may exhibit opposing actions, depending on the cell type and on systemic or local influences. Tumor necrosis factor weak inducer of apoptosis (TWEAK), a cytokine of the tumor necrosis (TNF) superfamily, is gaining attention as an important player in chronic inflammatory diseases. TWEAK can exist as a full-length membrane-associated (mTWEAK) form and as a soluble (sTWEAK) form and, by acting through its cognate receptor Fn14, can control many cellular activities including proliferation, migration, differentiation, apoptosis, angiogenesis, and inflammation. Notably, sTWEAK has been proposed as a biomarker of cardiovascular diseases. Here, we will review the recent findings relating to TWEAK and its receptor within the context of obesity and the associated disorder T2D. PMID:24416031

TWEAK: A New Player in Obesity and Diabetes.

PubMed

Vendrell, Joan; Chacón, Matilde R

2013-12-30

Obesity and type 2 diabetes (T2D) are associated with chronic low-grade inflammation. Mounting evidence suggests the involvement of an inflammatory switch in adipose tissue, both in mature adipocytes and immune-competent cells from the stromal vascular compartment, in the progression of obesity and insulin resistance. Several inflammatory cytokines secreted by obese adipose tissue, including TNFα and IL-6 have been described as hallmark molecules involved in this process, impairing insulin signaling in insulin-responsive organs. An increasing number of new molecules affecting the local and systemic inflammatory imbalance in obesity and T2D have been identified. In this complex condition, some molecules may exhibit opposing actions, depending on the cell type and on systemic or local influences. Tumor necrosis factor weak inducer of apoptosis (TWEAK), a cytokine of the tumor necrosis (TNF) superfamily, is gaining attention as an important player in chronic inflammatory diseases. TWEAK can exist as a full-length membrane-associated (mTWEAK) form and as a soluble (sTWEAK) form and, by acting through its cognate receptor Fn14, can control many cellular activities including proliferation, migration, differentiation, apoptosis, angiogenesis, and inflammation. Notably, sTWEAK has been proposed as a biomarker of cardiovascular diseases. Here, we will review the recent findings relating to TWEAK and its receptor within the context of obesity and the associated disorder T2D.

Depot-Specific Response of Adipose Tissue to Diet-Induced Inflammation: The Retinoid-Related Orphan Receptor α (RORα) Involved?

PubMed

Kadiri, Sarah; Auclair, Martine; Capeau, Jacqueline; Antoine, Bénédicte

2017-11-01

Epididymal adipose tissue (EAT), a visceral fat depot, is more closely associated with metabolic dysfunction than inguinal adipose tissue (IAT), a subcutaneous depot. This study evaluated whether the nuclear receptor RORα, which controls inflammatory processes, could be implicated. EAT and IAT were compared in a RORα loss-of-function mouse (sg/sg) and in wild-type (WT) littermates, fed a standard diet (SD) or a Western diet (WD), to evaluate the impact of RORα expression on inflammatory status and on insulin sensitivity (IS) of each fat depot according to the diet. Sg/sg mice fed the SD exhibited a decreased inflammatory status and a higher IS in their fat depots than WT mice. WD-induced obesity had distinct effects on the two fat depots. In WT mice, EAT exhibited increased inflammation and insulin resistance while IAT showed reduced inflammation and improved IS, together with a depot-specific increase of RORα, and its target gene IκBα, in the stroma vascular fraction (SVF). Conversely, in sg/sg mice, WD increased inflammation and lowered IS of IAT but not of EAT. These findings suggest an anti-inflammatory role for RORα in response to WD, which occurs at the level of SVF of IAT, thus possibly contributing to the "healthy" expansion of IAT. © 2017 The Obesity Society.

Association of IGF-I and IGF-II with myofiber regeneration in vivo.

PubMed

Keller, H L; St Pierre Schneider, B; Eppihimer, L A; Cannon, J G

1999-03-01

This study examined expression of insulinlike growth factor (IGF) in the myofibers and nonmyofibrillar structures of murine soleus muscle following contraction-induced damage. Identifying the cellular sources of this myogenic growth factor could improve muscle rehabilitation strategies. Immunohistochemical analysis of muscle sections indicated that the number of myofibers expressing both IGF-I and IGF-II increased significantly at 4, 7, and 10 days following injury, compared with control. Muscle spindles and vascular tissue expressed only IGF-II, and staining intensity did not change following injury. The number of fibers expressing developmental myosin heavy chain increased significantly at 7 and 10 days postinjury, and these usually coexpressed IGF. No IGF-specific staining of interstitial/inflammatory cells was observed. Therefore, expression of IGF after mechanically induced fiber damage occurs exclusively within regenerating fibers without supplemental delivery of IGF to the tissue by inflammatory cells or changes in constitutive expression of IGF-II in vascular tissue.

Heme-mediated cell activation: the inflammatory puzzle of sickle cell anemia.

PubMed

Guarda, Caroline Conceição da; Santiago, Rayra Pereira; Fiuza, Luciana Magalhães; Aleluia, Milena Magalhães; Ferreira, Júnia Raquel Dutra; Figueiredo, Camylla Vilas Boas; Yahouedehou, Setondji Cocou Modeste Alexandre; Oliveira, Rodrigo Mota de; Lyra, Isa Menezes; Gonçalves, Marilda de Souza

2017-06-01

Hemolysis triggers the onset of several clinical manifestations of sickle cell anemia (SCA). During hemolysis, heme, which is derived from hemoglobin (Hb), accumulates due to the inability of detoxification systems to scavenge sufficiently. Heme exerts multiple harmful effects, including leukocyte activation and migration, enhanced adhesion molecule expression by endothelial cells and the production of pro-oxidant molecules. Area covered: In this review, we describe the effects of heme on leukocytes and endothelial cells, as well as the features of vascular endothelial cells related to vaso-occlusion in SCA. Expert commentary: Free Hb, heme and iron, potent cytotoxic intravascular molecules released during hemolysis, can exacerbate, modulate and maintain the inflammatory response, a main feature of SCA. Endothelial cells in the vascular environment, as well as leukocytes, can become activated via the molecular signaling effects of heme. Due to the hemolytic nature of SCA, hemolysis represents an interesting therapeutic target for heme-scavenging purposes.

Ursodeoxycholic acid impairs atherogenesis and promotes plaque regression by cholesterol crystal dissolution in mice.

PubMed

Bode, Niklas; Grebe, Alena; Kerksiek, Anja; Lütjohann, Dieter; Werner, Nikos; Nickenig, Georg; Latz, Eicke; Zimmer, Sebastian

2016-09-09

Atherosclerosis is a chronic inflammatory disease driven primarily by a continuous retention of cholesterol within the subendothelial space where it precipitates to form cholesterol crystals (CC). These CC trigger a complex inflammatory response through activation of the NLRP3 inflammasome and promote lesion development. Here we examined whether increasing cholesterol solubility with ursodeoxycholic acid (UDCA) affects vascular CC formation and ultimately atherosclerotic lesion development. UDCA mediated intracellular CC dissolution in macrophages and reduced IL-1β production. In ApoE(-/-) mice, UDCA treatment not only impaired atherosclerotic plaque development but also mediated regression of established vascular lesions. Importantly, mice treated with UDCA had decreased CC-depositions in atherosclerotic plaques compared to controls. Together, our data demonstrate that UDCA impaired CC and NLRP3 dependent inflammation by increasing cholesterol solubility and diminished atherosclerosis in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

Reperfusion Strategies in the Management of Extremity Vascular Injury with Ischaemia

DTIC Science & Technology

2012-01-01

pyruvate Reduction of inflammatory response Crawford et al .11  2011 British Journal of Surgery Society Ltd www.bjs.co.uk British Journal of Surgery...Iraq and Afghanistan. Ann Surg 2011 ; 253: 1184–1189. 2 Clouse WD, Rasmussen TE, Peck MA, Eliason JL, Cox MW, Bowser AN et al . In-theater management of...reperfusion. J Vasc Surg 2011 ; 53: 1052–1062. 5 Gifford SM, Aidinian G, Clouse WD, Fox CJ, Porras CA, Jones WT et al . Effect of temporary vascular shunting on

Inhibition of Hydrogen Sulfide-induced Angiogenesis and Inflammation in Vascular Endothelial Cells: Potential Mechanisms of Gastric Cancer Prevention by Korean Red Ginseng.

PubMed

Choi, Ki-Seok; Song, Heup; Kim, Eun-Hee; Choi, Jae Hyung; Hong, Hua; Han, Young-Min; Hahm, Ki Baik

2012-04-01

Previously, we reported that Helicobacter pylori-associated gastritis and gastric cancer are closely associated with increased levels of hydrogen sulfide (H2S) and that Korean red ginseng significantly reduced the severity of H. pylori-associated gastric diseases by attenuating H2S generation. Because the incubation of endothelial cells with H2S has been known to enhance their angiogenic activities, we hypothesized that the amelioration of H2S-induced gastric inflammation or angiogenesis in human umbilical vascular endothelial cells (HUVECs) might explain the preventive effect of Korean red ginseng on H. pylori-associated carcinogenesis. The expression of inflammatory mediators, angiogenic growth factors, and angiogenic activities in the absence or presence of Korean red ginseng extracts (KRGE) were evaluated in HUVECs stimulated with the H2S generator sodium hydrogen sulfide (NaHS). KRGE efficiently decreased the expression of cystathionine β-synthase and cystathionine γ-lyase, enzymes that are essential for H2S synthesis. Concomitantly, a significant decrease in the expression of inflammatory mediators, including cyclooxygenase-2 and inducible nitric oxide synthase, and several angiogenic factors, including interleukin (IL)-8, hypoxia inducible factor-1a, vascular endothelial growth factor, IL-6, and matrix metalloproteinases, was observed; all of these factors are normally induced after NaHS. An in vitro angiogenesis assay demonstrated that NaHS significantly increased tube formation in endothelial cells, whereas KRGE pretreatment significantly attenuated tube formation. NaHS activated p38 and Akt, increasing the expression of angiogenic factors and the proliferation of HUVECs, whereas KRGE effectively abrogated this H2S-activated angiogenesis and the increase in inflammatory mediators in vascular endothelial cells. In conclusion, KRGE was able to mitigate H2S-induced angiogenesis, implying that antagonistic action against H2S-induced angiogenesis may be the mechanism underlying the gastric cancer preventive effects of KRGE in H. pylori infection.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yamawaki, Hideyuki, E-mail: yamawaki@vmas.kitasato-u.ac.jp; Kameshima, Satoshi; Usui, Tatsuya

Highlights: Black-Right-Pointing-Pointer Chemerin is a novel adipocytokine with almost unknown function in vasculature. Black-Right-Pointing-Pointer Chemerin activates Akt/eNOS/NO pathways in endothelial cells. Black-Right-Pointing-Pointer Chemerin inhibits TNF-{alpha}-induced monocyte adhesion to endothelial cells. Black-Right-Pointing-Pointer Chemerin inhibits TNF-induced VCAM-1 via suppressing NF-{kappa}B and p38 signal. Black-Right-Pointing-Pointer Chemerin is anti-inflammatory through producing NO in vascular endothelium. -- Abstract: Chemerin is a recently identified adipocytokine which plays a role on inflammation and adipocytes metabolism. However, its function in vasculature is largely unknown. We examined the effects of chemerin on vascular endothelial inflammatory states. Treatment of human umbilical vein endothelial cells with chemerin (300 ng/ml, 20 min)more » induced phosphorylation of Akt (Ser473) and endothelial nitric oxide (NO) synthase (eNOS) (Ser1177). Consistently, chemerin increased intracellular cyclic GMP content. Pretreatment with chemerin (1-300 ng/ml, 24 h) significantly inhibited phosphorylation of nuclear factor (NF)-{kappa}B p65 (Ser536) and p38 as well as vascular cell adhesion molecule (VCAM)-1 expression induced by tumor necrosis factor (TNF)-{alpha} (5 ng/ml, 20 min-6 h). Inhibitor of NF-{kappa}B or p38 significantly inhibited the TNF-{alpha}-induced VCAM-1 expression. Chemerin also inhibited TNF-{alpha}-induced VCAM-1 expression in rat isolated aorta. Moreover, chemerin significantly inhibited monocytes adhesion to TNF-{alpha}-stimulated endothelial cells. The inhibitory effect of chemerin on TNF-{alpha}-induced VCAM-1 was reversed by a NOS inhibitor. Conversely, an NO donor, sodium nitroprusside significantly inhibited TNF-{alpha}-induced VCAM-1. The present results for the first time demonstrate that chemerin plays anti-inflammatory roles by preventing TNF-{alpha}-induced VCAM-1 expression and monocytes adhesion in vascular endothelial cells. The effect is mediated via inhibiting activation of NF-{kappa}B and p38 through stimulation of Akt/eNOS signaling and NO production.« less

C-reactive protein as a prognostic marker after lacunar stroke: levels of inflammatory markers in the treatment of stroke study.

PubMed

Elkind, Mitchell S V; Luna, Jorge M; McClure, Leslie A; Zhang, Yu; Coffey, Christopher S; Roldan, Ana; Del Brutto, Oscar H; Pretell, Edwin Javier; Pettigrew, L Creed; Meyer, Brett C; Tapia, Jorge; White, Carole; Benavente, Oscar R

2014-03-01

Inflammatory biomarkers predict incident and recurrent cardiac events, but their relationship to stroke prognosis is uncertain. We hypothesized that high-sensitivity C-reactive protein (hsCRP) predicts recurrent ischemic stroke after recent lacunar stroke. Levels of Inflammatory Markers in the Treatment of Stroke (LIMITS) was an international, multicenter, prospective ancillary biomarker study nested within Secondary Prevention of Small Subcortical Strokes (SPS3), a phase III trial in patients with recent lacunar stroke. Patients were assigned in factorial design to aspirin versus aspirin plus clopidogrel, and higher versus lower blood pressure targets. Patients had blood samples collected at enrollment and hsCRP measured using nephelometry at a central laboratory. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for recurrence risks before and after adjusting for demographics, comorbidities, and statin use. Among 1244 patients with lacunar stroke (mean age, 63.3±10.8 years), median hsCRP was 2.16 mg/L. There were 83 recurrent ischemic strokes (including 45 lacunes) and 115 major vascular events (stroke, myocardial infarction, and vascular death). Compared with the bottom quartile, those in the top quartile (hsCRP>4.86 mg/L) were at increased risk of recurrent ischemic stroke (unadjusted HR, 2.54; 95% CI, 1.30-4.96), even after adjusting for demographics and risk factors (adjusted HR, 2.32; 95% CI, 1.15-4.68). hsCRP predicted increased risk of major vascular events (top quartile adjusted HR, 2.04; 95% CI, 1.14-3.67). There was no interaction with randomized antiplatelet treatment. Among recent lacunar stroke patients, hsCRP levels predict the risk of recurrent strokes and other vascular events. hsCRP did not predict the response to dual antiplatelets. http://www.clinicaltrials.gov. Unique identifier: NCT00059306.

[Multiple facets of ADA2 deficiency: Vasculitis, auto-inflammatory disease and immunodeficiency: A literature review of 135 cases from literature].

PubMed

Fayand, A; Sarrabay, G; Belot, A; Hentgen, V; Kone-Paut, I; Grateau, G; Melki, I; Georgin-Lavialle, S

2018-04-01

Deficiency of adenosine deaminase 2 (DADA2) is a recently described auto-inflammatory disorder. It is an autosomal recessive inherited disease, caused by mutations in the ADA2 gene (formerly known as CECR1) encoding ADA2 enzyme. Besides its role in the purine metabolism, it has been postulated that ADA2 may act as a growth factor for endothelial cells and in the differenciation of monocytes. Thus, deficiency of ADA2 would lead to endothelial damage and a skewing of monocytes into M1 pro-inflammatory macrophage, causing DADA2 manifestations. Three core clinical features have been described: inflammatory-vascular signs, hematologic abnormalities and immunodeficiency. Clinically, patients display intermittent fever, cutaneous vascular manifestations, such as livedo, ischemic strokes, arthralgia and abdominal pain crisis. Corticosteroids and immunosuppressive agents (i.e. cyclophosphamide, azathioprine, ciclosporin, methotrexate) appear to be poorly effective. Although the mechanism has not been elucidated, anti-TNF agents have been proven efficient in DADA2 and should therefore be used as first line therapy for vasculitis. Role of anti-platelet and anticoagulant therapies in stroke-prophylaxis remains to be discussed, as those patients display a high risk of intracranial bleeding. Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Ionizing Radiation-Induced Immune and Inflammatory Reactions in the Brain

PubMed Central

Lumniczky, Katalin; Szatmári, Tünde; Sáfrány, Géza

2017-01-01

Radiation-induced late brain injury consisting of vascular abnormalities, demyelination, white matter necrosis, and cognitive impairment has been described in patients subjected to cranial radiotherapy for brain tumors. Accumulating evidence suggests that various degrees of cognitive deficit can develop after much lower doses of ionizing radiation, as well. The pathophysiological mechanisms underlying these alterations are not elucidated so far. A permanent deficit in neurogenesis, chronic microvascular alterations, and blood–brain barrier dysfunctionality are considered among the main causative factors. Chronic neuroinflammation and altered immune reactions in the brain, which are inherent complications of brain irradiation, have also been directly implicated in the development of cognitive decline after radiation. This review aims to give a comprehensive overview on radiation-induced immune alterations and inflammatory reactions in the brain and summarizes how these processes can influence cognitive performance. The available data on the risk of low-dose radiation exposure in the development of cognitive impairment and the underlying mechanisms are also discussed. PMID:28529513

Inflammation, Fracture and Bone Repair

PubMed Central

Loi, Florence; Córdova, Luis A.; Pajarinen, Jukka; Lin, Tzu-hua; Yao, Zhenyu; Goodman, Stuart B.

2016-01-01

The reconstitution of lost bone is a subject that is germane to many orthopaedic conditions including fractures and non-unions, infection, inflammatory arthritis, osteoporosis, osteonecrosis, metabolic bone disease, tumors, and periprosthetic particle-associated osteolysis. In this regard, the processes of acute and chronic inflammation play an integral role. Acute inflammation is initiated by endogenous or exogenous adverse stimuli, and can become chronic in nature if not resolved by normal homeostatic mechanisms. Dysregulated inflammation leads to increased bone resorption and suppressed bone formation. Crosstalk amongst inflammatory cells (polymorphonuclear leukocytes and cells of the monocyte-macrophage-osteoclast lineage) and cells related to bone healing (cells of the mesenchymal stem cell-osteoblast lineage and vascular lineage) is essential to the formation, repair and remodeling of bone. In this review, the authors provide a comprehensive summary of the literature related to inflammation and bone repair. Special emphasis is placed on the underlying cellular and molecular mechanisms, and potential interventions that can favorably modulate the outcome of clinical conditions that involve bone repair. PMID:26946132

Inflammatory and vascular placental lesions are associated with neonatal amplitude integrated EEG recording in early premature neonates

PubMed Central

Goshen, Sharon; Richardson, Justin; Drunov, VIadimir; Staretz Chacham, Orna; Shany, Eilon

2017-01-01

Introduction Placental histologic examination can assist in revealing the mechanism leading to preterm birth. Accumulating evidence suggests an association between intrauterine pathological processes, morbidity and mortality of premature infants, and their long term outcome. Neonatal brain activity is increasingly monitored in neonatal intensive care units by amplitude integrated EEG (aEEG) and indices of background activity and sleep cycling patterns were correlated with long term outcome. We hypothesized an association between types of placental lesions and abnormal neonatal aEEG patterns. Objective To determine the association between the placental lesions observed in extreme preterm deliveries, and their neonatal aEEG patterns and survival. Patients and methods This prospective cohort study included extreme premature infants, who were born ≤ 28 weeks of gestation, their placentas were available for histologic examination, and had a continues aEEG, soon after birth)n = 34). Infants and maternal clinical data were collected. aEEG data was assessed for percentage of depressed daily activity in the first 3 days of life and for sleep cycling. Associations of placental histology with clinical findings and aEEG activity were explored using parametric and non-parametric statistics. Results Twenty two out of the 34 newborns survived to discharge. Preterm prelabor rupture of membranes (PPROM) or chorioamnionitis were associated with placental lesions consistent with fetal amniotic fluid infection (AFI) or maternal under perfusion (MUP) (P < 0.05). Lesions consistent with fetal response to AFI were associated with absence of SWC pattern during the 1st day of life. Fetal-vascular-thrombo-occlusive lesions of inflammatory type were negatively associated with depressed cerebral activity during the 1st day of life, and with aEEG cycling during the 2nd day of life (P<0.05). Placental lesions associated with MUP were associated with depressed neonatal cerebral activity during the first 3 days of life (P = 0.007). Conclusions Depressed neonatal aEEG patterns are associated with placental lesions consistent with maternal under perfusion, and amniotic fluid infection of fetal type, but not with fetal thrombo-oclusive vascular disease of inflammatory type. Our findings highlight the association between the intrauterine mechanisms leading to preterm parturition and subsequent depressed neonatal cerebral function early after birth, which eventually may put premature infants at risk for abnormal neurodevelopmental outcome. PMID:28644831

Giant-cell arteritis without cranial manifestations

PubMed Central

de Boysson, Hubert; Lambert, Marc; Liozon, Eric; Boutemy, Jonathan; Maigné, Gwénola; Ollivier, Yann; Ly, Kim; Manrique, Alain; Bienvenu, Boris; Aouba, Achille

2016-01-01

Abstract Diagnosis of giant-cell arteritis (GCA) is challenging in the absence of cardinal cranial symptoms/signs. We aimed to describe the clinical presentation, diagnostic process, and disease course of GCA patients without cranial symptoms, and to compare them to those of patients with typical cranial presentation. In this retrospective multicenter study, we enrolled patients with GCA who satisfied at least 3 of the 5 American College of Rheumatology criteria for GCA, or 2 criteria associated with contributory vascular biopsy other than temporal artery biopsy or with demonstration of large-vessel involvement; underwent iconographic evaluation of large arterial vessels (aortic CT scan or a positron emission tomography with 18F-fluorodeoxyglucose combined with computed tomography (FDG-PET/CT) scan or cardiac echography combined with a large-vessel Doppler) at diagnosis. We divided the cohort into 2 groups, distinguishing between patients without cranial symptoms/signs (i.e., headaches, clinical temporal artery anomaly, jaw claudication, ophthalmologic symptoms) and those with cranial symptoms/signs. In the entire cohort of 143 patients, all of whom underwent vascular biopsy and vascular imaging, we detected 31 (22%) patients with no cranial symptoms/signs. In the latter, diagnosis was biopsy proven in an arterial sample in 23 cases (74% of patients, on a temporal site in 20 cases and on an extratemporal site in 3). One-third of these 31 patients displayed extracranial symptoms/signs whereas the remaining two-thirds presented only with constitutional symptoms and/or inflammatory laboratory test results. Compared to the 112 patients with cardinal cranial clinical symptoms/signs, patients without cranial manifestations displayed lower levels of inflammatory laboratory parameters (C-reactive level: 68 [9–250] mg/L vs 120 [3–120] mg/L; P < 0.01), highest rate of aorta and aortic branch involvement identified (19/31 (61%) vs 42/112 (38%); P = 0.02) and also a lower rate of disease relapse (12/31 (39%) vs 67/112 (60%); P = 0.04). Our results suggest that patients without cranial symptoms/signs are prone to lower inflammatory laboratory parameters, fewer relapses, and more large-vessel involvement than those displaying cardinal cranial manifestations. Further studies are therefore required in order to determine whether these 2 subgroups of patients have a different prognosis, and therefore warrant different therapeutic and monitoring regimens. PMID:27367984

A Critical Role of Platelet Adhesion in the Initiation of Atherosclerotic Lesion Formation

PubMed Central

Massberg, Steffen; Brand, Korbinian; Grüner, Sabine; Page, Sharon; Müller, Elke; Müller, Iris; Bergmeier, Wolfgang; Richter, Thomas; Lorenz, Michael; Konrad, Ildiko; Nieswandt, Bernhard; Gawaz, Meinrad

2002-01-01

The contribution of platelets to the process of atherosclerosis remains unclear. Here, we show in vivo that platelets adhere to the vascular endothelium of the carotid artery in ApoE − / − mice before the development of manifest atherosclerotic lesions. Platelet–endothelial cell interaction involved both platelet glycoprotein (GP)Ibα and GPIIb-IIIa. Platelet adhesion to the endothelium coincides with inflammatory gene expression and preceded atherosclerotic plaque invasion by leukocytes. Prolonged blockade of platelet adhesion in ApoE − / − mice profoundly reduced leukocyte accumulation in the arterial intima and attenuated atherosclerotic lesion formation in the carotid artery bifurcation, the aortic sinus, and the coronary arteries. These findings establish the platelet as a major player in initiation of the atherogenetic process. PMID:12370251

NS-398, a selective COX-2 inhibitor, inhibits proliferation of IL-1{beta}-stimulated vascular smooth muscle cells by induction of {eta}{omicron}-1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Hyoung Chul; Kim, Hee Sun; Lee, Kwang Youn

2008-11-28

We investigated whether NS-398, a selective inhibitor of COX-2, induces HO-1 in IL-1{beta}-stimulated vascular smooth muscle cells (VSMC). NS-398 reduced the production of PGE{sub 2} without modulation of expression of COX-2 in IL-1{beta}-stimulated VSMC. NS-398 increased HO-1 mRNA and protein in a dose-dependent manner, but inhibited proliferation of IL-1{beta}-stimulated VSMC. Furthermore, SnPPIX, a HO-1 inhibitor, reversed the effects of NS-398 on PGE{sub 2} production, suggesting that COX-2 activity can be affected by HO-1. Hemin, a HO-1 inducer, also reduced the production of PGE{sub 2} and proliferation of IL-1{beta}-stimulated VSMC. CORM-2, a CO-releasing molecule, but not bilirubin inhibited proliferation of IL-1{beta}-stimulatedmore » VSMC. NS-398 inhibited proliferation of IL-1{beta}-stimulated VSMC in a HbO{sub 2}-sensitive manner. In conclusion, NS-398 inhibits proliferation of IL-1{beta}-stimulated VSMC by HO-1-derived CO. Thus, NS-398 may facilitate the healing process of vessels in vascular inflammatory disorders such as atherosclerosis.« less

Boron and Poloxamer (F68 and F127) Containing Hydrogel Formulation for Burn Wound Healing.

PubMed

Demirci, Selami; Doğan, Ayşegül; Karakuş, Emre; Halıcı, Zekai; Topçu, Atila; Demirci, Elif; Sahin, Fikrettin

2015-11-01

Burn injuries, the most common and destructive forms of wounds, are generally accompanied with life-threatening infections, inflammation, reduced angiogenesis, inadequate extracellular matrix production, and lack of growth factor stimulation. In the current study, a new antimicrobial carbopol-based hydrogel formulated with boron and pluronic block copolymers was evaluated for its healing activity using in vitro cell culture techniques and an experimental burn model. Cell viability, gene expression, and wound healing assays showed that gel formulation increased wound healing potential. In vitro tube-like structure formation and histopathological examinations revealed that gel not only increased wound closure by fibroblastic cell activity, but also induced vascularization process. Moreover, gel formulation exerted remarkable antimicrobial effects against bacteria, yeast, and fungi. Migration, angiogenesis, and contraction-related protein expressions including collagen, α-smooth muscle actin, transforming growth factor-β1, vimentin, and vascular endothelial growth factor were considerably enhanced in gel-treated groups. Macrophage-specific antigen showed an oscillating expression at the burn wounds, indicating the role of initial macrophage migration to the wound site and reduced inflammation phase. This is the first study indicating that boron containing hydrogel is able to heal burn wounds effectively. The formulation promoted burn wound healing via complex mechanisms including stimulation of cell migration, growth factor expression, inflammatory response, and vascularization.

Pictorial essay: Vascular interventions in extra cranial head and neck

PubMed Central

Kulkarni, Suyash S; Shetty, Nitin S; Dharia, Tejas P; Polnaya, Ashwin M

2012-01-01

Medicine is an ever changing field and interventional radiology (IR) procedures are becoming increasingly popular because of high efficacy and its minimally invasive nature of the procedure. Management of disease processes in the extra cranial head and neck (ECHN) has always been a challenge due to the complex anatomy of the region. Cross sectional imaging of the ECHN has grown and evolved tremendously and occupies a pivotal and integral position in the clinical management of variety of head and neck pathologies. Advances in angiographic technologies including flat panel detector systems, biplane, and 3-dimensional rotational angiography have consolidated and expanded the role of IR in the management of various ECHN pathologies. The ECHN is at cross roads between the origins of great vessels and the cerebral vasculature. Thorough knowledge of functional and technical aspects of neuroangiography is essential before embarking on head and neck vascular interventions. The vessels of the head and neck can be involved by infectious and inflammatory conditions, get irradiated during radiotherapy and injured due to trauma or iatrogenic cause. The ECHN is also a common site for various hypervascular neoplasms and vascular malformations, which can be treated with endovascular and percutaneous embolization. This pictorial essay provides a review of variety of ECHN pathologies which were managed by various IR procedures using different approaches. PMID:23833428

Is Pulp Inflammation a Prerequisite for Pulp Healing and Regeneration?

PubMed

Goldberg, Michel; Njeh, Akram; Uzunoglu, Emel

2015-01-01

The importance of inflammation has been underestimated in pulpal healing, and in the past, it has been considered only as an undesirable effect. Associated with moderate inflammation, necrosis includes pyroptosis, apoptosis, and nemosis. There are now evidences that inflammation is a prerequisite for pulp healing, with series of events ahead of regeneration. Immunocompetent cells are recruited in the apical part. They slide along the root and migrate toward the crown. Due to the high alkalinity of the capping agent, pulp cells display mild inflammation, proliferate, and increase in number and size and initiate mineralization. Pulp fibroblasts become odontoblast-like cells producing type I collagen, alkaline phosphatase, and SPARC/osteonectin. Molecules of the SIBLING family, matrix metalloproteinases, and vascular and nerve mediators are also implicated in the formation of a reparative dentinal bridge, osteo/orthodentin closing the pulp exposure. Beneath a calciotraumatic line, a thin layer identified as reactionary dentin underlines the periphery of the pulp chamber. Inflammatory and/or noninflammatory processes contribute to produce a reparative dentinal bridge closing the pulp exposure, with minute canaliculi and large tunnel defects. Depending on the form and severity of the inflammatory and noninflammatory processes, and according to the capping agent, pulp reactions are induced specifically.

Is Pulp Inflammation a Prerequisite for Pulp Healing and Regeneration?

PubMed Central

Goldberg, Michel; Njeh, Akram; Uzunoglu, Emel

2015-01-01

The importance of inflammation has been underestimated in pulpal healing, and in the past, it has been considered only as an undesirable effect. Associated with moderate inflammation, necrosis includes pyroptosis, apoptosis, and nemosis. There are now evidences that inflammation is a prerequisite for pulp healing, with series of events ahead of regeneration. Immunocompetent cells are recruited in the apical part. They slide along the root and migrate toward the crown. Due to the high alkalinity of the capping agent, pulp cells display mild inflammation, proliferate, and increase in number and size and initiate mineralization. Pulp fibroblasts become odontoblast-like cells producing type I collagen, alkaline phosphatase, and SPARC/osteonectin. Molecules of the SIBLING family, matrix metalloproteinases, and vascular and nerve mediators are also implicated in the formation of a reparative dentinal bridge, osteo/orthodentin closing the pulp exposure. Beneath a calciotraumatic line, a thin layer identified as reactionary dentin underlines the periphery of the pulp chamber. Inflammatory and/or noninflammatory processes contribute to produce a reparative dentinal bridge closing the pulp exposure, with minute canaliculi and large tunnel defects. Depending on the form and severity of the inflammatory and noninflammatory processes, and according to the capping agent, pulp reactions are induced specifically. PMID:26538825

Prostaglandins and Inflammation

PubMed Central

Ricciotti, Emanuela; FitzGerald, Garret A.

2011-01-01

Prostaglandins are lipid autacoids derived from arachidonic acid. They both sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. They are generated from arachidonate by the action of cyclooxygenase (COX) isoenzymes and their biosynthesis is blocked by nonsteroidal anti-inflammatory drugs (NSAIDs), including those selective for inhibition of COX-2. Despite the clinical efficacy of NSAIDs, prostaglandins may function in both the promotion and resolution of inflammation. This review summarizes insights into the mechanisms of prostaglandin generation and the roles of individual mediators and their receptors in modulating the inflammatory response. Prostaglandin biology has potential clinical relevance for atherosclerosis, the response to vascular injury and aortic aneurysm. PMID:21508345

Ganoderma lucidum Polysaccharides Reduce Lipopolysaccharide-Induced Interleukin-1β Expression in Cultured Smooth Muscle Cells and in Thoracic Aortas in Mice

PubMed Central

Liang, Chan-Jung; Lee, Chiang-Wen; Sung, Hsin-Ching; Chen, Yung-Hsiang; Hsu, Hsien-Yeh; Tseng, Ying-Chin; Li, Chi-Yuan; Wang, Shu-Huei

2014-01-01

The expression of inflammatory cytokines on vascular walls is a critical event in vascular diseases and inflammation. The aim of the present study was to examine the effects of an extract of Ganoderma lucidum (Reishi) polysaccharides (EORPs), which is effective against immunological disorders, on interleukin- (IL-) 1β expression by human aortic smooth muscle cells (HASMCs) and the underlying mechanism. The lipopolysaccharide- (LPS-) induced IL-1β expression was significantly reduced when HASMCs were pretreated with EORP by Western blot and immunofluorescent staining. Pretreatment with 10 μg/mL EORP decreased LPS-induced ERK, p38, JNK, and Akt phosphorylation. But the increase in IL-1β expression with LPS treatment was only inhibited by pretreatment with the ERK1/2 inhibitor, while the JNK and p38 inhibitors had no effect. In addition, EORP reduced the phosphorylation and nuclear translocation of nuclear factor- (NF-) κB p65 in LPS-treated HASMCs. Furthermore, in vivo, IL-1β expression was strongly expressed in thoracic aortas in LPS-treated mice. Oral administration of EORP decreased IL-1β expression. The level of IL-1β expression in LPS-treated or in LPS/EORP-treated group was very low and was similar to that of the saline-treated group in toll-like receptor 4-deficient (TLR4−/−) mice. These findings suggest that EORP has the anti-inflammatory property and could prove useful in the prevention of vascular diseases and inflammatory responses. PMID:24723958

Barrier protective effects of withaferin A in HMGB1-induced inflammatory responses in both cellular and animal models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Wonhwa; Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University; Kim, Tae Hoon

2012-07-01

Withaferin A (WFA), an active compound from Withania somnifera, is widely researched for its anti-inflammatory, cardioactive and central nervous system effects. In this study, we first investigated the possible barrier protective effects of WFA against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and in mice induced by high mobility group box 1 protein (HMGB1) and the associated signaling pathways. The barrier protective activities of WFA were determined by measuring permeability, leukocytes adhesion and migration, and activation of pro-inflammatory proteins in HMGB1-activated HUVECs. We found that WFA inhibited lipopolysaccharide (LPS)-induced HMGB1 release and HMGB1-mediated barrier disruption, expression of cellmore » adhesion molecules (CAMs) and adhesion/transendothelial migration of leukocytes to human endothelial cells. WFA also suppressed acetic acid-induced hyperpermeability and carboxymethylcellulose-induced leukocytes migration in vivo. Further studies revealed that WFA suppressed the production of interleukin 6, tumor necrosis factor-α (TNF-α) and activation of nuclear factor-κB (NF-κB) by HMGB1. Collectively, these results suggest that WFA protects vascular barrier integrity by inhibiting hyperpermeability, expression of CAMs, adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases. -- Highlights: ► Withaferin A inhibited LPS induced HMGB1 release. ► Withaferin A reduced HMGB1-mediated hyperpermeability. ► Withaferin A inhibited HMGB1-mediated adhesion and migration of leukocytes. ► Withaferin A inhibited HMGB1-mediated activation of NF-κB, IL-6 and TNF-α.« less

Targeted delivery of human iPS-ECs overexpressing IL-8 receptors inhibits neointimal and inflammatory responses to vascular injury in the rat.

PubMed

Giordano, Samantha; Zhao, Xiangmin; Xing, Daisy; Hage, Fadi; Oparil, Suzanne; Cooke, John P; Lee, Jieun; Nakayama, Karina H; Huang, Ngan F; Chen, Yiu-Fai

2016-03-15

Interleukin-8 (IL8) is highly expressed by injured arteries in a variety of diseases and is a chemoattractant for neutrophils which express IL8 receptors IL8RA and RB (IL8RA/B) on their membranes. Neutrophils interact with the damaged endothelium and initiate an inflammatory cascade at the site of injury. We have generated a novel translational targeted cell therapy for acute vascular injury using adenoviral vectors to overexpress IL8RA/B and green fluorescent protein (GFP) on the surface of endothelial cells (ECs) derived from human induced pluripotent stem cells (HiPS-IL8RA/B-ECs). We hypothesize that HiPS-IL8RA/B-ECs transfused intravenously into rats with balloon injury of the carotid artery will target to the injured site and compete with neutrophils, thus inhibiting inflammation and neointima formation. Young adult male Sprague-Dawley rats underwent balloon injury of the right carotid artery and received intravenous transfusion of saline vehicle, 1.5 × 10(6) HiPS-ECs, 1.5 × 10(6) HiPS-Null-ECs, or 1.5 × 10(6) HiPS-IL8RA/B-ECs immediately after endoluminal injury. Tissue distribution of HiPS-IL8RA/B-ECs was analyzed by a novel GFP DNA qPCR method. Cytokine and chemokine expression and leukocyte infiltration were measured in injured and uninjured arteries at 24 h postinjury by ELISA and immunohistochemistry, respectively. Neointimal, medial areas, and reendothelialization were measured 14 days postinjury. HiPS-IL8RA/B-ECs homed to injured arteries, inhibited inflammatory mediator expression and inflammatory cell infiltration, accelerated reendothelialization, and attenuated neointima formation after endoluminal injury while control HiPS-ECs and HiPS-Null-ECs did not. HiPS-IL8RA/B-ECs transfused into rats with endoluminal carotid artery injury target to the injured artery and provide a novel strategy to treat vascular injury.

Targeted delivery of human iPS-ECs overexpressing IL-8 receptors inhibits neointimal and inflammatory responses to vascular injury in the rat

PubMed Central

Giordano, Samantha; Zhao, Xiangmin; Xing, Daisy; Hage, Fadi; Oparil, Suzanne; Cooke, John P.; Lee, Jieun; Nakayama, Karina H.; Huang, Ngan F.

2016-01-01

Interleukin-8 (IL8) is highly expressed by injured arteries in a variety of diseases and is a chemoattractant for neutrophils which express IL8 receptors IL8RA and RB (IL8RA/B) on their membranes. Neutrophils interact with the damaged endothelium and initiate an inflammatory cascade at the site of injury. We have generated a novel translational targeted cell therapy for acute vascular injury using adenoviral vectors to overexpress IL8RA/B and green fluorescent protein (GFP) on the surface of endothelial cells (ECs) derived from human induced pluripotent stem cells (HiPS-IL8RA/B-ECs). We hypothesize that HiPS-IL8RA/B-ECs transfused intravenously into rats with balloon injury of the carotid artery will target to the injured site and compete with neutrophils, thus inhibiting inflammation and neointima formation. Young adult male Sprague-Dawley rats underwent balloon injury of the right carotid artery and received intravenous transfusion of saline vehicle, 1.5 × 106 HiPS-ECs, 1.5 × 106 HiPS-Null-ECs, or 1.5 × 106 HiPS-IL8RA/B-ECs immediately after endoluminal injury. Tissue distribution of HiPS-IL8RA/B-ECs was analyzed by a novel GFP DNA qPCR method. Cytokine and chemokine expression and leukocyte infiltration were measured in injured and uninjured arteries at 24 h postinjury by ELISA and immunohistochemistry, respectively. Neointimal, medial areas, and reendothelialization were measured 14 days postinjury. HiPS-IL8RA/B-ECs homed to injured arteries, inhibited inflammatory mediator expression and inflammatory cell infiltration, accelerated reendothelialization, and attenuated neointima formation after endoluminal injury while control HiPS-ECs and HiPS-Null-ECs did not. HiPS-IL8RA/B-ECs transfused into rats with endoluminal carotid artery injury target to the injured artery and provide a novel strategy to treat vascular injury. PMID:26801304

Effects of anisodamine on the expressions of vascular endothelial growth factor and intercellular adhesion molecule 1 in experimental infusion phlebitis.

PubMed

Zhang, Zhen-Xiang; Wang, Peng; Zhang, Qiu-Shi; Pan, Xue; Zhao, Qing-Xia; Wang, Xiao-Kai

2012-01-01

Infusion phlebitis is the most common side effect of clinical intravenous drug therapy and several clinical studies have demonstrated that anisodamine can effectively prevent the occurrence of infusion phlebitis. This study was designed to investigate effects of anisodamine on the expressions of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule 1 (ICAM-1) in a rabbit model of infusion phlebitis and to analyze the mechanisms of anisodamine effect on the prevention and treatment of experimental infusion phlebitis. Twenty-four specific pathogen-free male Japanese white rabbits were randomly assigned to the control group, the model group, the magnesium sulfate group and the anisodamine group. The rabbit model of infusion phlebitis, induced by intravenous administration, was established and expressions of VEGF and ICAM-1 were determined and contrasted with the control group treated with normal saline. We evaluated expression by histopathology, immunohistochemistry, reverse transcription-polymerase chain reaction, and Western blotting assay. Pathohistological changes of the model group were observed, such as loss of venous endothelial cells, inflammatory cell infiltration, edema and thrombus. The magnesium sulfate group and the anisodamine group showed significant protective effects on vascular congestion, inflammatory cell infiltration, proliferation, swelling of endothelium and perivascular hemorrhage. The model group showed the highest expressions of VEGF and ICAM-1 of the four groups (P < 0.01). On the contrary, anisodamine alleviated the inflammatory damage by significantly reducing the expressions of VEGF and ICAM-1 compared with the model group (P < 0.01). There was no significant difference in the expressions of VEGF and ICAM-1 between the magnesium sulfate group and the anisodamine group (P > 0.05). Anisodamine alleviates inflammatory damage by significantly reducing the expressions of VEGF and ICAM-1, and shows significant protective effects in an animal model of infusion phlebitis.

LPS inhibits caspase 3-dependent apoptosis in RAW264.7 macrophages induced by the AMPK activator AICAR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Russe, Otto Quintus, E-mail: quintus@russe.eu; Möser, Christine V., E-mail: chmoeser@hotmail.com; Kynast, Katharina L., E-mail: katharina.kynast@googlemail.com

2014-05-09

Highlights: • AMPK-activation induces caspase 3-dependent apoptosis in macrophages. • Apoptosis is associated with decreased mTOR and increased p21 levels. • All effects can be significantly inhibited by the TLR4 agonist lipopolysaccharide. - Abstract: AMP-activated kinase is a cellular energy sensor which is activated in stages of increased ATP consumption. Its activation has been associated with a number of beneficial effects such as decreasing inflammatory processes and the disease progress of diabetes and obesity, respectively. Furthermore, AMPK activation has been linked with induction of cell cycle arrest and apoptosis in cancer and vascular cells, indicating that it might have amore » therapeutic impact for the treatment of cancer and atherosclerosis. However, the impact of AMPK on the proliferation of macrophages, which also play a key role in the formation of atherosclerotic plaques and in inflammatory processes, has not been focused so far. We have assessed the influence of AICAR- and metformin-induced AMPK activation on cell viability of macrophages with and without inflammatory stimulation, respectively. In cells without inflammatory stimulation, we found a strong induction of caspase 3-dependent apoptosis associated with decreased mTOR levels and increased expression of p21. Interestingly, these effects could be inhibited by co-stimulation with bacterial lipopolysaccharide (LPS) but not by other proinflammatory cytokines suggesting that AICAR induces apoptosis via AMPK in a TLR4-pathway dependent manner. In conclusion, our results revealed that AMPK activation is not only associated with positive effects but might also contribute to risk factors by disturbing important features of macrophages. The fact that LPS is able to restore AMPK-associated apoptosis might indicate an important role of TLR4 agonists in preventing unfavorable cell death of immune cells.« less

The use of topical honey in the treatment of corneal abrasions and endotoxin-induced keratitis in an animal model.

PubMed

Uwaydat, Sami; Jha, Purushottam; Tytarenko, Ruslana; Brown, Harry; Wiggins, Michael; Bora, Puran S; Bora, Nalini S

2011-09-01

 To investigate the effect of topically applied honey on intact corneas, surgically induced corneal abrasions and endotoxin induced keratitis. The effect of honey on the cornea was investigated by application of honey on intact corneas, wounded corneas and endotoxin-induced keratitis in Lewis rats. The corneas were wounded by creating an epithelial defect using a surgical blade, and the keratitis was induced by topically applying Pseudomonas aeruginosa endotoxin to scarified corneas. After treatment rats were sacrificed and cornea harvested in each case. Corneas were processed for paraffin embedding for histological and immuno-fluorescence staining. Corneas were also harvested and processed for total ribonucleic acid (RNA) isolation for reverse transcriptase-polymerase chain reaction (RT-PCR) analysis for various growth factors and inflammatory chemokines/cytokines).  Histological analysis revealed that no inflammation or morphological changes occurred after honey treatment in naive intact corneas. Vascular endothelial growth factor (VEGF) levels were also not altered after honey treatment. Topical application of honey to injured corneas resulted in faster epithelial healing and decreased expression of VEGF, transforming growth factor beta (TGF-β), interferon gamma (IFN-γ), interleukin 12 (IL-12) and tumor necrosis factor alpha (TNF-α) in injured corneas. Our results also established that honey treatment reduced the inflammation in endotoxin-induced keratitis by reducing the levels of angiogenic factors (VEGF and TGF-β), inflammatory cytokines (IL-12) and chemokines (CC chemokine receptor 5(CCR-5)).  Short term use of honey on intact corneas can be safe. Honey has anti-angiogenic and anti-inflammatory properties that can be explored in several corneal inflammatory and infectious conditions.

Dispelling dogma and misconceptions regarding the most pharmacologically targetable source of reactive species in inflammatory disease, xanthine oxidoreductase.

PubMed

Kelley, Eric E

2015-08-01

Xanthine oxidoreductase (XOR), the molybdoflavin enzyme responsible for the terminal steps of purine degradation in humans, is also recognized as a significant source of reactive species contributory to inflammatory disease. In animal models and clinical studies, inhibition of XOR has resulted in diminution of symptoms and enhancement of function in a number of pathologies including heart failure, diabetes, sickle cell anemia, hypertension and ischemia-reperfusion injury. For decades, XOR involvement in pathologic processes has been established by salutary outcomes attained from treatment with the XOR inhibitor allopurinol. This has served to frame a working dogma that elevation of XOR-specific activity is associated with enhanced rates of reactive species generation that mediate negative outcomes. While adherence to this narrowly focused practice of designating elevated XOR activity to be "bad" has produced some benefit, it has also led to significant underdevelopment of the processes mediating XOR regulation, identification of alternative reactants and products as well as micro-environmental factors that alter enzymatic activity. This is exemplified by recent reports: (1) identifying XOR as a nitrite reductase and thus a source of beneficial nitric oxide ((•)NO) under in vivo conditions similar to those where XOR inhibition has been assumed an optimal treatment choice, (2) describing XOR-derived uric acid (UA) as a critical pro-inflammatory mediator in vascular and metabolic disease and (3) ascribing an antioxidant/protective role for XOR-derived UA. When taken together, these proposed and countervailing functions of XOR affirm the need for a more comprehensive evaluation of product formation as well as the factors that govern product identity. As such, this review will critically evaluate XOR-catalyzed oxidant, (•)NO and UA formation as well as identify factors that mediate their production, inhibition and the resultant impact on inflammatory disease.

Vascular Endothelial Growth Factor (VEGF) and Platelet (PF-4) Factor 4 Inputs Modulate Human Microvascular Endothelial Signaling in a Three-Dimensional Matrix Migration Context*

PubMed Central

Hang, Ta-Chun; Tedford, Nathan C.; Reddy, Raven J.; Rimchala, Tharathorn; Wells, Alan; White, Forest M.; Kamm, Roger D.; Lauffenburger, Douglas A.

2013-01-01

The process of angiogenesis is under complex regulation in adult organisms, particularly as it often occurs in an inflammatory post-wound environment. As such, there are many impacting factors that will regulate the generation of new blood vessels which include not only pro-angiogenic growth factors such as vascular endothelial growth factor, but also angiostatic factors. During initial postwound hemostasis, a large initial bolus of platelet factor 4 is released into localized areas of damage before progression of wound healing toward tissue homeostasis. Because of its early presence and high concentration, the angiostatic chemokine platelet factor 4, which can induce endothelial anoikis, can strongly affect angiogenesis. In our work, we explored signaling crosstalk interactions between vascular endothelial growth factor and platelet factor 4 using phosphotyrosine-enriched mass spectrometry methods on human dermal microvascular endothelial cells cultured under conditions facilitating migratory sprouting into collagen gel matrices. We developed new methods to enable mass spectrometry-based phosphorylation analysis of primary cells cultured on collagen gels, and quantified signaling pathways over the first 48 h of treatment with vascular endothelial growth factor in the presence or absence of platelet factor 4. By observing early and late signaling dynamics in tandem with correlation network modeling, we found that platelet factor 4 has significant crosstalk with vascular endothelial growth factor by modulating cell migration and polarization pathways, centered around P38α MAPK, Src family kinases Fyn and Lyn, along with FAK. Interestingly, we found EphA2 correlational topology to strongly involve key migration-related signaling nodes after introduction of platelet factor 4, indicating an influence of the angiostatic factor on this ambiguous but generally angiogenic signal in this complex environment. PMID:24023389

Sulforaphane suppresses vascular adhesion molecule-1 expression in TNF-α-stimulated mouse vascular smooth muscle cells: involvement of the MAPK, NF-κB and AP-1 signaling pathways.

PubMed

Kim, Ji-Yun; Park, Hye-Jin; Um, Sung Hee; Sohn, Eun-Hwa; Kim, Byung-Oh; Moon, Eun-Yi; Rhee, Dong-Kwon; Pyo, Suhkneung

2012-01-01

Atherosclerosis is a long-term inflammatory disease of the arterial wall. Increased expression of the cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) is associated with increased proliferation of vascular smooth muscle cells (VSMCs), leading to increased neointima or atherosclerotic lesion formation. Therefore, the functional inhibition of adhesion molecules could be a critical therapeutic target of inflammatory disease. In the present study, we investigate the effect of sulforaphane on the expression of VCAM-1 induced by TNF-α in cultured mouse vascular smooth muscle cell lines. Pretreatment of VSMCs for 2h with sulforaphane (1-5μg/ml) dose-dependently inhibited TNF-α-induced adhesion of THP-1 monocytic cells and protein expression of VCAM-1. Sulforaphane also suppressed TNF-α-induced production of intracellular reactive oxygen species (ROS) and activation of p38, ERK and JNK. Furthermore, sulforaphane inhibited NK-κB and AP-1 activation induced by TNF-α. Sulforaphane inhibited TNF-α-induced ΙκΒ kinase activation, subsequent degradation of ΙκΒα and nuclear translocation of p65 NF-κB and decreased c-Jun and c-Fos protein level. This study suggests that sulforaphane inhibits the adhesive capacity of VSMC and downregulates the TNF-α-mediated induction of VCAM-1 in VSMC by inhibiting the MAPK, NF-κB and AP-1 signaling pathways and intracellular ROS production. Thus, sulforaphane may have beneficial effects to suppress inflammation within the atherosclerotic lesion. Copyright © 2011 Elsevier Inc. All rights reserved.

Chronic psychological stress induces vascular inflammation in rabbits.

PubMed

Lu, Xiao Ting; Liu, Yun Fang; Zhao, Li; Li, Wen Jing; Yang, Rui Xue; Yan, Fang Fang; Zhao, Yu Xia; Jiang, Fan

2013-01-01

Psychological stress is associated with a systemic inflammatory response. It is unclear, however, whether psychological stress contributes to vascular inflammation. Here, we examined the effects of unpredictable chronic mild stress (UCMS) on vascular inflammation in rabbits. One hundred rabbits were randomly divided into control and stress groups. UCMS was induced by a set of defined adverse conditions applied in a shuffled order for 4, 8, 12, or 16 weeks, and rabbits were killed 24 h after the end of the UCMS protocol. Expression of different inflammatory molecules was analyzed by real-time polymerase chain reaction, immunohistochemistry, or enzyme-linked immunosorbent assay. UCMS resulted in depression-like behaviors, decreased body weight gain, and hypertension with no significant effects on serum lipids. Aortic mRNA and protein expression for tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), macrophage migration inhibitory factor, and expression of intercellular adhesion molecule-1 (ICAM-1) protein were increased. UCMS increased circulating concentrations of corticosterone, TNF-α, and CRP throughout. Moreover, stress downregulated the expression of endothelial nitric oxide synthase. At 16 weeks of UCMS, macrophage infiltration and lipid accumulation in the subendothelial space were detected in the aorta. In cultured murine vascular smooth muscle cells, treatment with serum from stressed rabbits significantly increased phosphorylation of p38 and c-Jun N-terminal kinase (JNK), and upregulated expression of MCP-1 and ICAM-1 mRNAs, in which the effect was blunted by a TNF-α neutralizing antibody or p38 and JNK inhibitors. Our results indicate that chronic psychological stress induces vascular inflammation via TNF-α and p38/JNK pathways, which may contribute to the development of atherosclerosis.

Chronic skin-specific inflammation promotes vascular inflammation and thrombosis.

PubMed

Wang, Yunmei; Gao, Huiyun; Loyd, Candace M; Fu, Wen; Diaconu, Doina; Liu, Shijian; Cooper, Kevin D; McCormick, Thomas S; Simon, Daniel I; Ward, Nicole L

2012-08-01

Patients with psoriasis have systemic and vascular inflammation and are at increased risk for myocardial infarction, stroke, and cardiovascular death. However, the underlying mechanism(s) mediating the link between psoriasis and vascular disease is incompletely defined. This study sought to determine whether chronic skin-specific inflammation has the capacity to promote vascular inflammation and thrombosis. Using the KC-Tie2 doxycycline-repressible (Dox-off) murine model of psoriasiform skin disease, spontaneous aortic root inflammation was observed in 33% of KC-Tie2 compared with 0% of control mice by 12 months of age (P=0.04) and was characterized by the accumulation of macrophages, T lymphocytes, and B lymphocytes, as well as by reduced collagen content and increased elastin breaks. Importantly, aortic inflammation was preceded by increases in serum tumor necrosis factor-α, IL-17A, vascular endothelial growth factor, IL-12, monocyte chemotactic protein-1, and S100A8/A9, as well as splenic and circulating CD11b(+)Ly-6C(hi) pro-inflammatory monocytes. Doxycycline treatment of old mice with severe skin disease eliminated skin inflammation and the presence of aortic root lesion in 1-year-old KC-Tie2 animals. Given the bidirectional link between inflammation and thrombosis, arterial thrombosis was assessed in KC-Tie2 and control mice; mean time to occlusive thrombus formation was shortened by 64% (P=0.002) in KC-Tie2 animals; and doxycycline treatment returned thrombosis clotting times to that of control mice (P=0.69). These findings demonstrate that sustained skin-specific inflammation promotes aortic root inflammation and thrombosis and suggest that aggressive treatment of skin inflammation may attenuate pro-inflammatory and pro-thrombotic pathways that produce cardiovascular disease in psoriasis patients.

Vascular Endothelial Cell-Specific Connective Tissue Growth Factor (CTGF) Is Necessary for Development of Chronic Hypoxia-Induced Pulmonary Hypertension.

PubMed

Pi, Liya; Fu, Chunhua; Lu, Yuanquing; Zhou, Junmei; Jorgensen, Marda; Shenoy, Vinayak; Lipson, Kenneth E; Scott, Edward W; Bryant, Andrew J

2018-01-01

Chronic hypoxia frequently complicates the care of patients with interstitial lung disease, contributing to the development of pulmonary hypertension (PH), and premature death. Connective tissue growth factor (CTGF), a matricellular protein of the Cyr61/CTGF/Nov (CCN) family, is known to exacerbate vascular remodeling within the lung. We have previously demonstrated that vascular endothelial-cell specific down-regulation of CTGF is associated with protection against the development of PH associated with hypoxia, though the mechanism for this effect is unknown. In this study, we generated a transgenic mouse line in which the Ctgf gene was floxed and deleted in vascular endothelial cells that expressed Cre recombinase under the control of VE-Cadherin promoter (eCTGF KO mice). Lack of vascular endothelial-derived CTGF protected against the development of PH secondary to chronic hypoxia, as well as in another model of bleomycin-induced pulmonary hypertension. Importantly, attenuation of PH was associated with a decrease in infiltrating inflammatory cells expressing CD11b or integrin α M (ITGAM), a known adhesion receptor for CTGF, in the lungs of hypoxia-exposed eCTGF KO mice. Moreover, these pathological changes were associated with activation of-Rho GTPase family member-cell division control protein 42 homolog (Cdc42) signaling, known to be associated with alteration in endothelial barrier function. These data indicate that endothelial-specific deletion of CTGF results in protection against development of chronic-hypoxia induced PH. This protection is conferred by both a decrease in inflammatory cell recruitment to the lung, and a reduction in lung Cdc42 activity. Based on our studies, CTGF inhibitor treatment should be investigated in patients with PH associated with chronic hypoxia secondary to chronic lung disease.

Effect of Pirfenidone on Vascular Proliferation, Inflammation and Fibrosis in an Abdominal Adhesion Rat Model.

PubMed

Hasdemir, Pinar Solmaz; Ozkut, Mahmud; Guvenal, Tevfik; Uner, Melis Aylin; Calik, Esat; Koltan, Semra Oruc; Koyuncu, Faik Mumtaz; Ozbilgin, Kemal

2017-02-01

To study the efficacy of pirfenidone for prevention of postoperative adhesion formation in an adhesion rat model. Eighteen female Wistar rats were subjected to right-sided parietal peritoneum and right uterine horn adhesion model. Rats were randomized into three groups: group 1 (control) (closure of midline abdominal incision without any agent administration), group 2 (closure of incision after intraperitoneal administration of pirfenidone), and group 3 (closure of incision and only oral administration of pirfenidone for 14 days). Relaparotomy was performed 14 days after the first surgery. Effect of pirfenidone on adhesion formation was assessed on light microscopy by scoring vascular proliferation, inflammation, fibrosis, and collagen formation in the scarred tissue. Effect of pirfenidone on inflammation was assessed by measurement of transforming growth factor-β and interleukin-17 levels in scarred tissue. The degree of vascular proliferation (1.32 ± 0.39 versus 2.34 ± 0.46, p < 0.001), inflammation (1.60 ± 0.70 versus 2.60 ± 0.52, p < 0.01), and fibrosis (1.50 ± 0.53 versus 2.40 ± 0.52, p < 0.01) were less prominent in group 2 compared to group 1, respectively. Only vascular proliferation was found to be less prominent in group 3 compared to group 1 (1.60 ± 0.42 versus 2.34 ± 0.46, p < 0.01). Intraperitoneal and oral administration of pirfenidone reduced tissue levels of inflammatory markers (TGF-β and IL-17) in parietal and visceral peritoneum compared to control group. Intraperitoneal administration of pirfenidone compared to oral administration was more effective in reducing tissue levels of inflammatory markers. Pirfenidone is an effective agent on the prevention of postoperative vascular proliferation, inflammation and fibrosis in scarred tissue particularly with intraperitoneal administration.

Anti-inflammatory activity of Odina wodier Roxb, an Indian folk remedy, through inhibition of toll-like receptor 4 signaling pathway.

PubMed

Ojha, Durbadal; Mukherjee, Hemanta; Mondal, Supriya; Jena, Aditya; Dwivedi, Ved Prakash; Mondal, Keshab C; Malhotra, Bharti; Samanta, Amalesh; Chattopadhyay, Debprasad

2014-01-01

Inflammation is part of self-limiting non-specific immune response, which occurs during bodily injury. In some disorders the inflammatory process becomes continuous, leading to the development of chronic inflammatory diseases including cardiovascular diseases, diabetes, cancer etc. Several Indian tribes used the bark of Odina wodier (OWB) for treating inflammatory disorders. Thus, we have evaluated the immunotherapeutic potential of OWB methanol extract and its major constituent chlorogenic acid (CA), using three popular in vivo antiinflammatory models: Carrageenan- and Dextran-induced paw edema, Cotton pellet granuloma, and Acetic acid-induced vascular permeability. To elucidate the possible anti-inflammatory mechanism of action we determine the level of major inflammatory mediators (NO, iNOS, COX-2-dependent prostaglandin E2 or PGE2), and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-12). Further, we determine the toll-like receptor 4 (TLR4), Myeloid differentiation primary response gene 88 (MyD88), c-Jun N-terminal kinases (JNK), nuclear factor kappa-B cells (NF-κB), and NF-kB inhibitor alpha (IK-Bα) by protein and mRNA expression, and Western blot analysis in drug treated LPS-induced murine macrophage model. Moreover, we determined the acute and sub-acute toxicity of OWB extract in BALB/c mice. Our study demonstrated a significant anti-inflammatory activity of OWB extract and CA along with the inhibition of TNF-α, IL-1β, IL-6 and IL-12 expressions. Further, the expression of TLR4, NF-κBp65, MyD88, iNOS and COX-2 molecules were reduced in drug-treated groups, but not in the LPS-stimulated untreated or control groups, Thus, our results collectively indicated that the OWB extract and CA can efficiently inhibit inflammation through the down regulation of TLR4/MyD88/NF-kB signaling pathway.

Anti-Inflammatory Activity of Odina wodier Roxb, an Indian Folk Remedy, through Inhibition of Toll-Like Receptor 4 Signaling Pathway

PubMed Central

Ojha, Durbadal; Mukherjee, Hemanta; Mondal, Supriya; Jena, Aditya; Dwivedi, Ved Prakash; Mondal, Keshab C.; Malhotra, Bharti; Samanta, Amalesh; Chattopadhyay, Debprasad

2014-01-01

Inflammation is part of self-limiting non-specific immune response, which occurs during bodily injury. In some disorders the inflammatory process becomes continuous, leading to the development of chronic inflammatory diseases including cardiovascular diseases, diabetes, cancer etc. Several Indian tribes used the bark of Odina wodier (OWB) for treating inflammatory disorders. Thus, we have evaluated the immunotherapeutic potential of OWB methanol extract and its major constituent chlorogenic acid (CA), using three popular in vivo antiinflammatory models: Carrageenan- and Dextran-induced paw edema, Cotton pellet granuloma, and Acetic acid-induced vascular permeability. To elucidate the possible anti-inflammatory mechanism of action we determine the level of major inflammatory mediators (NO, iNOS, COX-2-dependent prostaglandin E2 or PGE2), and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-12). Further, we determine the toll-like receptor 4 (TLR4), Myeloid differentiation primary response gene 88 (MyD88), c-Jun N-terminal kinases (JNK), nuclear factor kappa-B cells (NF-κB), and NF-kB inhibitor alpha (IK-Bα) by protein and mRNA expression, and Western blot analysis in drug treated LPS-induced murine macrophage model. Moreover, we determined the acute and sub-acute toxicity of OWB extract in BALB/c mice. Our study demonstrated a significant anti-inflammatory activity of OWB extract and CA along with the inhibition of TNF-α, IL-1β, IL-6 and IL-12 expressions. Further, the expression of TLR4, NF-κBp65, MyD88, iNOS and COX-2 molecules were reduced in drug-treated groups, but not in the LPS-stimulated untreated or control groups, Thus, our results collectively indicated that the OWB extract and CA can efficiently inhibit inflammation through the down regulation of TLR4/MyD88/NF-kB signaling pathway. PMID:25153081

Α-Melanocyte-Stimulating Hormone Protects Early Diabetic Retina from Blood-Retinal Barrier Breakdown and Vascular Leakage via MC4R.

PubMed

Cai, Siwei; Yang, Qianhui; Hou, Mengzhu; Han, Qian; Zhang, Hanyu; Wang, Jiantao; Qi, Chen; Bo, Qiyu; Ru, Yusha; Yang, Wei; Gu, Zhongxiu; Wei, Ruihua; Cao, Yunshan; Li, Xiaorong; Zhang, Yan

2018-01-01

Blood-retinal barrier (BRB) breakdown and vascular leakage is the leading cause of blindness of diabetic retinopathy (DR). Hyperglycemia-induced oxidative stress and inflammation are primary pathogenic factors of this severe DR complication. An effective interventional modality against the pathogenic factors during early DR is needed to curb BRB breakdown and vascular leakage. This study sought to examine the protective effects of α-Melanocyte-stimulating hormone (α-MSH) on early diabetic retina against vascular hyperpermeability, electrophysiological dysfunction, and morphological deterioration in a rat model of diabetes and probe the mechanisms underlying the α-MSH's anti-hyperpermeability in both rodent retinas and simian retinal vascular endothelial cells (RF6A). Sprague Dawley rats were injected through tail vein with streptozotocin to induce diabetes. The rats were intravitreally injected with α-MSH or saline at Week 1 and 3 after hyperglycemia. In another 2 weeks, Evans blue assay, transmission electron microscopy, electroretinogram (ERG), and hematoxylin and eosin (H&E) staining were performed to examine the protective effects of α-MSH in diabetic retinas. The expression of pro-inflammatory factors and tight junction at mRNA and protein levels in retinas was analyzed. Finally, the α-MSH's anti-hyperpermeability was confirmed in a high glucose (HG)-treated RF6A cell monolayer transwell culture by transendothelial electrical resistance (TEER) measurement and a fluorescein isothiocyanate-Dextran assay. Universal or specific melanocortin receptor (MCR) blockers were also employed to elucidate the MCR subtype mediating α-MSH's protection. Evans blue assay showed that BRB breakdown and vascular leakage was detected, and rescued by α-MSH both qualitatively and quantitatively in early diabetic retinas; electron microscopy revealed substantially improved retinal and choroidal vessel ultrastructures in α-MSH-treated diabetic retinas; scotopic ERG suggested partial rescue of functional defects by α-MSH in diabetic retinas; and H&E staining revealed significantly increased thickness of all layers in α-MSH-treated diabetic retinas. Mechanistically, α-MSH corrected aberrant transcript and protein expression of pro-inflammatory factor and tight junction genes in the diseased retinas; moreover, it prevented abnormal changes in TEER and permeability in HG-stimulated RF6A cells, and this anti-hyperpermeability was abolished by a universal MCR blocker or an antagonist specific to MC4R. This study showed previously undescribed protective effects of α-MSH on inhibiting BRB breakdown and vascular leakage, improving electrophysiological functions and morphology in early diabetic retinas, which may be due to its down-regulating pro-inflammatory factors and augmenting tight junctions. α-MSH acts predominantly on MC4R to antagonize hyperpermeability in retinal microvessel endothelial cells. © 2018 The Author(s). Published by S. Karger AG, Basel.

Reactive Oxygen Species in Inflammation and Tissue Injury

PubMed Central

Mittal, Manish; Siddiqui, Mohammad Rizwan; Tran, Khiem; Reddy, Sekhar P.

2014-01-01

Abstract Reactive oxygen species (ROS) are key signaling molecules that play an important role in the progression of inflammatory disorders. An enhanced ROS generation by polymorphonuclear neutrophils (PMNs) at the site of inflammation causes endothelial dysfunction and tissue injury. The vascular endothelium plays an important role in passage of macromolecules and inflammatory cells from the blood to tissue. Under the inflammatory conditions, oxidative stress produced by PMNs leads to the opening of inter-endothelial junctions and promotes the migration of inflammatory cells across the endothelial barrier. The migrated inflammatory cells not only help in the clearance of pathogens and foreign particles but also lead to tissue injury. The current review compiles the past and current research in the area of inflammation with particular emphasis on oxidative stress-mediated signaling mechanisms that are involved in inflammation and tissue injury. Antioxid. Redox Signal. 20, 1126–1167. PMID:23991888

Assessment of different energy delivery settings in laser and LED phototherapies in the inflammatory process of rat's TMJ induced by carrageenan.

PubMed

de Castro, Isabele C V; Rosa, Cristiane B; Carvalho, Carolina M; Aragão, Juliana S; Cangussu, Maria Cristina T; Dos Santos, Jean N; Pinheiro, Antonio L B

2015-11-01

Temporomandibular disorders (TMDs) are mostly inflammatory conditions widespread in the population. Previous studies have shown positive effects of either laser or light-emitting diode (LED) phototherapies on treating TMDs, but their action and mechanism in the inflammatory infiltrate of the temporomandibular joint are still poorly understood. The aim of this study was to assess, through histological analysis, the effectiveness of using laser light (λ 780 nm, 70 mW, continous wave (CW), 10 J) and LED (λ 850 ± 10 nm, 100 mW, CW, 10 J) on the inflammation of the temporomandibular joint of rats induced by carrageenan. Forty-five animals were divided into three groups with five animals each according to the experimental times of 2, 3, and 7 days: inflammation, inflammation+laser phototherapy, and inflammation+LED phototherapy. The first irradiation was performed 24 h after induction with an interval of 48 h between sessions. After animal death, specimens were processed and stained with hematoxylin-eosin (HE) and picrosirius. Then, the samples were examined histologically. Data were statistically analyzed. The inflammation group showed mild to moderate chronic inflammatory infiltrate between bone trabecules of the condyle. Over the time course of the study in the laser group, the region of the condyle presented mild chronic inflammation and intense vascularization. In the LED group, the condyle showed aspects of normality and absence of inflammation in some specimens. In all the time points, the laser-irradiated groups showed greater amount of collagen deposition in the condyle (p = 0.04) and in the disc (p = 0.03) when compared to the inflammation and LED groups, respectively. Laser- and LED-treated groups demonstrate a smaller number of layers of the synovial membrane when compared to the non-irradiated groups. It was concluded that, in general, laser and LED phototherapies resulted in a reduction of inflammatory infiltrate in the temporomandibular joint of rat.

Mouse Hepatitis Virus Infection Induces a Toll-Like Receptor 2-Dependent Activation of Inflammatory Functions in Liver Sinusoidal Endothelial Cells during Acute Hepatitis

PubMed Central

Bleau, Christian; Filliol, Aveline; Samson, Michel

2016-01-01

ABSTRACT Under physiological conditions, the liver sinusoidal endothelial cells (LSECs) mediate hepatic immune tolerance toward self or foreign antigens through constitutive expression of anti-inflammatory mediators. However, upon viral infection or Toll-like receptor 2 (TLR2) activation, LSECs can achieve proinflammatory functions, but their role in hepatic inflammation during acute viral hepatitis is unknown. Using the highly virulent mouse hepatitis virus type 3 (MHV3) and the attenuated variants 51.6-MHV3 and YAC-MHV3, exhibiting lower tropism for LSECs, we investigated in vivo and in vitro the consequence of LSEC infection on their proinflammatory profiles and the aggravation of acute hepatitis process. In vivo infection with virulent MHV3, in comparison to attenuated strains, resulted in fulminant hepatitis associated with higher hepatic viral load, tissue necrosis, and levels of inflammatory mediators and earlier recruitment of inflammatory cells. Such hepatic inflammatory disorders correlated with disturbed production of interleukin-10 (IL-10) and vascular factors by LSECs. We next showed in vitro that infection of LSECs by the virulent MHV3 strain altered their production of anti-inflammatory cytokines and promoted higher release of proinflammatory and procoagulant factors and earlier cell damage than infection by attenuated strains. This higher replication and proinflammatory activation in LSECs by the virulent MHV3 strain was associated with a specific activation of TLR2 signaling by the virus. We provide evidence that TLR2 activation of LSCEs by MHV3 is an aggravating factor of hepatic inflammation and correlates with the severity of hepatitis. Taken together, these results indicate that preservation of the immunotolerant properties of LSECs during acute viral hepatitis is imperative in order to limit hepatic inflammation and damage. IMPORTANCE Viral hepatitis B and C infections are serious health problems affecting over 350 million and 170 million people worldwide, respectively. It has been suggested that a balance between protection and liver damage mediated by the host's immune response during the acute phase of infection would be determinant in hepatitis outcome. Thus, it appears crucial to identify the factors that predispose in exacerbating liver inflammation to limit hepatocyte injury. Liver sinusoidal endothelial cells (LSECs) can express both anti- and proinflammatory functions, but their role in acute viral hepatitis has never been investigated. Using mouse hepatitis virus (MHV) infections as animal models of viral hepatitis, we report for the first time that in vitro and in vivo infection of LSECs by the pathogenic MHV3 serotype leads to a reversion of their intrinsic anti-inflammatory phenotype toward a proinflammatory profile as well to as disorders in vascular factors, correlating with the severity of hepatitis. These results highlight a new virus-promoted mechanism of exacerbation of liver inflammatory response during acute hepatitis. PMID:27489277

Mouse Hepatitis Virus Infection Induces a Toll-Like Receptor 2-Dependent Activation of Inflammatory Functions in Liver Sinusoidal Endothelial Cells during Acute Hepatitis.

PubMed

Bleau, Christian; Filliol, Aveline; Samson, Michel; Lamontagne, Lucie

2016-10-15

Under physiological conditions, the liver sinusoidal endothelial cells (LSECs) mediate hepatic immune tolerance toward self or foreign antigens through constitutive expression of anti-inflammatory mediators. However, upon viral infection or Toll-like receptor 2 (TLR2) activation, LSECs can achieve proinflammatory functions, but their role in hepatic inflammation during acute viral hepatitis is unknown. Using the highly virulent mouse hepatitis virus type 3 (MHV3) and the attenuated variants 51.6-MHV3 and YAC-MHV3, exhibiting lower tropism for LSECs, we investigated in vivo and in vitro the consequence of LSEC infection on their proinflammatory profiles and the aggravation of acute hepatitis process. In vivo infection with virulent MHV3, in comparison to attenuated strains, resulted in fulminant hepatitis associated with higher hepatic viral load, tissue necrosis, and levels of inflammatory mediators and earlier recruitment of inflammatory cells. Such hepatic inflammatory disorders correlated with disturbed production of interleukin-10 (IL-10) and vascular factors by LSECs. We next showed in vitro that infection of LSECs by the virulent MHV3 strain altered their production of anti-inflammatory cytokines and promoted higher release of proinflammatory and procoagulant factors and earlier cell damage than infection by attenuated strains. This higher replication and proinflammatory activation in LSECs by the virulent MHV3 strain was associated with a specific activation of TLR2 signaling by the virus. We provide evidence that TLR2 activation of LSCEs by MHV3 is an aggravating factor of hepatic inflammation and correlates with the severity of hepatitis. Taken together, these results indicate that preservation of the immunotolerant properties of LSECs during acute viral hepatitis is imperative in order to limit hepatic inflammation and damage. Viral hepatitis B and C infections are serious health problems affecting over 350 million and 170 million people worldwide, respectively. It has been suggested that a balance between protection and liver damage mediated by the host's immune response during the acute phase of infection would be determinant in hepatitis outcome. Thus, it appears crucial to identify the factors that predispose in exacerbating liver inflammation to limit hepatocyte injury. Liver sinusoidal endothelial cells (LSECs) can express both anti- and proinflammatory functions, but their role in acute viral hepatitis has never been investigated. Using mouse hepatitis virus (MHV) infections as animal models of viral hepatitis, we report for the first time that in vitro and in vivo infection of LSECs by the pathogenic MHV3 serotype leads to a reversion of their intrinsic anti-inflammatory phenotype toward a proinflammatory profile as well to as disorders in vascular factors, correlating with the severity of hepatitis. These results highlight a new virus-promoted mechanism of exacerbation of liver inflammatory response during acute hepatitis. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Regulation of Eosinophil Recruitment and Activation by Galectins in Allergic Asthma.

PubMed

Rao, Savita P; Ge, Xiao Na; Sriramarao, P

2017-01-01

Eosinophils are differentiated granulocytes that are recruited from the bone marrow to sites of inflammation via the vascular system. Allergic asthma is characterized by the presence of large numbers of eosinophils in the lungs and airways. Due to their capacity to rapidly release inflammatory mediators such as cytokines, chemokines, growth factors, and cytotoxic granule proteins upon stimulation, eosinophils play a critical role in pro-inflammatory processes in allergen-exposed lungs. Identifying key players and understanding the molecular mechanisms directing eosinophil trafficking and recruitment to inflamed airways is a key to developing therapeutic strategies to limit their influx. Recent studies have brought to light the important role of glycans and glycan binding proteins in regulating recruitment of eosinophils. In addition to the role of previously identified eosinophil- and endothelial-expressed adhesion molecules in mediating eosinophil trafficking and recruitment to the inflamed airways, studies have also indicated a role for galectins (galectin-3) in this process. Galectins are mammalian lectins expressed by various cell types including eosinophils. Intracellularly, they can regulate biological processes such as cell motility. Extracellularly, galectins interact with β-galactosides in cell surface-expressed glycans to regulate cellular responses like production of inflammatory mediators, cell adhesion, migration, and apoptosis. Eosinophils express galectins intracellularly or on the cell surface where they interact with cell surface glycoconjugate receptors. Depending on the type (galectin-1, -3, etc.) and location (extracellular or intracellular, endogenous or exogenously delivered), galectins differentially regulate eosinophil recruitment, activation, and apoptosis and thus exert a pro- or anti-inflammatory outcome. Here, we have reviewed information pertaining to galectins (galectin-1, -3 -9, and -10) that are expressed by eosinophils themselves and/or other cells that play a role in eosinophil recruitment and function in the context of allergic asthma and their potential use as disease biomarkers or therapeutic targets for immunomodulation.

Vitamin D ameliorates impaired wound healing in streptozotocin-induced diabetic mice by suppressing NF-κB-mediated inflammatory genes.

PubMed

Yuan, YiFeng; Das, Sushant K; Li, MaoQuan

2018-04-27

Diabetic wounds are characterized by delayed wound healing due to persistent inflammation and excessive production of reactive oxygen species. Vitamin D, which is well acknowledged to enhance intestinal calcium absorption and increase in plasma calcium level, has recently been shown to display beneficial effects in various vascular diseases by promoting angiogenesis and inhibiting inflammatory responses. However, the role of Vitamin D in diabetic wound healing is still unclear. In the present study, we investigated the role of Vitamin D in cutaneous wound healing in streptozotocin (STZ)-induced diabetic mice. Four weeks after injection of STZ, a full thickness excisional wound was created with a 6-mm diameter sterile biopsy punch on the dorsum of the mice. Vitamin D was given consecutively for 14 days by intraperitoneal injection. Vitamin D supplementation significantly accelerated wound healing in diabetic mice and improved the healing quality as assessed by measuring the wound closure rate and histomorphometric analyses. By monitoring the level of pro-inflammatory cytokines tumor necrosis factor-α ( TNF-α ), interleukin (IL) 6 ( IL-6 ), IL-1β ) in the wounds, reduced inflammatory response was found in VD treatment group. Furthermore, nuclear factor κB (NF-κB) pathway was found to be involved in the process of diabetic wound healing by assessing the relative proteins in diabetic wounds. Vitamin D supplementation obviously suppressed NF-κB pathway activation. These results demonstrated that Vitamin D improves impaired wound healing in STZ-induced diabetic mice through suppressing NF-κB-mediated inflammatory gene expression. © 2018 The Author(s).

NLRP3 inflammasome activation is associated with proliferative diabetic retinopathy.

PubMed

Loukovaara, Sirpa; Piippo, Niina; Kinnunen, Kati; Hytti, Maria; Kaarniranta, Kai; Kauppinen, Anu

2017-12-01

Innate immunity and dysregulation of inflammatory processes play a role in vascular diseases like atherosclerosis or diabetes. Nucleotide-binding domain and Leucine-rich repeat Receptor containing a Pyrin domain 3 (NLRP3) inflammasomes are pro-inflammatory signalling complexes that were found in 2002. In addition to pathogens and other extracellular threats, they can be activated by various endogenous danger signals. The purpose of this study was to find out whether NLRP3 activation occurs in patients with sight-threatening forms of diabetic retinopathy (DR). Inflammasome components NLRP3 and caspase-1, inflammasome-related pro-inflammatory cytokines IL-1β and IL-18, vascular endothelial growth factor (VEGF), acute-phase cytokines TNF-α and IL-6, as well as adaptive immunity-related cytokine interferon gamma (IFN-γ) were measured from the vitreous samples of 15 non-proliferative diabetic retinopathy (non-PDR) and 23 proliferative diabetic retinopathy (PDR) patients using the enzyme-linked immunosorbent assay (ELISA) method. The adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) was determined using the Western blot technique. Inflammasome components were present in the vitreous of DR patients. Along with VEGF, the levels of caspase-1 and IL-18 were significantly increased, especially in PDR eyes. Interestingly, clearly higher levels of NLRP3 were found in the PDR eyes with tractional retinal detachment (TRD) than from PDR eyes with fully attached retina. There were no significant differences in the amounts of IL-1β, TNF-α, IL-6, and IFN-γ that were detectable in the vitreous of both non-PDR and PDR patients. Our results suggest that NLRP3 inflammasome activation can be associated especially with the pathogenesis of PDR. The lack of differences in TNF-α, IL-6, and IFN-γ also alludes that acute inflammation or T-cell-mediated responses do not dominate in PDR pathogenesis. © 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Imaging vulnerable plaques by targeting inflammation in atherosclerosis using fluorescent-labeled dual-ligand microparticles of iron oxide and magnetic resonance imaging.

PubMed

Chan, Joyce M S; Monaco, Claudia; Wylezinska-Arridge, Marzena; Tremoleda, Jordi L; Cole, Jennifer E; Goddard, Michael; Cheung, Maggie S H; Bhakoo, Kishore K; Gibbs, Richard G J

2018-05-01

Identification of patients with high-risk asymptomatic carotid plaques remains an elusive but essential step in stroke prevention. Inflammation is a key process in plaque destabilization and a prelude to clinical sequelae. There are currently no clinical imaging tools to assess the inflammatory activity within plaques. This study characterized inflammation in atherosclerosis using dual-targeted microparticles of iron oxide (DT-MPIO) as a magnetic resonance imaging (MRI) probe. DT-MPIO were used to detect and characterize inflammatory markers, vascular cell adhesion molecule 1 (VCAM-1). and P-selectin on (1) tumor necrosis factor-α-treated cells by immunocytochemistry and (2) aortic root plaques of apolipoprotein-E deficient mice by in vivo MRI. Furthermore, apolipoprotein E-deficient mice with focal carotid plaques of different phenotypes were developed by means of periarterial cuff placement to allow in vivo molecular MRI using these probes. The association between biomarkers and the magnetic resonance signal in different contrast groups was assessed longitudinally in these models. Immunocytochemistry confirmed specificity and efficacy of DT-MPIO to VCAM-1 and P-selectin. Using this in vivo molecular MRI strategy, we demonstrated (1) the DT-MPIO-induced magnetic resonance signal tracked with VCAM-1 (r = 0.69; P = .014), P-selectin (r = 0.65; P = .022), and macrophage content (r = 0.59; P = .045) within aortic root plaques and (2) high-risk inflamed plaques were distinguished from noninflamed plaques in the murine carotid artery within a practical clinical imaging time frame. These molecular MRI probes constitute a novel imaging tool for in vivo characterization of plaque vulnerability and inflammatory activity in atherosclerosis. Further development and translation into the clinical arena will facilitate more accurate risk stratification in carotid atherosclerotic disease in the future. Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Contribution of endothelial progenitors and proangiogenic hematopoietic cells to vascularization of tumor and ischemic tissue

PubMed Central

Kopp, Hans-Georg; Ramos, Carlos A.; Rafii, Shahin

2010-01-01

Purpose of review During the last several years, a substantial amount of evidence from animal as well as human studies has advanced our knowledge of how bone marrow derived cells contribute to neoangiogenesis. In the light of recent findings, we may have to redefine our thinking of endothelial cells as well as of perivascular mural cells. Recent findings Inflammatory hematopoietic cells, such as macrophages, have been shown to promote neoangiogenesis during tumor growth and wound healing. Dendritic cells, B lymphocytes, monocytes, and other immune cells have also been found to be recruited to neoangiogenic niches and to support neovessel formation. These findings have led to the concept that subsets of hematopoietic cells comprise proangiogenic cells that drive adult revascularization processes. While evidence of the importance of endothelial progenitor cells in adult vasculogenesis increased further, the role of these comobilized hematopoietic cells has been intensely studied in the last few years. Summary Angiogenic factors promote mobilization of vascular endothelial growth factor receptor 1-positive hematopoietic cells through matrix metalloproteinase-9 mediated release of soluble kit-ligand and recruit these proangiogenic cells to areas of hypoxia, where perivascular mural cells present stromal-derived factor 1 (CXCL-12) as an important retention signal. The same factors are possibly involved in mobilization of vascular endothelial growth factor receptor 2-positive endothelial precursors that may participate in neovessel formation. The complete characterization of mechanisms, mediators and signaling pathways involved in these processes will provide novel targets for both anti and proangiogenic therapeutic strategies. PMID:16567962

Pathology of Human Coronary and Carotid Artery Atherosclerosis and Vascular Calcification in Diabetes Mellitus.

PubMed

Yahagi, Kazuyuki; Kolodgie, Frank D; Lutter, Christoph; Mori, Hiroyoshi; Romero, Maria E; Finn, Aloke V; Virmani, Renu

2017-02-01

The continuing increase in the prevalence of diabetes mellitus in the general population is predicted to result in a higher incidence of cardiovascular disease. Although the mechanisms of diabetes mellitus-associated progression of atherosclerosis are not fully understood, at clinical and pathological levels, there is an appreciation of increased disease burden and higher levels of arterial calcification in these subjects. Plaques within the coronary arteries of patients with diabetes mellitus generally exhibit larger necrotic cores and significantly greater inflammation consisting mainly of macrophages and T lymphocytes relative to patients without diabetes mellitus. Moreover, there is a higher incidence of healed plaque ruptures and positive remodeling in hearts from subjects with type 1 diabetes mellitus and type 2 diabetes mellitus, suggesting a more active atherogenic process. Lesion calcification in the coronary, carotid, and other arterial beds is also more extensive. Although the role of coronary artery calcification in identifying cardiovascular disease and predicting its outcome is undeniable, our understanding of how key hormonal and physiological alterations associated with diabetes mellitus such as insulin resistance and hyperglycemia influence the process of vascular calcification continues to grow. Important drivers of atherosclerotic calcification in diabetes mellitus include oxidative stress, endothelial dysfunction, alterations in mineral metabolism, increased inflammatory cytokine production, and release of osteoprogenitor cells from the marrow into the circulation. Our review will focus on the pathophysiology of type 1 diabetes mellitus- and type 2 diabetes mellitus-associated vascular disease with particular focus on coronary and carotid atherosclerotic calcification. © 2016 American Heart Association, Inc.

Enhancing Stent Effectiveness with Nanofeatures

PubMed Central

Bassous, Nicole; Cooke, John P.; Webster, Thomas J.

2016-01-01

Drug-eluting stents are an effective therapy for symptomatic arterial obstructions, substantially reducing the incidence of restenosis by suppressing the migration and proliferation of vascular smooth muscle cells into the intima. However, current drug-eluting stents also inhibit the growth of endothelial cells, which are required to cover the vascular stent to reduce an excessive inflammatory response. As a result, the endothelial lining of the lumen is not regenerated. Since the loss of this homeostatic monolayer increases the risk of thrombosis, patients with drug-eluting stents require long-term antithrombotic therapy. Thus, there is a need for improved devices with enhanced effectiveness and physiological compatibility towards endothelial cells. Current developments in nanomaterials may enhance the function of commercially available vascular devices. In particular, modified design schemes might incorporate nanopatterns or nanoparticle-eluting features that reduce restenosis and enhance re-endothelialization. The intent of this review is to discuss emerging nanotechnologies that will improve the performance of vascular stents. PMID:27826371

Flavonol-rich RVHxR from Rhus verniciflua Stokes and its major compound fisetin inhibits inflammation-related cytokines and angiogenic factor in rheumatoid arthritic fibroblast-like synovial cells and in vivo models.

PubMed

Lee, Jae-Dong; Huh, Jeong-Eun; Jeon, GeumSeon; Yang, Ha-Ru; Woo, Hyun-Su; Choi, Do-Young; Park, Dong-Suk

2009-03-01

Rheumatoid arthritis (RA) is an aggressive inflammatory disease in which cytokines/chemokines are thought to recruit leukocytes and induce angiogenesis. The aim of this study is to investigate the effect of flavonol-rich residual layer of hexane fraction from Rhus verniciflua Stokes (RVHxR) and its major compound fisetin on inflammatory cytokine/chemokine production and angiogenic factor in IL-1beta-stimulated RA fibroblast-like synovial cells (FLS) and inflammatory in vivo models. Flavonol-rich RVHxR and its major compound fisetin significantly inhibited IL-1beta-induced FLS proliferation in a dose-dependent manner. Flavonol-rich RVHxR and fisetin significantly decreased IL-1beta-induced inflammatory cytokines (TNF-alpha, interleukin (IL)-6)/chemokines (IL-8, monocyte chemoattractant protein (MCP)-1), and vascular endothelial growth factor (VEGF) of RA FLS. Flavonol-rich RVHxR dose dependently diminished the phophorylation of extracellular signal regulated kinase (ERK) and phospho-Jun NH((2))-terminal kinase (JNK), and its down regulation induced by RVHxR at nontoxic concentrations, while activated the phosphorylation of p38 MAPK in IL-1beta-stimulated RA FLS. The p38 specific inhibitor SB203580 cotreatment with RVHxR effectively increased the expression of VEGF and blocked the phosphorylation of p38 MAPK in IL-1beta-stimulated RA FLS, confirming a critical role of p38 MAPK pathway in angiogenesis inhibition. In experimental inflammation-related models, flavonol-rich RVHxR and fisetin have shown significant anti-inflammatory activities on vascular permeability, leukocyte migration and cellular immunity. Also, flavonol-rich RVHxR and fisetin treatments significantly reduced the incidence and severity of collagen-induced arthritis model. These results suggest that RVHxR and its major compound fisetin have shown potent suppressive effects on some inflammatory cytokines/chemokines and angiogenic factor in IL-1beta-stimulated RA FLS and inflammatory in vivo models. We believe that flavonol-rich RVHxR is a potential therapeutic agent in the treatment of inflammatory and angiogenesis related diseases.

Urticarial Reactions: Vascular Erythema, Urticaria, Vasculitis

PubMed Central

Sibbald, R. Gary

1987-01-01

Vascular erythemas, including urticaria and vasculitis, represent diagnostic and therapeutic challenges. A careful systemic approach to history and physical examination should be followed by appropriate investigations to rule out systemic disease. Chronic urticaria patients should be physically tested to identify cholinergic, dermagraphic, and cold-induced responses. Food diaries and careful drug history may be important to identify exacerbating factors in chronic urticaria. A skin biopsy is necessary to diagnose vasculitis. Therapy of any underlying cause is supplemented with H1 antihistamines in urticaria patients, while vasculitis requires a different anti-inflammatory approach. PMID:21263956

Direct and Indirect Effects of PM on the Cardiovascular System

PubMed Central

Nelin, Timothy D.; Joseph, Allan M.; Gorr, Matthew W.; Wold, Loren E.

2011-01-01

Human exposure to particulate matter (PM) elicits a variety of responses on the cardiovascular system through both direct and indirect pathways. Indirect effects of PM on the cardiovascular system are mediated through the autonomic nervous system, which controls heart rate variability, and inflammatory responses, which augment acute cardiovascular events and atherosclerosis. Recent research demonstrates that PM also affects the cardiovascular system directly by entry into the systemic circulation. This process causes myocardial dysfunction through mechanisms of reactive oxygen species production, calcium ion interference, and vascular dysfunction. In this review, we will present key evidence in both the direct and indirect pathways, suggest clinical applications of the current literature, and recommend directions for future research. PMID:22119171

[The role of metalloprotease in pathogenesis of nervous system diseases].

PubMed

Mirowska, D; Członkowska, A

2001-01-01

Matrix Metalloproteases (MMPs) comprise a big family of proteolytic enzymes secreted into extracellular matrix and involved in remodelling of many tissues. The MMPs' activity is regulated on many levels. It is also determined by specific inhibitors known as tissue inhibitors of metalloproteases (TIMPs). Several studies revealed that MMPs have a role not only in physiological processes but also in pathophysiology of nervous system diseases, such as multiplex sclerosis, Guillan-Barré syndrome and strokes. Concerning demyelination MMPs are responsible for degradation of myelin components and facilitation of immune cells migration into inflammatory sites by degrading vascular basement membrane. We still investigate substances with positive clinical effect on the nervous system diseases due to MMPs inactivation.

[Correlation of fibroblast growth factor 23 with 
adverse prognosis of chronic kidney disease and
therapy strategy].

PubMed

Liu, Haiyang; Liu, Hong

2018-05-28

Fibroblast growth factor 23 (FGF23) is a hormone secreted by the bone. It is not only involved in the pathophysiological process of chronic kidney disease (CKD), but also associated with the poor prognosis. In patients with CKD, serum FGF23 levels are elevated in early phase. The increased FGF23 levels gradually lead to myocardial hypertrophy, inflammatory, vascular calcification, and low level of vitamin D, which contribute to the progress of CKD, cardiovascular complications and even death. Presently, there are several ways to reduce FGF23 levels, including decrease of intake and block of phosphorus absorption, supplement of FGF23 antibody and pseudo calcium or renal transplantation.

Cerebral Embolic Activity in a Patient during Acute Crisis of Takayasu's Arteritis

PubMed Central

Nogueira, Ricardo de Carvalho; Bor-Seng-Shu, Edson; Marchiori, Paulo Eurípedes; Teixeira, Manoel Jacobsen

2012-01-01

Takayasu's arteritis is a disease that affects large vessels and may cause neurological symptoms either by stenoses/occlusions or embolisms from vessels with an inflammatory process. Transcranial Doppler (TCD) ultrasound can provide useful information for diagnosis and monitoring during the active phase of the disease. Cerebral embolic signals can be detected by TCD and have been considered a risk factor for vascular events. We report a patient in whom TCD ultrasound was used to monitor cerebral embolic signals during the active phase of the disease. This case report suggests that embolic activity in Takayasu's arteritis may represent disease activity, and its monitoring may be useful for evaluating the response to therapy. PMID:22379479

Ostial left main stenosis due to takayasu arteritis: multimodality imaging and surgical ostioplasty.

PubMed

Bansal, Neeraj; Wang, Nan; Choo, Daniel; Bansal, Ramesh C

2011-01-01

Takayasu's arteritis is an inflammatory process, involving larger blood vessels-namely the aorta and its branches. The majority of these patients present with symptoms of vascular obstruction. We report a case of a 38-year-old Chinese female who presented with one month history of angina pectoris as the initial manifestation. Coronary angiography showed 99% ostial left main coronary stenosis. The diagnosis was first suspected in the operating room by TEE and subsequently supported by laboratory studies and aortic biopsy. The technique of myocardial revascularization was altered and she underwent patch ostioplasty of the left main coronary artery and aortic valve repair to correct aortic regurgitation. © 2010, Wiley Periodicals, Inc.

A hemangioma on the floor of the mouth presenting as a ranula.

PubMed

Skoulakis, Charalampos E; Khaldi, Lubna; Serletis, Demetre; Semertzidis, Themistoklis

2008-11-01

A painless, bluish, submucosal swelling on one side of the floor of the mouth usually indicates the presence of a ranula. Rarely, such a swelling may be caused by an inflammatory disease process in a salivary gland, a neoplasm in the sublingual salivary gland, a lymphatic nodular swelling, or embryologic cysts. We report a patient with swelling in the floor of her mouth that was clinically diagnosed as a ranula. Suspicion arose during surgery that it was a vascular tumor and, on histologic testing, the swelling was confirmed to be a hemangioma. To our knowledge, this is the first report in the literature of a hemangioma presenting as a ranula.

Identification of New Anti-inflammatory Peptides from Zein Hydrolysate after Simulated Gastrointestinal Digestion and Transport in Caco-2 Cells.

PubMed

Liang, Qiufang; Chalamaiah, Meram; Ren, Xiaofeng; Ma, Haile; Wu, Jianping

2018-02-07

Chronic inflammation is an underlying contributor to various chronic diseases. The objectives of this study were to investigate the anti-inflammatory activity of zein hydrolysate after simulated gastrointestinal digestion and Caco-2 cell absorption and to identify novel anti-inflammatory peptides after transport across Caco-2 cells. Three zein hydrolysates were prepared and further digested using gastrointestinal proteases; their transports were studied in Caco-2 cells. Anti-inflammatory activity was studied in endothelial EA.hy926 cells. Three zein hydrolysates and their digests significantly decreased the expression of tumor necrosis factor-α (TNF-α) induced pro-inflammatory vascular cell adhesion molecule-1 (VCAM-1) by 37.3-66.0%. Eleven novel peptides with 5-9 amino acid residues were sequenced; three peptides showed strong anti-inflammatory activity by inhibiting the VCAM-1 by 54-38.9% and intercellular cell adhesion molecule-1 (ICAM-1) by 36.5-28.6% at 0.2 mM. A new approach to identify novel anti-inflammatory peptides that could survive gastrointestinal digestion and absorption was developed.

Anti-inflammatory effects of vinpocetine in atherosclerosis and ischemic stroke: a review of the literature.

PubMed

Zhang, Linjie; Yang, Li

2014-12-26

Immune responses play an important role in the pathophysiology of atherosclerosis and ischemic stroke. Atherosclerosis is a common condition that increases the risk of stroke. Hyperlipidemia damages endothelial cells, thus initiating chemokine pathways and the release of inflammatory cytokines-this represents the first step in the inflammatory response to atherosclerosis. Blocking blood flow in the brain leads to ischemic stroke, and deprives neurons of oxygen and energy. Damaged neurons release danger-associated molecular patterns, which promote the activation of innate immune cells and the release of inflammatory cytokines. The nuclear factor κ-light-chain-enhancer of activated B cells κB (NF-κB) pathway plays a key role in the pathogenesis of atherosclerosis and ischemic stroke. Vinpocetine is believed to be a potent anti-inflammatory agent and has been used to treat cerebrovascular disorders. Vinpocetine improves neuronal plasticity and reduces the release of inflammatory cytokines and chemokines from endothelial cells, vascular smooth muscle cells, macrophages, and microglia, by inhibiting the inhibitor of the NF-κB pathway. This review clarifies the anti-inflammatory role of vinpocetine in atherosclerosis and ischemic stroke.

Inflammation and Cardiovascular Disease Risk: A Case Study of HIV and Inflammatory Joint Disease.

PubMed

Rahman, Faisal; Martin, Seth S; Whelton, Seamus P; Mody, Freny V; Vaishnav, Joban; McEvoy, John William

2018-04-01

The epidemiologic data associating infection and inflammation with increased risk of cardiovascular disease is well established. Patients with chronically upregulated inflammatory pathways, such as those with HIV and inflammatory joint diseases, often have a risk of future cardiovascular risk that is similar to or higher than patients with diabetes. Thus, it is of heightened importance for clinicians to consider the cardiovascular risk of patients with these conditions. HIV and inflammatory joint diseases are archetypal examples of how inflammatory disorders contribute to vascular disease and provide illustrative lessons that can be leveraged in the prevention of cardiovascular disease. Managing chronic inflammatory diseases calls for a multifaceted approach to evaluation and treatment of suboptimal lifestyle habits, accurate estimation of cardiovascular disease risk with potential upwards recalibration due to chronic inflammation, and more intensive treatment of risk factors because current tools often underestimate the risk in this population. This approach is further supported by the recently published CANTOS trial demonstrating that reducing inflammation can serve as a therapeutic target among persons with residual inflammatory risk for cardiovascular disease. Copyright © 2018 Elsevier Inc. All rights reserved.

Concord Grape Juice Supplementation Improves Memory Function In Older Adults with Mild Cognitive Impairment

USDA-ARS?s Scientific Manuscript database

Concord grape juice contains flavonoid polyphenol compounds, which have antioxidant and anti-inflammatory properties and influence neuronal signaling. Concord grape juice supplementation has been shown to reduce inflammation, blood pressure, and vascular pathology in individuals with cardiovascular...

Emodin Inhibits Homocysteine-Induced C-Reactive Protein Generation in Vascular Smooth Muscle Cells by Regulating PPARγ Expression and ROS-ERK1/2/p38 Signal Pathway

PubMed Central

Pang, Xiaoming; Liu, Juntian; Li, Yuxia; Zhao, Jingjing; Zhang, Xiaolu

2015-01-01

Atherosclerosis is an inflammatory disease. As an inflammatory molecule, C-reactive protein (CRP) plays a direct role in atherogenesis. It is known that the elevated plasma homocysteine (Hcy) level is an independent risk factor for atherosclerosis. We previously reported that Hcy produces a pro-inflammatory effect by inducing CRP expression in vascular smooth muscle cells (VSMCs). In the present study, we observed effect of emodin on Hcy-induced CRP expression in rat VSMCs and molecular mechanisms. The in vitro results showed that pretreatment of VSMCs with emodin inhibited Hcy-induced mRNA and protein expression of CRP in a concentration-dependent manner. The in vivo experiments displayed that emodin not only inhibited CRP expression in the vessel walls in mRNA and protein levels, but also reduced the circulating CRP level in hyperhomocysteinemic rats. Further study revealed that emodin diminished Hcy-stimulated generation of reactive oxygen species (ROS), attenuated Hcy-activated phosphorylation of ERK1/2 and p38, and upregulated Hcy-inhibited expression of peroxisome proliferator-activated receptor gamma (PPARγ) in VSMCs. These demonstrate that emodin is able to inhibit Hcy-induced CRP generation in VSMCs, which is related to interfering with ROS-ERK1/2/p38 signal pathway and upregulating PPARγ expression. The present study provides new evidence for the anti-inflammatory and anti-atherosclerotic effects of emodin. PMID:26131983

Cysteine, histidine and glycine exhibit anti-inflammatory effects in human coronary arterial endothelial cells.

PubMed

Hasegawa, S; Ichiyama, T; Sonaka, I; Ohsaki, A; Okada, S; Wakiguchi, H; Kudo, K; Kittaka, S; Hara, M; Furukawa, S

2012-02-01

The activation of nuclear factor-kappa B (NF-κB) in vascular endothelial cells may be involved in vascular pathogeneses such as vasculitis or atherosclerosis. Recently, it has been reported that some amino acids exhibit anti-inflammatory effects. We investigated the inhibitory effects of a panel of amino acids on cytokine production or expression of adhesion molecules that are involved in inflammatory diseases in various cell types. The activation of NF-κB was determined in human coronary arterial endothelial cells (HCAECs) because NF-κB modulates the production of many cytokines and the expression of adhesion molecules. We examined the inhibitory effects of the amino acids cysteine, histidine and glycine on the induction of NF-κB activation, expression of CD62E (E-selectin) and the production of interleukin (IL)-6 in HCAECs stimulated with tumour necrosis factor (TNF)-α. Cysteine, histidine and glycine significantly reduced NF-κB activation and inhibitor κBα (IκBα) degradation in HCAECs stimulated with TNF-α. Additionally, all the amino acids inhibited the expression of E-selectin and the production of IL-6 in HCAECs, and the effects of cysteine were the most significant. Our results show that glycine, histidine and cysteine can inhibit NF-κB activation, IκBα degradation, CD62E expression and IL-6 production in HCAECs, suggesting that these amino acids may exhibit anti-inflammatory effects during endothelial inflammation. © 2012 The Authors. Clinical and Experimental Immunology © 2012 British Society for Immunology.

Role of Hemichannels in CNS Inflammation and the Inflammasome Pathway.

PubMed

Kim, Yeri; Davidson, Joanne O; Gunn, Katherine C; Phillips, Anthony R; Green, Colin R; Gunn, Alistair J

2016-01-01

Neurodegenerative, cardiovascular, and metabolic disorders, once triggered, share a number of common features, including sustained inflammatory cell activation and vascular disruption. These shared pathways are induced independently of any genetic predisposition to the disease or the precise external stimulus. Glial cells respond to injury with an innate immune response that includes release of proinflammatory cytokines and chemokines. Vascular endothelial cells may also be affected, leading to opening of the blood-brain barrier that facilitates invasion by circulating inflammatory cells. Inflammation can trigger acute neural injury followed by chronic inflammation that plays a key role in neurodegenerative conditions. Gap junction channels normally allow direct cell-to-cell communication. They are formed by the docking of two hemichannels, one contributed by each of the neighboring cells. While the opening probability of these channels is tightly controlled under resting conditions, hemichannels can open in response to injury or inflammatory factors, forming a large, relatively nonselective membrane pore. In this review, we consider the CNS immune system from the perspective that modulating connexin hemichannel opening can prevent tissue damage arising from excessive and uncontrolled inflammation. We discuss connexin channel roles in microglia, astrocytes, and endothelial cells in both acute and chronic inflammatory conditions, and in particular describe the role of connexin hemichannels in the inflammasome pathway where they contribute to both its activation and its spread to neighboring cells. Finally, we describe the benefits of hemichannel block in animal models of brain injury. © 2016 Elsevier Inc. All rights reserved.

Cafestol Inhibits Cyclic-Strain-Induced Interleukin-8, Intercellular Adhesion Molecule-1, and Monocyte Chemoattractant Protein-1 Production in Vascular Endothelial Cells

PubMed Central

Hao, Wen-Rui; Sung, Li-Chin; Chen, Chun-Chao; Chen, Jin-Jer

2018-01-01

Moderate coffee consumption is inversely associated with cardiovascular disease mortality; however, mechanisms underlying this causal effect remain unclear. Cafestol, a diterpene found in coffee, has various properties, including an anti-inflammatory property. This study investigated the effect of cafestol on cyclic-strain-induced inflammatory molecule secretion in vascular endothelial cells. Cells were cultured under static or cyclic strain conditions, and the secretion of inflammatory molecules was determined using enzyme-linked immunosorbent assay. The effects of cafestol on mitogen-activated protein kinases (MAPK), heme oxygenase-1 (HO-1), and sirtuin 1 (Sirt1) signaling pathways were examined using Western blotting and specific inhibitors. Cafestol attenuated cyclic-strain-stimulated intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein- (MCP-) 1, and interleukin- (IL-) 8 secretion. Cafestol inhibited the cyclic-strain-induced phosphorylation of extracellular signal-regulated kinase and p38 MAPK. By contrast, cafestol upregulated cyclic-strain-induced HO-1 and Sirt1 expression. The addition of zinc protoporphyrin IX, sirtinol, or Sirt1 silencing (transfected with Sirt1 siRNA) significantly attenuated cafestol-mediated modulatory effects on cyclic-strain-stimulated ICAM-1, MCP-1, and IL-8 secretion. This is the first study to report that cafestol inhibited cyclic-strain-induced inflammatory molecule secretion, possibly through the activation of HO-1 and Sirt1 in endothelial cells. The results provide valuable insights into molecular pathways that may contribute to the effects of cafestol. PMID:29854096

Beneficial Effects of Galectin-3 Blockade in Vascular and Aortic Valve Alterations in an Experimental Pressure Overload Model

PubMed Central

Ibarrola, Jaime; Martínez-Martínez, Ernesto; Sádaba, J. Rafael; Arrieta, Vanessa; García-Peña, Amaia; Álvarez, Virginia; Fernández-Celis, Amaya; Gainza, Alicia; Rossignol, Patrick; Cachofeiro Ramos, Victoria; López-Andrés, Natalia

2017-01-01

Galectin-3 (Gal-3) is involved in cardiovascular fibrosis and aortic valve (AV) calcification. We hypothesized that Gal-3 pharmacological inhibition with modified citrus pectin (MCP) could reduce aortic and AV remodeling in normotensive rats with pressure overload (PO). Six weeks after aortic constriction, vascular Gal-3 expression was up-regulated in male Wistar rats. Gal-3 overexpression was accompanied by an increase in the aortic media layer thickness, enhanced total collagen, and augmented expression of fibrotic mediators. Further, vascular inflammatory markers as well as inflammatory cells content were greater in aorta from PO rats. MCP treatment (100 mg/kg/day) prevented the increase in Gal-3, media thickness, fibrosis, and inflammation in the aorta of PO rats. Gal-3 levels were higher in AVs from PO rats. This paralleled enhanced AV fibrosis, inflammation, as well as greater expression of calcification markers. MCP treatment prevented the increase in Gal-3 as well as fibrosis, inflammation, and calcification in AVs. Overall, Gal-3 is overexpressed in aorta and AVs from PO rats. Gal-3 pharmacological inhibition blocks aortic and AV remodeling in experimental PO. Gal-3 could be a new therapeutic approach to delay the progression and the development of aortic remodeling and AV calcification in PO. PMID:28758988

Asthma causes inflammation of human pulmonary arteries and decreases vasodilatation induced by prostaglandin I2 analogs.

PubMed

Foudi, Nabil; Badi, Aouatef; Amrane, Mounira; Hodroj, Wassim

2017-12-01

Asthma is a chronic inflammatory disease associated with increased cardiovascular events. This study assesses the presence of inflammation and the vascular reactivity of pulmonary arteries in patients with acute asthma. Rings of human pulmonary arteries obtained from non-asthmatic and asthmatic patients were set up in organ bath for vascular tone monitoring. Reactivity was induced by vasoconstrictor and vasodilator agents. Protein expression of inflammatory markers was detected by western blot. Prostanoid releases and cyclic adenosine monophosphate (cAMP) levels were quantified using specific enzymatic kits. Protein expression of cluster of differentiation 68, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and cyclooxygenase-2 was significantly increased in arteries obtained from asthmatic patients. These effects were accompanied by an alteration of vasodilatation induced by iloprost and treprostinil, a decrease in cAMP levels and an increase in prostaglandin (PG) E 2 and PGI 2 synthesis. The use of forskolin (50 µmol/L) has restored the vasodilatation and cAMP release. No difference was observed between the two groups in reactivity induced by norepinephrine, angiotensin II, PGE 2 , KCl, sodium nitroprusside, and acetylcholine. Acute asthma causes inflammation of pulmonary arteries and decreases vasodilation induced by PGI 2 analogs through the impairment of cAMP pathway.

Baicalein attenuates vinorelbine-induced vascular endothelial cell injury and chemotherapeutic phlebitis in rabbits.

PubMed

Ge, Gang-Feng; Shi, Wei-Wen; Yu, Chen-Huan; Jin, Xiao-Yin; Zhang, Huan-Huan; Zhang, Wen-You; Wang, Lu-Chen; Yu, Bing

2017-03-01

Chemotherapy is one of the major strategies for cancer treatment. Several antineoplastic drugs including vinorelbine (VRB) are commonly intravenously infused and liable to cause serious phlebitis. The therapeutic drugs for preventing this complication are limited. In this study, the mechanism of baicalein (BCN) was investigated on VRB-induced phlebitis in vivo and vascular endothelial cell injury in vitro. Treatment with BCN obviously attenuated vascular endothelial cell loss, edema, inflammatory cell infiltration and blood clots, and reduced the serum levels of TNF-α, IL-1β, IL-6 and ICAM-1 in the rabbit model of phlebitis induced by intravenous injection of VRB compared with vehicle. Further tests in vitro demonstrated that BCN lessened VRB-induced endothelial cell apoptosis, decreased intracellular ROS levels, suppressed phosphorylation of p38 and eventually inhibited activation of NF-κB signaling pathway. And these effects could be reversed by p38 agonist P79350. These results suggested that BCN exerted the protective effects against VRB-induced endothelial disruption in the rabbit model of phlebitis via inhibition of intracellular ROS generation and inactivation of p38/NF-κB pathway, leading to the decreased production of pro-inflammatory cytokines. Thus, BCN could be used as a potential agent for the treatment of phlebitis. Copyright © 2017 Elsevier Inc. All rights reserved.

Interleukin-6 is associated with cognitive function: the Northern Manhattan Study

PubMed Central

Wright, C.B.; Sacco, R.L.; Rundek, T.R.; Delman, J.B.; Rabbani, L.E.; Elkind, M.S.V.

2006-01-01

Background and purpose Inflammation has been linked to cognitive decline and dementia but the mechanism is not clear and few studies have included Hispanic and black subjects that may be at increased risk of these disorders. Methods We performed a cross-sectional analysis of the association between inflammatory marker levels and cognition in the stroke-free population-based cohort of the Northern Manhattan Study. Mini Mental State Exam (MMSE) scores were the continuous outcome and we adjusted for sociodemographic and vascular risk factors as well as subclinical atherosclerosis. Results Of the inflammatory markers, only interleukin (IL)-6 levels were associated with the MMSE. In univariate analysis age, hypertension, diabetes, smoking, moderate alcohol use, total homocysteine, carotid intima media thickness, and body mass index were positively associated with IL-6 levels. Hispanics compared to whites, those with less than a high school education, hypertension, cardiac disease, and total homocysteine were associated with lower MMSE scores. In a multivariate linear regression model, IL-6 was negatively associated with MMSE score adjusting for sociodemographic and vascular risk factors. Conclusions IL-6 levels were negatively associated with performance on the MMSE in this multiethnic cohort. Adjusting for vascular disease and subclinical atherosclerosis did not attenuate the association, suggesting a direct effect on the brain. PMID:16501663

Inflammatory Process Modulation by Homeopathic Arnica montana 6CH: The Role of Individual Variation

PubMed Central

Kawakami, Ana Paula; Sato, Cesar; Cardoso, Thayna Neves; Bonamin, Leoni Villano

2011-01-01

The effects of Arnica montana 6cH on the individual modulation of acute inflammation kinetics in rats were evaluated. Adult male Wistar rats were inoculated with 1% carrageenan into the footpad and treated with Arnica montana 6cH, dexamethasone (4.0 mg/kg; positive control) or 5% hydroalcoholic solution (negative control), per os, each 15 minutes, between 30 and 180 minutes after the irritant inoculation. Histopathological and immunohistochemistry procedures were done in order to get a panel of inflammatory positive cells for CD3 (T lymphocytes), CD45RA (B lymphocytes), CD18 (beta 2 integrin), CD163 (ED2 protein), CD54 (ICAM-1), and MAC 387 (monocytes and macrophages). The statistical treatment of data included a posteriori classification of animals from each group (N = 20) in two subgroups presenting spontaneous precocious or late oedema. Animals that presented precocious oedema were less responsible to Arnica montana 6cH in relation to hemodynamic changes. Instead, rats that exhibited late oedema presented less intense oedema (P = .01), lower percentage of mast cell degranulation (P = .0001), and increase in lymphatic vessels diameter (P = .05). The data suggest an individually qualitative adjustment of inflammatory vascular events by Arnica montana 6cH. PMID:21318109

In vitro Flow Adhesion Assay for Analyzing Shear-resistant Adhesion of Metastatic Cancer Cells to Endothelial Cells.

PubMed

Kang, Shin-Ae; Bajana, Sandra; Tanaka, Takemi

2016-02-20

Hematogenous metastasis is a primary cause of mortality from metastatic cancer. The shear-resistant adhesion of circulating tumor cells to the vascular endothelial cell surface under blood flow is an essential step in cell extravasation and further tissue invasion. This is similar to a process exploited by leukocytes for adhesion to inflamed blood vessels (leukocyte mimicry). The shear resistant adhesion is mediated by high affinity interactions between endothelial adhesion molecules and their counter receptor ligand expressed on circulating cells. Thus, weak interaction results in a rapid detachment of circulating cells from endothelium. Despite the critical role of vascular adhesion of cancer cells in hematogenous metastasis, our knowledge regarding this process has been limited due to the difficulty of mimicking dynamic flow conditions in vitro . In order to gain better insight into the shear-resistant adhesion of cancer cells to the endothelium, we developed a protocol for measuring the shear resistant adhesion of circulating tumor cells to endothelial cells under physiologic flow conditions by adapting a well established flow adhesion assay for inflammatory cells. This technique is useful to evaluate 1) the shear resistant adhesion competency of cancer cells and 2) the endothelial adhesion molecules necessary to support cancer cell adhesion (Kang et al. , 2015).

Adrenomedullin, a Novel Target for Neurodegenerative Diseases.

PubMed

Ferrero, Hilda; Larrayoz, Ignacio M; Gil-Bea, Francisco J; Martínez, Alfredo; Ramírez, María J

2018-03-29

Neurodegenerative diseases represent a heterogeneous group of disorders whose common characteristic is the progressive degeneration of neuronal structure and function. Although much knowledge has been accumulated on the pathophysiology of neurodegenerative diseases over the years, more efforts are needed to understand the processes that underlie these diseases and hence to propose new treatments. Adrenomedullin (AM) is a multifunctional peptide involved in vasodilation, hormone secretion, antimicrobial defense, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins that interfere with microtubule dynamics. Furthermore, AM may intervene in neuronal dysfunction through other mechanisms such as immune and inflammatory response, apoptosis, or calcium dyshomeostasis. Alterations in AM expression have been described in neurodegenerative processes such as Alzheimer's disease or vascular dementia. This review addresses the current state of knowledge on AM and its possible implication in neurodegenerative diseases.

Endocannabinoid receptor blockade increases vascular endothelial growth factor and inflammatory markers in obese women with polycystic ovary syndrome.

PubMed

Sathyapalan, Thozhukat; Javed, Zeeshan; Kilpatrick, Eric S; Coady, Anne-Marie; Atkin, Stephen L

2017-03-01

Animal studies suggest that cannabinoid receptor-1 (CB-1) blockade reduces inflammation and neovascularization by decreasing vascular endothelial growth factor (VEGF) levels associated with a reduction in inflammatory markers, thereby potentially reducing cardiovascular risk. To determine the impact of CB1 antagonism by rimonabant on VEGF and inflammatory markers in obese PCOS women. Randomized, open-labelled parallel study. Endocrinology outpatient clinic in a referral centre. Twenty patients with PCOS (PCOS) and biochemical hyperandrogenaemia with a body mass index of ≥30 kg/m 2 were recruited. Patients were randomized to 1·5 g daily of metformin or 20 mg daily of rimonabant. Post hoc review to detect VEGF and pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 before and after 12 weeks of treatment. After 12 weeks of rimonabant treatment, there was a significant increase in VEGF (99·2 ± 17·6 vs 116·2 ± 15·8 pg/ml, P < 0·01) and IL-8 (7·4 ± 11·0 vs 18·1 ± 13·2 pg/ml, P < 0·05) but not after metformin (VEGF P = 0·7; IL-8 P = 0·9). There was no significant difference in the pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 following either treatment. This study suggests that rimonabant CB-I blockade paradoxically raised VEGF and the cytokine IL-8 in obese women with PCOS that may have offset the potential benefit associated with weight loss. © 2016 John Wiley & Sons Ltd.

Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations

PubMed Central

Csiszar, Anna; Labinskyy, Nazar; Podlutsky, Andrej; Kaminski, Pawel M.; Wolin, Michael S.; Zhang, Cuihua; Mukhopadhyay, Partha; Pacher, Pal; Hu, Furong; de Cabo, Rafael; Ballabh, Praveen; Ungvari, Zoltan

2008-01-01

The dietary polyphenolic compound resveratrol, by activating the protein deacetylase enzyme silent information regulator 2/sirtuin 1 (SIRT1), prolongs life span in evolutionarily distant organisms and may mimic the cytoprotective effects of dietary restriction. The present study was designed to elucidate the effects of resveratrol on cigarette smoke-induced vascular oxidative stress and inflammation, which is a clinically highly relevant model of accelerated vascular aging. Cigarette smoke exposure of rats impaired the acetylcholine-induced relaxation of carotid arteries, which could be prevented by resveratrol treatment. Smoking and in vitro treatment with cigarette smoke extract (CSE) increased reactive oxygen species production in rat arteries and cultured coronary arterial endothelial cells (CAECs), respectively, which was attenuated by resveratrol treatment. The smoking-induced upregulation of inflammatory markers (ICAM-1, inducible nitric oxide synthase, IL-6, and TNF-α) in rat arteries was also abrogated by resveratrol treatment. Resveratrol also inhibited CSE-induced NF-κB activation and inflammatory gene expression in CAECs. In CAECs, the aforementioned protective effects of resveratrol were abolished by knockdown of SIRT1, whereas the overexpression of SIRT1 mimicked the effects of resveratrol. Resveratrol treatment of rats protected aortic endothelial cells against cigarette smoking-induced apoptotic cell death. Resveratrol also exerted antiapoptotic effects in CSE-treated CAECs, which could be abrogated by knockdown of SIRT1. Resveratrol treatment also attenuated CSE-induced DNA damage in CAECs (comet assay). Thus resveratrol and SIRT1 exert antioxidant, anti-inflammatory, and antiapoptotic effects, which protect the endothelial cells against the adverse effects of cigarette smoking-induced oxidative stress. The vasoprotective effects of resveratrol will likely contribute to its anti-aging action in mammals and may be especially beneficial in patho-physiological conditions associated with accelerated vascular aging. PMID:18424637

Orf virus interleukin-10 and vascular endothelial growth factor-E modulate gene expression in cultured equine dermal fibroblasts.

PubMed

Wise, Lyn M; Bodaan, Christa J; Mercer, Andrew A; Riley, Christopher B; Theoret, Christine L

2016-10-01

Wounds in horses often exhibit sustained inflammation and inefficient vascularization, leading to excessive fibrosis and clinical complications such as "proud flesh". Orf virus-derived proteins, vascular endothelial growth factor (VEGF)-E and interleukin (ovIL)-10, enhance angiogenesis and control inflammation and fibrosis in skin wounds of laboratory animals. The study aimed to determine if equine dermal cells respond to VEGF-E and ovIL-10. Equine dermal cells are expected to express VEGF and IL-10 receptors, so viral protein treatment is likely to alter cellular gene expression and behaviour in a manner conducive to healing. Skin samples were harvested from the lateral thoracic wall of two healthy thoroughbred horses. Equine dermal cells were isolated using a skin explant method and their phenotype assessed by immunofluorescence. Cells were treated with recombinant proteins, with or without inflammatory stimuli. Gene expression was examined using standard and quantitative reverse transcriptase PCR. Cell behaviour was evaluated in a scratch assay. Cultured cells were half vimentin(+ve) fibroblasts and half alpha smooth muscle actin(+ve) and vimentin(+ve) myofibroblasts. VEGF-E increased basal expression of IL-10 mRNA, whereas VEGF-A and collagenase-1 mRNA expression was increased by ovIL-10. In cells exposed to inflammatory stimulus, both treatments dampened tumour necrosis factor mRNA expression, and ovIL-10 exacerbated expression of monocyte chemoattractant protein. Neither viral protein influenced cell migration greatly. This study shows that VEGF-E and ovIL-10 are active on equine dermal cells and exert anti-inflammatory and anti-fibrotic effects that may enhance skin wound healing in horses. © 2016 ESVD and ACVD.

Pregnancy outcome and placental findings in pregnancies complicated by fetal growth restriction with and without preeclampsia.

PubMed

Kovo, Michal; Schreiber, Letizia; Elyashiv, Osnat; Ben-Haroush, Avi; Abraham, Golan; Bar, Jacob

2015-03-01

To compare pregnancy outcome and placental pathology in pregnancies complicated by fetal growth restriction (FGR) with and without preeclampsia. Labor, fetal/neonatal outcome, and placental pathology parameters from neonates with a birth weight below the 10 th percentile (FGR), born between 24 and 42 weeks of gestation, were reviewed. Results were compared between pregnancies complicated with preeclampsia (hypertensive FGR [H-FGR]) to those without preeclampsia (normotensive FGR [N-FGR]). Composite neonatal outcome, defined as 1 or more of early complication (respiratory distress, necrotizing enterocolitis, sepsis, transfusion, ventilation, seizure, hypoxic-ischemic encephalopathy, phototherapy, or death), Apgar score ≤ 7 at 5 minutes, and days of hospitalization, were compared between the groups. Placental lesions, classified as lesions related to maternal vascular supply, lesions consistent with fetal thrombo-occlusive disease and inflammatory lesions, maternal inflammatory response, and fetal inflammatory response, were also compared. Women in the H-FGR group (n = 72) were older, with higher body mass index (BMI) and higher rate of preterm labor (<34 weeks) than in the N-FGR group (n = 270), P < .001 for all. Composite neonatal outcome was worse in the H-FGR than in the N-FGR group, 50% versus 15.5%, P < .001. Higher rate of maternal placental vascular lesions was detected in H-FGR compared with N-FGR, 82% versus 57.7%, P < .001. Using a stepwise logistic regression model, maternal BMI (1.13 odds ratio [OR], confidence interval [CI] 1.035-1.227, P = .006) and neonatal birth weight (0.996 OR, CI 0.995-0.998, P < .001) were independently associated with worse neonatal outcome. Worse neonatal outcome and more maternal placental vascular lesions in pregnancy complicated by FGR with preeclampsia versus FGR without preeclampsia suggest different pathophysiology in these entities. © The Author(s) 2014.

Metalloproteinase 2 and 9 Activity Increase in Epicardial Adipose Tissue of Patients with Coronary Artery Disease.

PubMed

Miksztowicz, Verónica; Morales, Celina; Barchuk, Magalí; López, Graciela; Póveda, Ricardo; Gelpi, Ricardo; Schreier, Laura; Rubio, Miguel; Berg, Gabriela

2017-01-01

Epicardial adipose tissue (EAT) is a visceral adipose tissue (AT) surrounding and infiltrating myocardium and coronary arteries. Increased EAT may represent a chronic inflammatory injury and a link with coronary artery disease (CAD). Metalloproteinases (MMPs) are involved in expansion of AT. To evaluate MMP-2 and -9 behaviour in EAT from CAD patients. In EAT and subcutaneous AT (SAT) from patients undergoing coronary artery bypass graft (CABG, n=26) or valve replacement (No CABG, n=18), MMP-2 and -9 activity and localization, inflammatory cells and vascular endothelial growth factor (VEGF) levels were determined. In EAT from CABG, MMP-2 and -9 activity was increased compared with No CABG (p=0.041 and p=0.027, respectively) and compared with SAT (p=0.005 and p=0.048, respectively). In CABG patients EAT showed higher infiltration of macrophages and T lymphocytes than SAT (p=0.01 and p=0.002, respectively). In No CABG patients no sign of cellular retention was observed in EAT or SAT. Vascular density was higher in EAT from CABG than No CABG (p=0.015) and it was directly correlated with MMP-2 (p=0.006) and MMP-9 (p=0.02). VEGF levels in EAT were directly associated with MMP-2 (p=0.016). In EAT from CABG patients the increase of MMP-2 and -9 activity and the presence of inflammatory cells would be partially responsible for extracellular matrix (ECM) remodeling and major vascular density necessary for EAT expansion. Improved knowledge of EAT behaviour may allow to identify new therapeutic targets for the treatment of CAD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Exaggerated Acute Lung Injury and Impaired Antibacterial Defenses During Staphylococcus aureus Infection in Rats with the Metabolic Syndrome

PubMed Central

Feng, Xiaomei; Maze, Mervyn; Koch, Lauren G.; Britton, Steven L.; Hellman, Judith

2015-01-01

Rats with Metabolic Syndrome (MetaS) have a dysregulated immune response to the aseptic trauma of surgery. We hypothesized that rats with MetaS would have dysregulated inflammation, increased lung injury, and less effective antibacterial defenses during Staphylococcus (S.) aureus sepsis as compared to rats without MetaS. Low capacity runner (LCR; a model of MetaS) and high capacity runner (HCR) rats were challenged intravenously with S. aureus bacteria. After 48 h, inflammatory mediators and bacteria were quantified in the blood, bronchoalveolar lavage fluid (BALF), and lung homogenates. Lungs were analyzed histologically. BALF protein and lung wet-dry ratios were quantified to assess for vascular leak. Endpoints were compared in infected LCR vs HCR rats. LCR rats had higher blood and lung S. aureus counts, as well as higher levels of IL-6 in plasma, lungs and BALF, MIP-2 in plasma and lung, and IL-17A in lungs. Conversely, LCR rats had lower levels of IL-10 in plasma and lungs. Although lactate levels, and liver and renal function tests were similar between groups, LCR rats had higher BALF protein and lung wet-dry ratios, and more pronounced acute lung injury histologically. During S. aureus bacteremia, as compared with HCR rats, LCR (MetaS) rats have heightened pro-inflammatory responses, accompanied by increased acute lung injury and vascular leak. Notably, despite an augmented pro-inflammatory phenotype, LCR rats have higher bacterial levels in their blood and lungs. The MetaS state may exacerbate lung injury and vascular leak by attenuating the inflammation-resolving response, and by weakening antimicrobial defenses. PMID:25978669

Predicting the severity of systemic inflammatory response syndrome (SIRS)-associated coagulopathy with hemostatic molecular markers and vascular endothelial injury markers.

PubMed

Iba, Toshiaki; Gando, Satoshi; Murata, Atsuo; Kushimoto, Shigeki; Saitoh, Daizoh; Eguchi, Yutaka; Ohtomo, Yasuhiro; Okamoto, Kohji; Koseki, Kazuhide; Mayumi, Toshihiko; Ikeda, Toshiaki; Ishhikura, Hiroyasu; Ueyama, Masashi; Ogura, Yuji; Endo, Shigeatsu; Shimazaki, Shuji

2007-11-01

The changes in biomarkers of coagulation or fibrinolysis, anticoagulation, inflammation, and endothelial damage occur in patients with systemic inflammatory response syndrome (SIRS). The purpose of this study is to assess the prognostic value of these markers in patients with SIRS-associated hypercoagulopathy. Sixty-six SIRS patients with a platelet count less than 15.0 x 10(4)/mm3 in three university hospital intensive care units were enrolled in this prospective, comparative study. Blood samples were obtained on day 0 and day 2. Twelve hemostatic, inflammatory, and vascular endothelial indices were measured and the data were compared between the severe group (patients with a total maximum Sequential Organ Failure Assessment score of 10 or more and nonsurvivors; n = 25) and the less-severe group (Sequential Organ Failure Assessment score <10; n = 41). Significant changes between the groups were observed in platelet count, fibrin or fibrinogen degradation products, interleukin-6, soluble thrombomodulin, antithrombin (AT) activity, and protein C activity, both on day 0 and on day 2. In contrast, the d-dimer, soluble fibrin, plasmin-[alpha]2-antiplasmin complex, and E-selectin levels were higher in the severe group only on day 2. No significant difference was seen regarding the thrombin-AT complex and total plasminogen activator inhibitor on both days. A comparison of the areas under the receiver operating characteristic curve revealed the AT activity to be the best predictor of a progression of organ dysfunction. The changes in some hemostatic molecular markers and vascular endothelial markers were conspicuous in patients with organ dysfunction. The AT activity is considered to be the most useful predictor of organ dysfunction.

Arctigenin improves vascular tone and decreases inflammation in human saphenous vein.

PubMed

Daci, Armond; Neziri, Burim; Krasniqi, Shaip; Cavolli, Raif; Alaj, Rame; Norata, Giuseppe Danilo; Beretta, Giangiacomo

2017-09-05

The goal of this study was to test the effects of bioactive phenylpropanoid dibenzylbutyrolactone lignan arctigenin (ATG) in vascular tone. Human bypass graft vessel, from a saphenous vein (SV), were set up in organ bath system and contracted with potassium chloride (KCl, 40mM). Two concentration-response curves of noradrenaline (NE) (10nM-100μM) separated with an incubation period of 30min without (Control) or with ATG (3-100μM) were established. Inhibitors of nitric oxide, prostaglandins, K + related channels or calcium influx were used to delineate the molecular mechanisms beyond ATG effects. To investigate anti-inflammatory actions, SV were treated with 10μM or 100μM ATG and incubated for 18h in the absence or presence of both interleukin-1beta (IL-1β) and lipopolysaccharide (LPS) to mimic the physiological or inflamed tissue conditions. Proatherogenic and inflammatory mediators İnterleukine-1 beta (IL-1β), Monocyte Chemoattractant Proteine-1 (MCP-1), Tumor Necrosis Factor- α (TNF-α), İnterleukine-6 (IL-6), Prostaglandin E 2 (PGE 2 ) and İnterleukine-8 (IL-8) in the supernatant were measured. ATG significantly decreased vascular contractile response to NE. Moreover, it reduced contractions induced by KCl and cumulative addition of CaCl 2. The mediators were significantly increased in inflammatory conditions compared to normal conditions, an effect which was inhibited by ATG (10 and 100µM). ATG reduces contractions in SV and decreases the production of proinflammatory-proatherogenic mediators, setting the stage for further evaluating the effect of ATG in cardiovascular diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

Magnetic resonance imaging differential diagnosis of brainstem lesions in children

PubMed Central

Quattrocchi, Carlo Cosimo; Errante, Yuri; Rossi Espagnet, Maria Camilla; Galassi, Stefania; Della Sala, Sabino Walter; Bernardi, Bruno; Fariello, Giuseppe; Longo, Daniela

2016-01-01

Differential diagnosis of brainstem lesions, either isolated or in association with cerebellar and supra-tentorial lesions, can be challenging. Knowledge of the structural organization is crucial for the differential diagnosis and establishment of prognosis of pathologies with involvement of the brainstem. Familiarity with the location of the lesions in the brainstem is essential, especially in the pediatric population. Magnetic resonance imaging (MRI) is the most sensitive and specific imaging technique for diagnosing disorders of the posterior fossa and, particularly, the brainstem. High magnetic static field MRI allows detailed visualization of the morphology, signal intensity and metabolic content of the brainstem nuclei, together with visualization of the normal development and myelination. In this pictorial essay we review the brainstem pathology in pediatric patients and consider the MR imaging patterns that may help the radiologist to differentiate among vascular, toxico-metabolic, infective-inflammatory, degenerative and neoplastic processes. Helpful MR tips can guide the differential diagnosis: These include the location and morphology of lesions, the brainstem vascularization territories, gray and white matter distribution and tissue selective vulnerability. PMID:26834941

BLOOD VESSELS IN GANGLIA IN HUMAN ESOPHAGUS MIGHT EXPLAIN THE HIGHER FREQUENCY OF MEGAESOPHAGUS COMPARED WITH MEGACOLON

PubMed Central

Adad, Sheila Jorge; Etchebehere, Renata Margarida; Jammal, Alessandro Adad

2014-01-01

This study aimed to determine the existence of blood vessels within ganglia of the myenteric plexus of the human esophagus and colon. At necropsy, 15 stillborns, newborns and children up to two years of age, with no gastrointestinal disorders, were examined. Rings of the esophagus and colon were analyzed and then fixed in formalin and processed for paraffin. Histological sections were stained by hematoxylin-eosin, Giemsa and immunohistochemistry for the characterization of endothelial cells, using antibodies for anti-factor VIII and CD31. Blood vessels were identified within the ganglia of the myenteric plexus of the esophagus, and no blood vessels were found in any ganglia of the colon. It was concluded that the ganglia of the myenteric plexus of the esophagus are vascularized, while the ganglia of the colon are avascular. Vascularization within the esophageal ganglia could facilitate the entrance of infectious agents, as well as the development of inflammatory responses (ganglionitis) and denervation, as found in Chagas disease and idiopathic achalasia. This could explain the higher frequency of megaesophagus compared with megacolon. PMID:25351549

Sulforaphane enhances the activity of the Nrf2-ARE pathway and attenuates inflammation in OxyHb-induced rat vascular smooth muscle cells.

PubMed

Zhao, X-D; Zhou, Y-T; Lu, X-J

2013-09-01

A growing body of evidence indicates that the nuclear factor erythroid 2-related factor 2-antioxidant response element (Nrf2-ARE) pathway plays a protective role in many physiological stress processes such as inflammatory damage, oxidative stress, and the accumulation of toxic metabolites, which are all involved in the cerebral vasospasm following subarachnoid hemorrhage (SAH). We hypothesized that the Nrf2-ARE pathway might have a protective role in cerebral vasospasm following SAH. In our study, we investigate whether the oxyhemoglobin (OxyHb) can induce the activation of the Nrf2-ARE pathway in vascular smooth muscle cells (VSMCs), and evaluate the modulatory effects of sulforaphane (SUL) on OxyHb-induced inflammation in VSMCs. As a result, both the protein level and the mRNA level of the nuclear Nrf2 were significantly increased, while the mRNA levels of two Nrf2-regulated gene products, both heme oxygenase-1 and NAD(P)H: quinone oxidoreductase-1, were also up-regulated in VSMCs induced with OxyHb. A marked increase of inflammatory cytokines such as IL-1β, IL-6 and TNF-α release was observed at 48 h after cells were treated with OxyHb. SUL enhanced the activity of the Nrf2-ARE pathway and suppressed cytokine release. Our results indicate that the Nrf2-ARE pathway was activated in OxyHb-induced VSMCs. SUL suppressed cytokine release via the activation of the Nrf2-ARE pathway in OxyHb-induced VSMCs.

Role of the Retinal Vascular Endothelial Cell in Ocular Disease

PubMed Central

Bharadwaj, Arpita S.; Appukuttan, Binoy; Wilmarth, Phillip A.; Pan, Yuzhen; Stempel, Andrew J.; Chipps, Timothy J.; Benedetti, Eric E.; Zamora, David O.; Choi, Dongseok; David, Larry L.; Smith, Justine R.

2012-01-01

Retinal endothelial cells line the arborizing microvasculature that supplies and drains the neural retina. The anatomical and physiological characteristics of these endothelial cells are consistent with nutritional requirements and protection of a tissue critical to vision. On the one hand, the endothelium must ensure the supply of oxygen and other nutrients to the metabolically active retina, and allow access to circulating cells that maintain the vasculature or survey the retina for the presence of potential pathogens. On the other hand, the endothelium contributes to the blood-retinal barrier that protects the retina by excluding circulating molecular toxins, microorganisms, and pro-inflammatory leukocytes. Features required to fulfill these functions may also predispose to disease processes, such as retinal vascular leakage and neovascularization, and trafficking of microbes and inflammatory cells. Thus, the retinal endothelial cell is a key participant in retinal ischemic vasculopathies that include diabetic retinopathy and retinopathy of prematurity, and retinal inflammation or infection, as occurs in posterior uveitis. Using gene expression and proteomic profiling, it has been possible to explore the molecular phenotype of the human retinal endothelial cell and contribute to understanding of the pathogenesis of these diseases. In addition to providing support for the involvement of well-characterized endothelial molecules, profiling has the power to identify new players in retinal pathologies. Findings may have implications for the design of new biological therapies. Additional progress in this field is anticipated as other technologies, including epigenetic profiling methods, whole transcriptome shotgun sequencing, and metabolomics, are used to study the human retinal endothelial cell. PMID:22982179

Canines as sentinel species for assessing chronic exposures to air pollutants: part 1. Respiratory pathology.

PubMed

Calderón-Garcidueñas, L; Mora-Tiscareño, A; Fordham, L A; Chung, C J; García, R; Osnaya, N; Hernández, J; Acuña, H; Gambling, T M; Villarreal-Calderón, A; Carson, J; Koren, H S; Devlin, R B

2001-06-01

A complex mixture of air pollutants is present in the ambient air in urban areas. People, animals, and vegetation are chronically and sequentially exposed to outdoor pollutants. The objective of this first of 2 studies is to evaluate by light and electron microscopy the lungs of Mexico City dogs and compare the results to those of 3 less polluted cities in MEXICO: One hundred fifty-two clinically healthy stray mongrel dogs (91 males/61 females), including 43 dogs from 3 less polluted cities, and 109 from southwest and northeast metropolitian Mexico City (SWMMC, NEMMC) were studied. Lungs of dogs living in Mexico City and Cuernavaca exhibited patchy chronic mononuclear cell infiltrates along with macrophages loaded with particulate matter (PM) surrounding the bronchiolar walls and extending into adjacent vascular structures; bronchiolar epithelial and smooth muscle hyperplasia, peribronchiolar fibrosis, microthrombi, and capillary and venule polymorphonuclear leukocytes (PMN) margination. Ultrafine PM was seen in alveolar type I and II cells, endothelial cells, interstitial macrophages (Mtheta), and intravascular Mtheta-like cells. Bronchoalveolar lavage showed significant numbers of alveolar macrophages undergoing proliferation. Exposure to complex mixtures of pollutants-predominantly particulate matter and ozone-is causing lung structural changes induced by the sustained inflammatory process and resulting in airway and vascular remodeling and altered repair. Cytokines released from both, circulating inflammatory and resident lung cells in response to endothelial and epithelial injury may be playing a role in the pathology described here. Deep concern exists for the potential of an increasing rise in lung diseases in child populations exposed to Mexico City's environment.

[From acute pulmonary embolism to chronic thromboembolic pulmonary hypertension: Pathobiology and pathophysiology].

PubMed

Beltrán-Gámez, Miguel E; Sandoval-Zárate, Julio; Pulido, Tomás

Chronic thromboembolic pulmonary hypertension (CTEPH) represents a unique subtype of pulmonary hypertension characterized by the presence of mechanical obstruction of the major pulmonary vessels caused by venous thromboembolism. CTEPH is a progressive and devastating disease if not treated, and is the only subset of PH potentially curable by a surgical procedure known as pulmonary endarterectomy. The clot burden and pulmonary embolism recurrence may contribute to the development of CTEPH however only few thrombophilic factors have been found to be associated. A current hypothesis is that CTEPH results from the incomplete resolution and organization of thrombus modified by inflammatory, immunologic and genetic mechanisms, leading to the development of fibrotic stenosis and adaptive vascular remodeling of resistance vessels. The causes of thrombus non-resolution have yet to be fully clarified. CTEPH patients often display severe PH that cannot be fully explained by the degree of pulmonary vascular obstruction apparent on imaging studies. In such cases, the small vessel disease and distal obstructive thrombotic lesions beyond the sub-segmental level may contribute for out of proportion elevated PVR. The processes implicated in the development of arteriopathy and micro-vascular changes might explain the progressive nature of PH and gradual clinical deterioration with poor prognosis, as well as lack of correlation between measurable hemodynamic parameters and vascular obstruction even in the absence of recurrent venous thromboembolism. This review summarizes the most relevant up-to-date aspects on pathobiology and pathophysiology of CTEPH. Copyright © 2016 Instituto Nacional de Cardiología Ignacio Chávez. Publicado por Masson Doyma México S.A. All rights reserved.

Targeting inflammation in diabetes: Newer therapeutic options

PubMed Central

Agrawal, Neeraj Kumar; Kant, Saket

2014-01-01

Inflammation has been recognised to both decrease beta cell insulin secretion and increase insulin resistance. Circulating cytokines can affect beta cell function directly leading to secretory dysfunction and increased apoptosis. These cytokines can also indirectly affect beta cell function by increasing adipocyte inflammation.The resulting glucotoxicity and lipotoxicity further enhance the inflammatory process resulting in a vicious cycle. Weight reduction and drugs such as metformin have been shown to decrease the levels of C-Reactive Protein by 31% and 13%, respectively. Pioglitazone, insulin and statins have anti-inflammatory effects. Interleukin 1 and tumor necrosis factor-α antagonists are in trials and NSAIDs such as salsalate have shown an improvement in insulin sensitivity. Inhibition of 12-lipo-oxygenase, histone de-acetylases, and activation of sirtuin-1 are upcoming molecular targets to reduce inflammation. These therapies have also been shown to decrease the conversion of pre-diabetes state to diabetes. Drugs like glicazide, troglitazone, N-acetylcysteine and selective COX-2 inhibitors have shown benefit in diabetic neuropathy by decreasing inflammatory markers. Retinopathy drugs are used to target vascular endothelial growth factor, angiopoietin-2, various proteinases and chemokines. Drugs targeting the proteinases and various chemokines are pentoxifylline, inhibitors of nuclear factor-kappa B and mammalian target of rapamycin and are in clinical trials for diabetic nephropathy. Commonly used drugs such as insulin, metformin, peroxisome proliferator-activated receptors, glucagon like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors also decrease inflammation. Anti-inflammatory therapies represent a potential approach for the therapy of diabetes and its complications. PMID:25317247

ROS-activated calcium signaling mechanisms regulating endothelial barrier function.

PubMed

Di, Anke; Mehta, Dolly; Malik, Asrar B

2016-09-01

Increased vascular permeability is a common pathogenic feature in many inflammatory diseases. For example in acute lung injury (ALI) and its most severe form, the acute respiratory distress syndrome (ARDS), lung microvessel endothelia lose their junctional integrity resulting in leakiness of the endothelial barrier and accumulation of protein rich edema. Increased reactive oxygen species (ROS) generated by neutrophils (PMNs) and other inflammatory cells play an important role in increasing endothelial permeability. In essence, multiple inflammatory syndromes are caused by dysfunction and compromise of the barrier properties of the endothelium as a consequence of unregulated acute inflammatory response. This review focuses on the role of ROS signaling in controlling endothelial permeability with particular focus on ALI. We summarize below recent progress in defining signaling events leading to increased endothelial permeability and ALI. Copyright © 2016 Elsevier Ltd. All rights reserved.

Green tea polyphenols avert chronic inflammation-induced myocardial fibrosis of female rats

USDA-ARS?s Scientific Manuscript database

Objective: Green tea proposes anti-inflammatory properties which may attenuate chronic inflammation-induced fibrosis of vessels. This study evaluated whether green tea polyphenols (GTP) can avert fibrosis or vascular disruption along with mechanisms in rats with chronic inflammation. Treatments: Fo...

Macrophage Metalloelastase (MMP-12) Deficiency Mitigates Retinal Inflammation and Pathological Angiogenesis in Ischemic Retinopathy

PubMed Central

Li, Jingming; Wang, Joshua J.; Peng, Qisheng; Chen, Chen; Humphrey, Mary Beth; Heinecke, Jay; Zhang, Sarah X.

2012-01-01

Pathological angiogenesis is a major cause of vision loss in ischemic and inflammatory retinal diseases. Recent evidence implicates macrophage metalloelastase (MMP-12), a macrophage-derived elastinolytic protease in inflammation, tissue remodeling and angiogenesis. However, little is known about the role of MMP-12 in retinal pathophysiology. The present study aims to explore the enzyme’s contributions to retinal angiogenesis in oxygen-induced retinopathy (OIR) using MMP-12 knockout (KO) mice. We find that MMP-12 expression was upregulated in OIR, accompanied by elevated macrophage infiltration and increased inflammatory markers. Compared to wildtype mice, MMP-12 KO mice had decreased levels of adhesion molecule and inflammatory cytokines and reduced vascular leakage in OIR. Concomitantly, these mice had markedly reduced macrophage content in the retina with impaired macrophage migratory capacity. Significantly, loss of MMP-12 attenuated retinal capillary dropout in early OIR and mitigated pathological retinal neovascularization (NV). Similar results were observed in the study using MMP408, a pharmacological inhibitor of MMP-12. Intriguingly, in contrast to reducing pathological angiogenesis, lack of MMP-12 accelerated revascularization of avascular retina in OIR. Taken together, we conclude that MMP-12 is a key regulator of macrophage infiltration and inflammation, contributing to retinal vascular dysfunction and pathological angiogenesis. PMID:23285156

Pharmacological modulation of endothelial cell-associated adhesion molecule expression: implications for future treatment of dermatological diseases.

PubMed

Foster, C A; Dreyfuss, M; Mandak, B; Meingassner, J G; Naegeli, H U; Nussbaumer, A; Oberer, L; Scheel, G; Swoboda, E M

1994-11-01

Skin diseases with an inflammatory component, regardless of their etiology, are characterized at some point by the extravasation and subsequent infiltration of leukocytes into the dermal and/or epidermal compartments. This trafficking pattern is determined by a complex series of events whereby the leukocytes interact with cell adhesion molecules (CAM), particularly those induced on endothelial cells following activation with various inflammatory mediators. Vascular CAMs belonging to the selectin family (i.e., P-selectin and E-selectin) are thought to mediate early and reversible events involving leukocyte rolling and margination along the lumenal surface of microvascular cells (post-capillary venules). Certain members of the immunoglobulin supergene family (i.e., VCAM-1 and ICAM-1) regulate later and irreversible steps which lead to firm attachment and subsequent diapedesis of leukocytes. Accumulating evidence suggests that if one blocks the ligand-binding sites between leukocytes and endothelial cells, or inhibits vascular CAM expression, hematopoietic cell extravasation and progressive inflammatory events can be greatly diminished. To identify such inhibitors we developed a cell-based Elisa using the human microvascular cell line HMEC-1. As reported in the present paper, this approach yielded a naturally-occurring, low molecular weight compound which potently inhibits cytokine-induced adhesion molecule expression on cultured endothelial cells, without modulating "house-keeping" proteins.

Neurogenic vasodilatation and plasma leakage in the skin.

PubMed

Holzer, P

1998-01-01

1. Primary afferent nerve fibers control cutaneous blood flow and vascular permeability by releasing vasoactive peptides. These vascular reactions and the additional recruitment of leukocytes are commonly embodied in the term neurogenic inflammation. 2. Calcitonin gene-related peptide (CGRP) acting via CGRP1 receptors is the principal transmitter of neurogenic dilatation of arterioles whereas substance P (SP) and neurokinin A (NKA) acting via NK1 receptors mediate the increase in venular permeability. 3. Neurogenic vasodilatation and plasma protein leakage play a role in inflammation because many inflammatory and immune mediators including interleukin-1 beta, nitric oxide, prostanoids, protons, bradykinin, histamine, and 5-hydroxytryptamine can stimulate peptidergic afferent nerve fibers or enhance their excitability. 4. Neurogenic inflammatory reactions can be suppressed by alpha 2-adrenoceptor agonists, histamine acting via H1 receptors, 5-hydroxytryptamine acting via 5-HT1B receptors, opioid peptides, and somatostatin through prejunctional inhibition of peptide release from vasoactive afferent nerve fibers. CGRP, SP, and NKA receptor antagonists are powerful pharmacological tools to inhibit neurogenic inflammation at the postjunctional level. 5. Imbalance between the facilitatory and inhibitory influences on afferent nerve activity has a bearing on chronic inflammatory disease. Impaired nerve function represents a deficit in skin homeostasis while neuronal overactivity is a factor in allergic and hyperreactive disorders of the skin.

Cerebral Autoregulation in Hypertension and Ischemic Stroke: A Mini Review

PubMed Central

Shekhar, Shashank; Liu, Ruen; Travis, Olivia K; Roman, Richard J; Fan, Fan

2017-01-01

Aging and chronic hypertension are associated with dysfunction in vascular smooth muscle, endothelial cells, and neurovascular coupling. These dysfunctions induce impaired myogenic response and cerebral autoregulation, which diminish the protection of cerebral arterioles to the cerebral microcirculation from elevated pressure in hypertension. Chronic hypertension promotes cerebral focal ischemia in response to reductions in blood pressure that are often seen in sedentary elderly patients on antihypertensive therapy. Cerebral autoregulatory dysfunction evokes Blood-Brain Barrier (BBB) leakage, allowing the circulating inflammatory factors to infiltrate the brain to activate glia. The impaired cerebral autoregulation-induced inflammatory and ischemic injury could cause neuronal cell death and synaptic dysfunction which promote cognitive deficits. In this brief review, we summarize the pathogenesis and signaling mechanisms of cerebral autoregulation in hypertension and ischemic stroke-induced cognitive deficits, and discuss our new targets including 20-Hydroxyeicosatetraenoic acid (20-HETE), Gamma-Adducin (Add3) and Matrix Metalloproteinase-9 (MMP-9) that may contribute to the altered cerebral vascular function. PMID:29333537

Uric Acid, Hyperuricemia and Vascular Diseases

PubMed Central

Jin, Ming; Yang, Fan; Yang, Irene; Yin, Ying; Luo, Jin Jun; Wang, Hong; Yang, Xiao-Feng

2011-01-01

Uric acid is the product of purine metabolism. It is known that hyperuricemia, defined as high levels of blood uric acid, is the major etiological factor of gout. A number of epidemiological reports have increasingly linked hyperuricemia with cardiovascular and neurological diseases. Studies highlighting the pathogenic mechanisms of uric acid point to an inflammatory response as the primary mechanism for inducing gout and possibly contributing to uric acid's vascular effects. Monosodium urate (MSU) crystals induce an inflammatory reaction, which are recognized by Toll-like receptors (TLRs). These TLRs then activate NALP3 inflammasome. MSU also triggers neutrophil activation and further produces immune mediators, which lead to a proinflammatory response. In addition, soluble uric acid can also mediate the generation of free radicals and function as a pro-oxidant. This review summarizes the epidemiological studies of hyperuricemia and cardiovascular disease, takes a brief look at hyperuricemia and its role in neurological diseases, and highlights the studies of the advanced pathological mechanisms of uric acid and inflammation. PMID:22201767

Impact of Sex Hormone Metabolism on the Vascular Effects of Menopausal Hormone Therapy in Cardiovascular Disease

PubMed Central

Masood, Durr-e-Nayab; Roach, Emir C.; Beauregard, Katie G.; Khalil, Raouf A.

2010-01-01

Epidemiological studies have shown that cardiovascular disease (CVD) is less common in pre-menopausal women (Pre-MW) compared to men of the same age or post-menopausal women (Post-MW), suggesting cardiovascular benefits of estrogen. Estrogen receptors (ERs) have been identified in the vasculature, and experimental studies have demonstrated vasodilator effects of estrogen/ER on the endothelium, vascular smooth muscle (VSM) and extracellular matrix. Several natural and synthetic estrogenic preparations have been developed for relief of menopausal vasomotor symptoms. However, whether menopausal hormone therapy (MHT) is beneficial in postmenopausal CVD remains controversial. Despite reports of vascular benefits of MHT from observational and experimental studies, randomized clinical trials (RCTs), such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women’s Health Initiative (WHI), have suggested that, contrary to expectations, MHT may increase the risk of CVD. These discrepancies could be due to age-related changes in sex hormone synthesis and metabolism, which would influence the effective dose of MHT and the sex hormone environment in Post-MW. Age-related changes in the vascular ER subtype, structure, expression, distribution, and post-ER signaling pathways in the endothelium and VSM, along with factors related to the design of RCTs, preexisting CVD condition, and structural changes in the blood vessels architecture have also been suggested as possible causes of MHT failure in CVD. Careful examination of these factors should help in identifying the causes of the changes in the vascular effects of estrogen with age. The sex hormone metabolic pathways, the active versus inactive estrogen metabolites, and their effects on vascular function, the mitochondria, the inflammatory process and angiogenesis should be further examined. Also, the genomic and non-genomic effects of estrogenic compounds should be viewed as integrated rather than discrete responses. The complex interactions between these factors highlight the importance of careful design of MHT RCTs, and the need of a more customized approach for each individual patient in order to enhance the vascular benefits of MHT in postmenopausal CVD. PMID:21189141

The Role of Macrophage Phenotype in Vascularization of Tissue Engineering Scaffolds

PubMed Central

Spiller, Kara L.; Anfang, Rachel; Spiller, Krista J.; Ng, Johnathan; Nakazawa, Kenneth R.; Daulton, Jeffrey W.; Vunjak-Novakovic, Gordana

2014-01-01

Angiogenesis is crucial for the success of most tissue engineering strategies. The natural inflammatory response is a major regulator of vascularization, through the activity of different types of macrophages and the cytokines they secrete. Macrophages exist on a spectrum of diverse phenotypes, from “classically activated” M1 to “alternatively activated” M2 macrophages. M2 macrophages, including the subsets M2a and M2c, are typically considered to promote angiogenesis and tissue regeneration, while M1 macrophages are considered to be anti-angiogenic, although these classifications are controversial. Here we show that in contrast to this traditional paradigm, primary human M1 macrophages secrete the highest levels of potent angiogenic stimulators including VEGF; M2a macrophages secrete the highest levels of PDGF-BB, a chemoattractant stabilizing pericytes, and also promote anastomosis of sprouting endothelial cells in vitro; and M2c macrophages secrete the highest levels of MMP9, an important protease involved in vascular remodeling. In a murine subcutaneous implantation model, porous collagen scaffolds were surrounded by a fibrous capsule, coincident with high expression of M2 macrophage markers, while scaffolds coated with the bacterial lipopolysaccharide were degraded by inflammatory macrophages, and glutaraldehyde-crosslinked scaffolds were infiltrated by substantial numbers of blood vessels accompanied by high levels of M1 and M2 macrophages. These results suggest that coordinated efforts by both M1 and M2 macrophages are required for angiogenesis and scaffold vascularization, which may explain some of the controversy over which phenotype is the angiogenic phenotype. PMID:24589361

Baicalein attenuates vinorelbine-induced vascular endothelial cell injury and chemotherapeutic phlebitis in rabbits

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ge, Gang-Feng

Chemotherapy is one of the major strategies for cancer treatment. Several antineoplastic drugs including vinorelbine (VRB) are commonly intravenously infused and liable to cause serious phlebitis. The therapeutic drugs for preventing this complication are limited. In this study, the mechanism of baicalein (BCN) was investigated on VRB-induced phlebitis in vivo and vascular endothelial cell injury in vitro. Treatment with BCN obviously attenuated vascular endothelial cell loss, edema, inflammatory cell infiltration and blood clots, and reduced the serum levels of TNF-α, IL-1β, IL-6 and ICAM-1 in the rabbit model of phlebitis induced by intravenous injection of VRB compared with vehicle. Furthermore » tests in vitro demonstrated that BCN lessened VRB-induced endothelial cell apoptosis, decreased intracellular ROS levels, suppressed phosphorylation of p38 and eventually inhibited activation of NF-κB signaling pathway. And these effects could be reversed by p38 agonist P79350. These results suggested that BCN exerted the protective effects against VRB-induced endothelial disruption in the rabbit model of phlebitis via inhibition of intracellular ROS generation and inactivation of p38/NF-κB pathway, leading to the decreased production of pro-inflammatory cytokines. Thus, BCN could be used as a potential agent for the treatment of phlebitis. - Highlights: • Baicalein attenuated vinorelbine-induced vascular endothelial cell apoptosis. • Baicalein inhibited vinorelbine-induced oxidative stress in HUVECs. • Baicalein inhibited activation of p38/NF-κB signaling. • Baicalein attenuated vinorelbine-induced phlebitis and inflammation in rabbits.« less

Effect of a prolonged endurance marathon on vascular endothelial and inflammation markers in runners with exercise-induced hypertension.

PubMed

Jee, Haemi; Park, Jaehyun; Oh, Jae-Gun; Lee, Yoon-Hee; Shin, Kyung-A; Kim, Young-Joo

2013-06-01

The aim of this study was to observe the changes in endothelial and inflammatory markers in middle-aged male runners with exercise-induced hypertension (EIH) at baseline and at 100-km, 200-km, and 308-km checkpoints during a prolonged endurance ultramarathon. Among a total of 62 ultramarathon volunteers, 8 with systolic blood pressure higher than 210 mm Hg and 8 with normal systolic blood pressure were selected for this study. The subjects were designated to EIH and control (CON) groups. Blood was collected for the analysis of soluble vascular cell adhesion molecule-1, soluble E-selectin, leukocytes, creatine kinase, and high-sensitivity C-reactive protein. Soluble vascular cell adhesion molecule-1 showed a significantly greater increase in the EIH group than in the CON group at 100 km and 200 km. Soluble E-selectin also showed a significantly greater increase in the EIH group than in the CON group at 100 km. Leukocytes significantly increased in the EIH group than in the CON group at 308 km. Creatine kinase and high-sensitivity C-reactive protein showed no group differences. Leukocytes, creatine kinase, and high-sensitivity C-reactive protein showed delayed-onset increases in both groups. Increased exercise intensity may stimulate greater endothelial responses independent of the inflammatory markers in EIH. The loss of a protective effect may be greater in those with EIH than in CONs. Acknowledging and prescribing proper exercise intensity may be critical in preventing possible vascular-related complications in runners with EIH.

Heterogeneous histomorphology, yet homogeneous vascular smooth muscle cell dedifferentiation, characterize human aneurysm disease.

PubMed

Busch, Albert; Hartmann, Elena; Grimm, Caroline; Ergün, Süleyman; Kickuth, Ralph; Otto, Christoph; Kellersmann, Richard; Lorenz, Udo

2017-11-01

Abdominal aortic aneurysm (AAA) is a frequent, potentially life-threatening, disease that can only be treated by surgical means such as open surgery or endovascular repair. No alternative treatment is currently available, and despite expanding knowledge about the pathomechanism, clinical trials on medical aneurysm abrogation have led to inconclusive results. The heterogeneity of human AAA based on histologic examination is thereby generally neglected. In this study we aimed to further elucidate the role of these differences in aneurysm disease. Tissue samples from AAA and popliteal artery aneurysm patients were examined by histomorphologic analysis, immunohistochemistry, Western blot, and polymerase chain reaction. The results were correlated with clinical data such as aneurysm diameter and laboratory results. The morphology of human AAA vessel wall probes varies tremendously based on the grade of inflammation. This correlates with increasing intima/media thickness and upregulation of the vascular endothelial growth factor cascade but not with any clinical parameter or the aneurysm diameter. The phenotypic switch of vascular smooth muscle cells occurred regardless of the inflammatory state and expressional changes of the transcription factors Kruppel-like factor-4 and transforming growth factor-β lead to differential protein localization in aneurysmal compared with control arteries. These changes were in similar manner also observed in samples from popliteal artery aneurysms, which, however, showed a more homogenous phenotype. Heterogeneity of AAA vessel walls based on inflammatory morphology does not correlate with AAA diameter yet harbors specific implications for basic research and possible aneurysm detection. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Micro-RNA-126 Reduces the Blood Thrombogenicity in Diabetes Mellitus via Targeting of Tissue Factor.

PubMed

Witkowski, Marco; Weithauser, Alice; Tabaraie, Termeh; Steffens, Daniel; Kränkel, Nicolle; Witkowski, Mario; Stratmann, Bernd; Tschoepe, Diethelm; Landmesser, Ulf; Rauch-Kroehnert, Ursula

2016-06-01

Diabetes mellitus involves vascular inflammatory processes and is a main contributor to cardiovascular mortality. Notably, heightened levels of circulating tissue factor (TF) account for the increased thrombogenicity and put those patients at risk for thromboembolic events. Here, we sought to investigate the role of micro-RNA (miR)-driven TF expression and thrombogenicity in diabetes mellitus. Plasma samples of patients with diabetes mellitus were analyzed for TF protein and activity as well as miR-126 expression before and after optimization of the antidiabetic treatment. We found low miR-126 levels to be associated with markedly increased TF protein and TF-mediated thrombogenicity. Reduced miR-126 expression was accompanied by increased vascular inflammation as evident from the levels of vascular adhesion molecule-1 and fibrinogen, as well as leukocyte counts. With optimization of the antidiabetic treatment miR-126 levels increased and thrombogenicity was reduced. Using a luciferase reporter system, we demonstrated miR-126 to directly bind to the F3-3'-untranslated region, thereby reducing TF expression both on mRNA and on protein levels in human microvascular endothelial cells as well as TF mRNA and activity in monocytes. Circulating miR-126 exhibits antithrombotic properties via regulating post-transcriptional TF expression, thereby impacting the hemostatic balance of the vasculature in diabetes mellitus. © 2016 The Authors.

Supplementation with Resveratrol and Curcumin Does Not Affect the Inflammatory Response to a High-Fat Meal in Older Adults with Abdominal Obesity: A Randomized, Placebo-Controlled Crossover Trial.

PubMed

Vors, Cécile; Couillard, Charles; Paradis, Marie-Eve; Gigleux, Iris; Marin, Johanne; Vohl, Marie-Claude; Couture, Patrick; Lamarche, Benoît

2018-03-01

High-fat meals induce postprandial inflammation. Resveratrol is a polyphenol known to prevent comorbidities associated with cardiovascular disease and exerts an anti-inflammatory action. There is also an increasing body of evidence supporting the role of curcumin, a polyphenol from the curcuminoid family, as a modulator of proinflammatory processes. The objectives of this study were to investigate the following: 1) the bioavailability of resveratrol consumed in combination with curcumin after consumption of a high-fat meal; and 2) the acute combined effects of this combination on the postprandial inflammatory response of subjects with abdominal obesity. In a double blind, crossover, randomized, placebo-controlled study, 11 men and 11 postmenopausal women [mean ± SD age: 62 ± 5 y; mean ± SD body mass index (in kg/m2): 29 ± 3] underwent a 6-h oral fat tolerance test on 2 occasions separated by 1-2 wk: once after consumption of a dietary supplement (200 mg resveratrol and 100 mg curcumin, Res/Cur) and once after consumption of a placebo (cellulose). Plasma concentrations of total resveratrol and its major metabolites as well as inflammatory markers, adhesion molecules, and whole blood NFκB1 and PPARA gene expression were measured during both fat tolerance tests. Kinetics of resveratrol and identified metabolites revealed rapid absorption patterns but also relatively limited bioavailability based on free resveratrol concentrations. Supplementation with Res/Cur did not modify postprandial variations in circulating inflammatory markers (C-reactive protein, IL-6, IL-8, monocyte chemoattractant protein-1) and adhesion molecules [soluble E-selectin, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1] compared to placebo (PTreatment×Time > 0.05). However, Res/Cur significantly decreased the cumulative postprandial response of sVCAM-1, compared to placebo (incremental area under the curve -4643%, P = 0.01). Postprandial variations of whole-blood PPARA and NFKB1 gene expression were not different between Res/Cur and placebo treatments. Acute supplementation with Res/Cur has no impact on the postprandial inflammation response to a high-fat meal in abdominally obese older adults. Further studies are warranted to examine how resveratrol and curcumin may alter the vascular response to a high-fat meal. This trial was registered at clinicaltrials.gov as NCT01964846.

Tissue-engineered vascular grafts for use in the treatment of congenital heart disease: from the bench to the clinic and back again.

PubMed

Patterson, Joseph T; Gilliland, Thomas; Maxfield, Mark W; Church, Spencer; Naito, Yuji; Shinoka, Toshiharu; Breuer, Christopher K

2012-05-01

Since the first tissue-engineered vascular graft (TEVG) was implanted in a child over a decade ago, growth in the field of vascular tissue engineering has been driven by clinical demand for improved vascular prostheses with performance and durability similar to an autologous blood vessel. Great strides were made in pediatric congenital heart surgery using the classical tissue engineering paradigm, and cell seeding of scaffolds in vitro remained the cornerstone of neotissue formation. Our second-generation bone marrow cell-seeded TEVG diverged from tissue engineering dogma with a design that induces the recipient to regenerate vascular tissue in situ. New insights suggest that neovessel development is guided by cell signals derived from both seeded cells and host inflammatory cells that infiltrate the graft. The identification of these signals and the regulatory interactions that influence cell migration, phenotype and extracellular matrix deposition during TEVG remodeling are yielding a next-generation TEVG engineered to guide neotissue regeneration without the use of seeded cells. These developments represent steady progress towards our goal of an off-the-shelf tissue-engineered vascular conduit for pediatric congenital heart surgery.

Regulation of thrombosis and vascular function by protein methionine oxidation

PubMed Central

Gu, Sean X.; Stevens, Jeff W.

2015-01-01

Redox biology is fundamental to both normal cellular homeostasis and pathological states associated with excessive oxidative stress. Reactive oxygen species function not only as signaling molecules but also as redox regulators of protein function. In the vascular system, redox reactions help regulate key physiologic responses such as cell adhesion, vasoconstriction, platelet aggregation, angiogenesis, inflammatory gene expression, and apoptosis. During pathologic states, altered redox balance can cause vascular cell dysfunction and affect the equilibrium between procoagulant and anticoagulant systems, contributing to thrombotic vascular disease. This review focuses on the emerging role of a specific reversible redox reaction, protein methionine oxidation, in vascular disease and thrombosis. A growing number of cardiovascular and hemostatic proteins are recognized to undergo reversible methionine oxidation, in which methionine residues are posttranslationally oxidized to methionine sulfoxide. Protein methionine oxidation can be reversed by the action of stereospecific enzymes known as methionine sulfoxide reductases. Calcium/calmodulin-dependent protein kinase II is a prototypical methionine redox sensor that responds to changes in the intracellular redox state via reversible oxidation of tandem methionine residues in its regulatory domain. Several other proteins with oxidation-sensitive methionine residues, including apolipoprotein A-I, thrombomodulin, and von Willebrand factor, may contribute to vascular disease and thrombosis. PMID:25900980

Mechanistic insights into the vascular effects of blueberries: Evidence from recent studies.

PubMed

Cutler, Brett Ronald; Petersen, Chrissa; Anandh Babu, Pon Velayutham

2017-06-01

Cardiovascular disease is the leading cause of death in the United States. Dietary habits influence a variety of cardiovascular complications such as peripheral artery disease, heart failure, and kidney disease. We along with others have previously reported the cardiovascular beneficial effects of dietary flavonoids. Anthocyanins, one class of flavonoids widely available in berries, have recently drawn wide scientific attention because of their diverse health benefits. Epidemiological, clinical, and animal studies indicate that blueberry anthocyanins exert protection against cardiovascular complications by acting on multiple targets in the vascular system. These include activating endothelial nitric oxide synthase signaling, reducing oxidative stress, improving inflammatory pathways, and ameliorating dyslipidemia. Anthocyanins are extensively metabolized in humans suggesting that their vascular benefits are likely mediated by their circulating metabolites. However, the bioactivities of blueberry metabolites are unknown. Evaluating the bioactivities of metabolites, analyzing their structure-activity relationship, and well-designed human trials are needed to understand the potential vascular effects of blueberries and their metabolites. Understanding the vascular effects will provide a solid scientific foundation to recommend blueberries to improve vascular health. This review highlights the recent developments in the understanding of the vascular effects of blueberries with special emphasis on the molecular mechanisms involved. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Histopathological reaction over prosthesis surface covered with silicone and polyurethane foam implanted in rats.

PubMed

Wagenführ-Júnior, Jorge; Ribas Filho, Jurandir Marcondes; Nascimento, Marcelo Mazza do; Ribas, Fernanda Marcondes; Wanka, Marcus Vinícius; Godoi, Andressa de Lima

2012-12-01

To evaluate whether polyurethane foam leads more intense foreign-body reaction than silicone foam. To compare the vascularization of the capsules surrounding the foam implants. To investigate if the capsule of polyurethane foam implanted has greater amount of collagen than that of silicone foam. Sixty-four young male Wistar rats were allocated into two groups: polyurethane foam and silicone foam. Subcutaneous discs were implanted into the dorsum of the animals in both groups. The capsules were assessed 28 days, two months, three months and six months postoperatively. Microscopic analysis with H&E stain was performed to evaluate the acute and chronic inflammatory process, foreign-body reaction and neovascularization. The analysis with picrosirius red was performed using the ImageProPlus software, to measure the number of vessels and collagen types I and III. There were no statistical differences between the two groups regarding the acute and chronic inflammatory processes. All rats from the polyurethane group, in all times, exhibited moderate or intense foreign-body reaction, with statistic significant difference (p=0.046) when compared with the silicone group, in which the reaction was either mild or nonexistent at two months. Vascular proliferation was significantly different between the groups at 28 days (p=0.0002), with the polyurethane group displaying greater neovascularization with H&E stain. Similar results were obtained with picrosirius red, which revealed in the polyurethane group a much greater number of vessels than in the silicone group (p=0.001). The collagen area was larger in the polyurethane group, significantly at 28 days (p=0.001) and at two months (p=0.030). Polyurethane foam elicited more intense foreign-body reaction when compared with silicone foam. The number of vessels was higher in the capsules of the polyurethane foam implants 28 days after the operation. The capsule of the polyurethane foam implants showed a greater amount of collagen than that of the silicone foam implants.

Intermittent Fasting Pretreatment Prevents Cognitive Impairment in a Rat Model of Chronic Cerebral Hypoperfusion.

PubMed

Hu, Yuan; Yang, Ying; Zhang, Miao; Deng, Min; Zhang, Jun-Jian

2017-07-01

Background: Whether intermittent fasting (IF) pretreatment can prevent vascular cognitive dysfunction remains unknown to our knowledge. Objective: We investigated the effects and underlying mechanisms of IF pretreatment on cognitive dysfunction in a permanent 2-vessel occlusion (2VO) vascular dementia rat model. Methods: Male Wistar rats weighing 200 g were subjected to either IF or ad libitum feeding for 12 wk before 2VO surgery. Rats in the IF protocol underwent alternative-day feed deprivation (FD). Memory of the animals was assessed by using the Morris water maze (MWM) and the novel object recognition (NOR) test 6 wk after the surgery. After behavioral testing, malondialdehyde and glutathione concentrations, superoxide dismutase (SOD) activity, gene expression of antioxidative enzymes, inflammatory protein concentrations, and microglia density were determined in the hippocampus of rats. Results: 2-vessel occlusion operation ad libitum (2VO-AL) rats had significantly longer escape latencies on day 4 of the training phase and spent a lower percentage of time in the target quadrant (25% compared with 38% and 41%) in the MWM, and had lower discrimination ratios (47% compared with 65% and 67%) in the NOR test than 2-vessel operation and alternate-day feed deprivation (2VO-FD) and sham operation ad libitum (Sham-AL) rats, respectively ( P < 0.05). This indicates that IF helps to prevent vascular cognitive deficits. 2VO-AL rats also had higher malondialdehyde (3.54 compared with 2.15 and 1.66 nmol/mg protein) and lower glutathione concentrations (53.25 compared with 66.41 and 91.71 nmol/mg protein), lower SOD activity (100.1 compared with 133.3 and 138.5 U/mg protein), lower gene expression of antioxidative enzymes, higher expression of inflammatory proteins, and higher microglia density in the hippocampus than 2VO-FD and Sham-AL rats, respectively ( P < 0.05). This suggests that IF has antioxidative and anti-inflammatory effects. Conclusions: IF pretreatment provided sustained neuroprotection in a rat model of vascular dementia. These effects were associated with reduced oxidative stress and neuroinflammation. © 2017 American Society for Nutrition.

Far-infrared protects vascular endothelial cells from advanced glycation end products-induced injury via PLZF-mediated autophagy in diabetic mice

PubMed Central

Chen, Cheng-Hsien; Chen, Tso-Hsiao; Wu, Mei-Yi; Chou, Tz-Chong; Chen, Jia-Rung; Wei, Meng-Jun; Lee, San-Liang; Hong, Li-Yu; Zheng, Cai-Mei; Chiu, I-Jen; Lin, Yuh-Feng; Hsu, Ching-Min; Hsu, Yung-Ho

2017-01-01

The accumulation of advanced glycation end products (AGEs) in diabetic patients induces vascular endothelial injury. Promyelocytic leukemia zinc finger protein (PLZF) is a transcription factor that can be activated by low-temperature far-infrared (FIR) irradiation to exert beneficial effects on the vascular endothelium. In the present study, we investigated the influence of FIR-induced PLZF activation on AGE-induced endothelial injury both in vitro and in vivo. FIR irradiation inhibited AGE-induced apoptosis in human umbilical vein endothelial cells (HUVECs). PLZF activation increased the expression of phosphatidylinositol-3 kinases (PI3K), which are important kinases in the autophagic signaling pathway. FIR-induced PLZF activation led to autophagy in HUVEC, which was mediated through the upregulation of PI3K. Immunofluorescence staining showed that AGEs were engulfed by HUVECs and localized to lysosomes. FIR-induced autophagy promoted AGEs degradation in HUVECs. In nicotinamide/streptozotocin-induced diabetic mice, FIR therapy reduced serum AGEs and AGEs deposition at the vascular endothelium. FIR therapy also reduced diabetes-induced inflammatory markers in the vascular endothelium and improved vascular endothelial function. These protective effects of FIR therapy were not found in PLZF-knockout mice. Our data suggest that FIR-induced PLZF activation in vascular endothelial cells protects the vascular endothelium in diabetic mice from AGE-induced injury. PMID:28071754

Defining the Relationship between Biomarkers of Oxidative and Inflammatory Stress and the Risk for Atherosclerosis in Astronauts during and after Long-duration Spaceflight

NASA Technical Reports Server (NTRS)

Lee, Stuart M. C.; Westby, Christian M.; Stenger, Michael B.; Smith, Scott M.; Zwart, Sara; Ploutz-Snyder, Robert J.; Platts, Steven H.

2014-01-01

Future human space travel will consist primarily of long-duration missions onboard the International Space Station (ISS) or exploration-class missions to Mars, its moons, or nearby asteroids. These missions will expose astronauts to increased risk of oxidative and inflammatory damage from a variety of sources, including radiation, psychological stress, reduced physical activity, diminished nutritional status, and hyperoxic exposure during extravehicular activity. Evidence exists that increased oxidative damage and inflammation can accelerate the development of atherosclerosis. PURPOSE The purpose of this investigation is to determine whether biomarkers of oxidative and inflammatory stress are elevated during and after long-duration spaceflight and investigate if a relation exists between levels of these biomarkers and structural and functional indices of atherosclerotic risk measured in the carotid and brachial arteries. This is the first study to propose assessing atherosclerotic risk using biochemical, structural, and functional measures before, during, and immediately after spaceflight, and structural and functional measures for up to 5 years after landing. METHODS We will study 12 astronauts before, during, and up to 5 years after long-duration ISS missions. A panel of biomarkers of oxidative and inflammatory stress will be measured twice before flight, early (flight days 15 and 60) and late (2 weeks before landing) during the mission, and early in the postflight recovery phase (approx 3 days after landing). Arterial structure and vascular compliance will be measured at the same times and also at 1, 3, and 5 years after landing (surveillance). Arterial function will be measured using the same preflight, postflight, and surveillance schedule as arterial structure and vascular compliance measures, but will not be measured inflight. Biomarkers, some of which we have previously shown to be elevated with spaceflight, will be measured in venous blood samples and 24-h (in-flight) and 48-h (pre- and post-flight) urine pools. Arterial structure will be assessed from measures of carotid intima-media thickness, which have been shown to be better indicators of atherosclerotic than the Framingham Risk Score. Arterial function will be assessed using brachial flow-mediated dilation, a well-validated measure used to assess endothelium-dependent vasodilation and is a sensitive predictor of atherosclerotic risk. Arterial pulse pressure measured in the brachial artery and stroke volume measured from cardiac ultrasound will be used to assess hemodynamic status, cardiac function, and systemic vascular compliance. Three astronauts are actively participating in the preflight data collection and training activities. One astronaut has completed all preflight activities and will participate in the first in-flight data collection sessions by the end of 2013. The first post-flight data collection sessions will occur in the spring of 2014. EXPECTED RESULTS We hypothesize that biomarkers of oxidative and inflammatory stress will increased with spaceflight and will correlate with increased carotid intima-media thickness during and after flight and with decreased flow-mediated dilation after the mission. Furthermore, we hypothesize that measures of oxidative stress will return to baseline after flight, but biomarkers of inflammatory stress and vascular indices of atherosclerotic risk will remain elevated.

Interaction of the Human Contact System with Pathogens-An Update.

PubMed

Oehmcke-Hecht, Sonja; Köhler, Juliane

2018-01-01

The name human contact system is related to its mode of action, as "contact" with artificial negatively charged surfaces triggers its activation. Today, it is generally believed that the contact system is an inflammatory response mechanism not only against artificial material but also against misfolded proteins and foreign organisms. Upon activation, the contact system is involved in at least two distinct (patho)physiologic processes: i . the trigger of the intrinsic coagulation via factor XI and ii . the cleavage of high molecular weight kininogen with release of bradykinin and antimicrobial peptides (AMPs). Bradykinin is involved in the regulation of inflammatory processes, vascular permeability, and blood pressure. Due to the release of AMPs, the contact system is regarded as a branch of the innate immune defense against microorganisms. There is an increasing list of pathogens that interact with contact factors, in addition to bacteria also fungi and viruses bind and activate the system. In spite of that, pathogens have developed their own mechanisms to activate the contact system, resulting in manipulation of this host immune response. In this up-to-date review, we summarize present research on the interaction of pathogens with the human contact system, focusing particularly on bacterial and viral mechanisms that trigger inflammation via contact system activation.

Anti-oxidative, anti-inflammatory and hepato-protective effects of Ligustrum robustum.

PubMed

Lau, Kit-Man; He, Zhen-Dan; Dong, Hui; Fung, Kwok-Pui; But, Paul Pui-Hay

2002-11-01

Aqueous extract of processed leaves of Ligustrum robustum could dose-dependently scavenge superoxide radicals, inhibit lipid peroxidation, and prevent AAPH-induced hemolysis of red blood cells. In comparison with green tea, oolong tea and black tea, processed leaves of L. robustum exhibited comparable antioxidant potency in scavenging superoxide radicals and in preventing red blood cell hemolysis. By activity-guided fractionation, a glycoside-rich fraction named fraction B2 was separated and demonstrated to possess strong antioxidant effect. It was evaluated for its anti-inflammatory and hepato-protective activities. A single oral dose of fraction B2 at 0.5 g/kg could provide 51.5% inhibition on the vascular permeability change induced by intraperitoneal injection of acetic acid, but it could not inhibit croton oil-induced ear edema. On the other hand, fraction B2 exhibited moderate hepato-protective effect. Intragastric application of fraction B2 at 1.25, 2.5 or 5 g/kg 6 h after carbon tetrachloride administration could reduce the elevations of serum levels of aminotransferases (AST and ALT). Also, liver integrity was preserved, as liver sections from rats post-treated with fraction B2 showed a milder degree of fatty accumulation and necrosis. These results offer partial support to the traditional uses of the leaves of L. robustum as Ku-Ding-Cha.

Whole-mount Confocal Microscopy for Adult Ear Skin: A Model System to Study Neuro-vascular Branching Morphogenesis and Immune Cell Distribution.

PubMed

Yamazaki, Tomoko; Li, Wenling; Mukouyama, Yoh-Suke

2018-03-29

Here, we present a protocol of a whole-mount adult ear skin imaging technique to study comprehensive three-dimensional neuro-vascular branching morphogenesis and patterning, as well as immune cell distribution at a cellular level. The analysis of peripheral nerve and blood vessel anatomical structures in adult tissues provides some insights into the understanding of functional neuro-vascular wiring and neuro-vascular degeneration in pathological conditions such as wound healing. As a highly informative model system, we have focused our studies on adult ear skin, which is readily accessible for dissection. Our simple and reproducible protocol provides an accurate depiction of the cellular components in the entire skin, such as peripheral nerves (sensory axons, sympathetic axons, and Schwann cells), blood vessels (endothelial cells and vascular smooth muscle cells), and inflammatory cells. We believe this protocol will pave the way to investigate morphological abnormalities in peripheral nerves and blood vessels as well as the inflammation in the adult ear skin under different pathological conditions.

[Molecular mechanisms in vascular osteocartilaginous metaplasia: systematic review].

PubMed

Rosero Salazar, Doris Haydee

2016-01-01

The cartilage and bone metaplasia occurring in both the heart and blood vessels, are the result of risk factors or chronic diseases that gradually adversely affect the performance of a person in society; however, clinical signs are reversible in early and intermediate stages of alterations. To establish how the molecular mechanisms underlying the increased vascular metaplastic changes and possible aspects of treatment and prevention. A systematic review was performed by searching for articles indexed in PubMed, Scopus and Science Direct data from 1995 to 2015. The MeSH descriptors used were metaplasia and vascular calcification, which terms associated were molecular mechanisms, condrogenic and osteogenic. Multiple factors influence the metaplastic change, especially the pro-inflammatory associated with vascular oxidation and the presence of free radicals; this development is reversible by treatment with antioxidants and changes in lifestyle and secondary prevention as there is a diagnosis of chronic degenerative disease. The literature evidences that factors that reduce the tissue oxidative stress and promote the maintenance of vascular phenotype are protective and / or reducing the osteochondral metaplastic formations.

Characterization of the early pulmonary inflammatory response associated with PTFE fume exposure

NASA Technical Reports Server (NTRS)

Johnston, C. J.; Finkelstein, J. N.; Gelein, R.; Baggs, R.; Oberdorster, G.; Clarkson, T. W. (Principal Investigator)

1996-01-01

Heating of polytetrafluoroethylene (PTFE) has been described to release fumes containing ultrafine particles (approximately 18 nm diam). These fumes can be highly toxic in the respiratory tract inducing extensive pulmonary edema with hemorrhagic inflammation. Fischer-344 rats were exposed to PTFE fumes generated by temperatures ranging from 450 to 460 degrees C for 15 min at an exposure concentration of 5 x 10(5) particles/cm3, equivalent to approximately 50 micrograms/m3. Responses were examined 4 hr post-treatment when these rats demonstrated 60-85% neutrophils (PMNs) in their lung lavage. Increases in abundance for messages encoding the antioxidants manganese superoxide dismutase and metallothionein (MT) increased 15- and 40-fold, respectively. For messages encoding the pro- and anti-inflammatory cytokines: inducible nitric oxide synthase, interleukin 1 alpha, 1 beta, and 6 (IL-1 alpha, IL-1 beta, and IL-6), macrophage inflammatory protein-2, and tumor necrosis factor-alpha (TNF alpha) increases of 5-, 5-, 10-, 40-, 40-, and 15-fold were present. Vascular endothelial growth factor, which may play a role in the integrity of the endothelial barrier, was decreased to 20% of controls. In situ sections were hybridized with 33P cRNA probes encoding IL-6, MT, surfactant protein C, and TNF alpha. Increased mRNA abundance for MT and IL-6 was expressed around all airways and interstitial regions with MT and IL-6 demonstrating similar spatial distribution. Large numbers of activated PMNs expressed IL-6, MT, and TNF alpha. Additionally, pulmonary macrophages and epithelial cells were actively involved. These observations support the notion that PTFE fumes containing ultrafine particles initiate a severe inflammatory response at low inhaled particle mass concentrations, which is suggestive of an oxidative injury. Furthermore, PMNs may actively regulate the inflammatory process through cytokine and antioxidant expression.

Immune Modulation of Cardiac Repair and Regeneration: The Art of Mending Broken Hearts

PubMed Central

Zlatanova, Ivana; Pinto, Cristina; Silvestre, Jean-Sébastien

2016-01-01

The accumulation of immune cells is among the earliest responses that manifest in the cardiac tissue after injury. Both innate and adaptive immunity coordinate distinct and mutually non-exclusive events governing cardiac repair, including elimination of the cellular debris, compensatory growth of the remaining cardiac tissue, activation of resident or circulating precursor cells, quantitative and qualitative modifications of the vascular network, and formation of a fibrotic scar. The present review summarizes the mounting evidence suggesting that the inflammatory response also guides the regenerative process following cardiac damage. In particular, recent literature has reinforced the central role of monocytes/macrophages in poising the refreshment of cardiomyocytes in myocardial infarction- or apical resection-induced cardiac insult. Macrophages dictate cardiac myocyte renewal through stimulation of preexisting cardiomyocyte proliferation and/or neovascularization. Nevertheless, substantial efforts are required to identify the nature of these macrophage-derived factors as well as the molecular mechanisms engendered by the distinct subsets of macrophages pertaining in the cardiac tissue. Among the growing inflammatory intermediaries that have been recognized as essential player in heart regeneration, we will focus on the role of interleukin (IL)-6 and IL-13. Finally, it is likely that within the mayhem of the injured cardiac tissue, additional types of inflammatory cells, such as neutrophils, will enter the dance to ignite and refresh the broken heart. However, the protective and detrimental inflammatory pathways have been mainly deciphered in animal models. Future research should be focused on understanding the cellular effectors and molecular signals regulating inflammation in human heart to pave the way for the development of factual therapies targeting the inflammatory compartment in cardiac diseases. PMID:27790620

Immune Modulation of Cardiac Repair and Regeneration: The Art of Mending Broken Hearts.

PubMed

Zlatanova, Ivana; Pinto, Cristina; Silvestre, Jean-Sébastien

2016-01-01

The accumulation of immune cells is among the earliest responses that manifest in the cardiac tissue after injury. Both innate and adaptive immunity coordinate distinct and mutually non-exclusive events governing cardiac repair, including elimination of the cellular debris, compensatory growth of the remaining cardiac tissue, activation of resident or circulating precursor cells, quantitative and qualitative modifications of the vascular network, and formation of a fibrotic scar. The present review summarizes the mounting evidence suggesting that the inflammatory response also guides the regenerative process following cardiac damage. In particular, recent literature has reinforced the central role of monocytes/macrophages in poising the refreshment of cardiomyocytes in myocardial infarction- or apical resection-induced cardiac insult. Macrophages dictate cardiac myocyte renewal through stimulation of preexisting cardiomyocyte proliferation and/or neovascularization. Nevertheless, substantial efforts are required to identify the nature of these macrophage-derived factors as well as the molecular mechanisms engendered by the distinct subsets of macrophages pertaining in the cardiac tissue. Among the growing inflammatory intermediaries that have been recognized as essential player in heart regeneration, we will focus on the role of interleukin (IL)-6 and IL-13. Finally, it is likely that within the mayhem of the injured cardiac tissue, additional types of inflammatory cells, such as neutrophils, will enter the dance to ignite and refresh the broken heart. However, the protective and detrimental inflammatory pathways have been mainly deciphered in animal models. Future research should be focused on understanding the cellular effectors and molecular signals regulating inflammation in human heart to pave the way for the development of factual therapies targeting the inflammatory compartment in cardiac diseases.

Clinical, Cellular, and Molecular Aspects in the Pathophysiology of Rosacea

PubMed Central

Steinhoff, Martin; Buddenkotte, Jörg; Aubert, Jerome; Sulk, Mathias; Novak, Pawel; Schwab, Verena D.; Mess, Christian; Cevikbas, Ferda; Rivier, Michel; Carlavan, Isabelle; Déret, Sophie; Rosignoli, Carine; Metze, Dieter; Luger, Thomas A.; Voegel, Johannes J.

2013-01-01

Rosacea is a chronic inflammatory skin disease of unknown etiology. Although described centuries ago, the pathophysiology of this disease is still poorly understood. Epidemiological studies indicate a genetic component, but a rosacea gene has not been identified yet. Four subtypes and several variants of rosacea have been described. It is still unclear whether these subtypes represent a “developmental march” of different stages or are merely part of a syndrome that develops independently but overlaps clinically. Clinical and histopathological characteristics of rosacea make it a fascinating “human disease model” for learning about the connection between the cutaneous vascular, nervous, and immune systems. Innate immune mechanisms and dysregulation of the neurovascular system are involved in rosacea initiation and perpetuation, although the complex network of primary induction and secondary reaction of neuroimmune communication is still unclear. Later, rosacea may result in fibrotic facial changes, suggesting a strong connection between chronic inflammatory processes and skin fibrosis development. This review highlights recent molecular (gene array) and cellular findings and aims to integrate the different body defense mechanisms into a modern concept of rosacea pathophysiology. PMID:22076321

In vitro protective effects of two extracts from bergamot peels on human endothelial cells exposed to tumor necrosis factor-alpha (TNF-alpha).

PubMed

Trombetta, Domenico; Cimino, Francesco; Cristani, Mariateresa; Mandalari, Giuseppina; Saija, Antonella; Ginestra, Giovanna; Speciale, Antonio; Chirafisi, Joselita; Bisignano, Giuseppe; Waldron, Keith; Narbad, Arjan; Faulds, Craig B

2010-07-28

Bergamot ( Citrus bergamia Risso) is a less commercialized Citrus fruit, mainly used for its essential oil extracted from the peel. Bergamot peel (BP) represents about 60% of the processed fruits and is regarded as primary waste. However, it contains good amounts of useful compounds, such as pectins and flavonoids. Many of the bioactivities of Citrus flavonoids appear to impact vascular endothelial cells. Herein, we report the protective effect of two flavonoid-rich extracts from BP (endowed with radical-scavenging properties and lacking genotoxic activity) against alterations in cell modifications induced by the pleiotropic inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) on human umbilical vein endothelial cells (HUVECs), as demonstrated by monitoring intracellular levels of malondialdehyde/4-hydroxynonenal, reduced and oxidized glutathione and superoxide dismutase activity, and the activation status of nuclear factor-kappaB (NF-kappaB). Thus, BP appears to be a potential source of natural antioxidant/anti-inflammatory phytocomplexes to be employed as ingredients of nutraceutical products or functional foods.

Acute coronary disease Athero-Inflammation: Therapeutic approach

PubMed Central

Altman, Raul

2003-01-01

Antithrombotic therapy is the cornerstone of the treatment of acute coronary syndromes, but there is now evidence which indicates that by blocking inflammation, thrombosis and thus, acute coronary events, could be lowered. The concept of athero-inflammation emerges as the meeting point of different morbidities; dyslipemia, diabetes, hypertension, obesity, immunity, infection, hyperhomocyteinemia, smoking, etc. usual named as risk factors. Thus, beside specific drugs, earliest treatment, in the stage of inflammation, using anti-inflammatory drugs, should be considered since in patients with increased risk of acute coronary process are likely to have many point of origen throughout the coronary arteries. There are a body of evidences for supporting the potential of anti-inflammatory therapy to the prevention of inflammation and atherosclerosis. COX-2 inhibition may decrease endothelial inflammation reducing monocytes infiltration improving vascular cells function, plaque stability and probably resulting in a decrease of coronary atherothrombotic events. Trials including large numbers of patients in prospective double-blind randomized studies worthwhile to confirm the efficacy of NSAID, mainly, COX-2 inhibitors, together with aspirin in the prevention of coronary events in patients with acute coronary disease. PMID:12904261

Metformin inhibits inflammatory response via AMPK-PTEN pathway in vascular smooth muscle cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Sun Ae; Choi, Hyoung Chul, E-mail: hcchoi@med.yu.ac.kr

2012-09-07

Highlights: Black-Right-Pointing-Pointer PTEN was induced by metformin and inhibited by compound C and AMPK siRNA. Black-Right-Pointing-Pointer Metformin suppressed TNF-{alpha}-induced COX-2 and iNOS mRNA expression. Black-Right-Pointing-Pointer Compound C and bpv (pic) increased iNOS and COX-2 protein expression. Black-Right-Pointing-Pointer NF-{kappa}B activation was restored by inhibiting AMPK and PTEN. Black-Right-Pointing-Pointer AMPK and PTEN regulated TNF-{alpha}-induced ROS production in VSMCs. -- Abstract: Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), amore » key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK-PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2 mM) and inhibited by compound C (10 {mu}M) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-{alpha}) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-{kappa}B. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-{kappa}B activation decreased in response to metformin and was restored by inhibiting AMPK and PTEN. Inhibiting AMPK and PTEN restored ROS levels stimulated with TNF-{alpha}. Taken together, PTEN could be a possible downstream regulator of AMPK, and the AMPK-PTEN pathway might be important in the regulation of the inflammatory response in VSMCs.« less

Biocompatibility, Inflammatory Response, and Recannalization Characteristics of Nonradioactive Resin Microspheres: Histological Findings

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bilbao, Jose I., E-mail: Jibilbao@unav.e; Martino, Alba de; Luis, Esther de

2009-07-15

Intra-arterial radiotherapy with yttrium-90 microspheres (radioembolization) is a therapeutic procedure exclusively applied to the liver that allows the direct delivery of high-dose radiation to liver tumors, by means of endovascular catheters, selectively placed within the tumor vasculature. The aim of the study was to describe the distribution of spheres within the precapillaries, inflammatory response, and recannalization characteristics after embolization with nonradioactive resin microspheres in the kidney and liver. We performed a partial embolization of the liver and kidney vessels in nine white pigs. The left renal and left hepatic arteries were catheterized and filled with nonradioactive resin microspheres. Embolization wasmore » defined as the initiation of near-stasis of blood flow, rather than total occlusion of the vessels. The hepatic circulation was not isolated so that the effects of reflux of microspheres into stomach could be observed. Animals were sacrificed at 48 h, 4 weeks, and 8 weeks, and tissue samples from the kidney, liver, lung, and stomach evaluated. Microscopic evaluation revealed clusters of 10-30 microspheres (15-30 {mu}m in diameter) in the small vessels of the kidney (the arciform arteries, vasa recti, and glomerular afferent vessels) and liver. Aggregates were associated with focal ischemia and mild vascular wall damage. Occlusion of the small vessels was associated with a mild perivascular inflammatory reaction. After filling of the left hepatic artery with microspheres, there was some evidence of arteriovenous shunting into the lungs, and one case of cholecystitis and one case of marked gastritis and ulceration at the site of arterial occlusion due to the presence of clusters of microspheres. Beyond 48 h, microspheres were progressively integrated into the vascular wall by phagocytosis and the lumen recannalized. Eight-week evaluation found that the perivascular inflammatory reaction was mild. Liver cell damage, bile duct injury, and portal space fibrosis were not observed. In conclusion, resin microspheres (15-30 {mu}m diameter) trigger virtually no inflammatory response in target tissues (liver and kidney). Clusters rather than individual microspheres were associated with a mild to moderate perivascular inflammatory reaction. There was no evidence of either a prolonged inflammatory reaction or fibrosis in the liver parenchyma following recannalization.« less

A novel imidazopyridine derivative, X22, attenuates sepsis-induced lung and liver injury by inhibiting the inflammatory response in vitro and in vivo

PubMed Central

Ge, Xiangting; Feng, Zhiguo; Xu, Tingting; Wu, Beibei; Chen, Hongjin; Xu, Fengli; Fu, Lili; Shan, Xiaoou; Dai, Yuanrong; Zhang, Yali; Liang, Guang

2016-01-01

Sepsis remains a leading cause of death worldwide. Despite years of extensive research, effective drugs to treat sepsis in the clinic are lacking. In this study, we found a novel imidazopyridine derivative, X22, which has powerful anti-inflammatory activity. X22 dose-dependently inhibited lipopolysaccharide (LPS)-induced proinflammatory cytokine production in mouse primary peritoneal macrophages and RAW 264.7 macrophages. X22 also downregulated the LPS-induced proinflammatory gene expression in vitro. In vivo, X22 exhibited a significant protection against LPS-induced death. Pretreatment or treatment with X22 attenuated the sepsis-induced lung and liver injury by inhibiting the inflammatory response. In addition, X22 showed protection against LPS-induced acute lung injury. We additionally found that pretreatment with X22 reduced the inflammatory pain in the acetic acid and formalin models and reduced the dimethylbenzene-induced ear swelling and acetic acid-increased vascular permeability. Together, these data confirmed that X22 has multiple anti-inflammatory effects and may be a potential therapeutic option in the treatment of inflammatory diseases. PMID:27390516

A novel imidazopyridine derivative, X22, attenuates sepsis-induced lung and liver injury by inhibiting the inflammatory response in vitro and in vivo.

PubMed

Ge, Xiangting; Feng, Zhiguo; Xu, Tingting; Wu, Beibei; Chen, Hongjin; Xu, Fengli; Fu, Lili; Shan, Xiaoou; Dai, Yuanrong; Zhang, Yali; Liang, Guang

2016-01-01

Sepsis remains a leading cause of death worldwide. Despite years of extensive research, effective drugs to treat sepsis in the clinic are lacking. In this study, we found a novel imidazopyridine derivative, X22, which has powerful anti-inflammatory activity. X22 dose-dependently inhibited lipopolysaccharide (LPS)-induced proinflammatory cytokine production in mouse primary peritoneal macrophages and RAW 264.7 macrophages. X22 also downregulated the LPS-induced proinflammatory gene expression in vitro. In vivo, X22 exhibited a significant protection against LPS-induced death. Pretreatment or treatment with X22 attenuated the sepsis-induced lung and liver injury by inhibiting the inflammatory response. In addition, X22 showed protection against LPS-induced acute lung injury. We additionally found that pretreatment with X22 reduced the inflammatory pain in the acetic acid and formalin models and reduced the dimethylbenzene-induced ear swelling and acetic acid-increased vascular permeability. Together, these data confirmed that X22 has multiple anti-inflammatory effects and may be a potential therapeutic option in the treatment of inflammatory diseases.

CANTOS: A breakthrough that proves the inflammatory hypothesis of atherosclerosis

PubMed Central

Atherosclerosis is no longer considered solely a disorder of subintimal deposition of modified low-density lipoprotein particles in the arterial wall. Rather, it is known to be a chronic inflammatory disorder. No evidence has shown that reducing vascular inflammation in the absence of concomitant lowering of lipoproteins levels reduces the rates of adverse cardiovascular (CV) events. Canakinumab, a fully human monoclonal antibody that neutralizes interleukin (IL)-1β, significantly reduced the rate of recurrent CV events in patients with prior myocardial infarction in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS). Canakinumab has no effect on CV or all-cause mortality, however it was associated with high incidence of fatal infections. Thus, the net benefit needs to be properly addressed in future studies that evaluate the potential benefit of the anti-inflammatory therapies and whether it can change clinical practice in the near future. PMID:29644229

Residential proximity to abandoned uranium mines and serum inflammatory potential in chronically exposed Navajo communities.

PubMed

Harmon, Molly E; Lewis, Johnnye; Miller, Curtis; Hoover, Joseph; Ali, Abdul-Mehdi S; Shuey, Chris; Cajero, Miranda; Lucas, Selita; Zychowski, Katherine; Pacheco, Bernadette; Erdei, Esther; Ramone, Sandy; Nez, Teddy; Gonzales, Melissa; Campen, Matthew J

2017-07-01

Members of the Navajo Nation, who possess a high prevalence of cardiometabolic disease, reside near hundreds of local abandoned uranium mines (AUM), which contribute uranium, arsenic and other metals to the soil, water and air. We recently reported that hypertension is associated with mine waste exposures in this population. Inflammation is a major player in the development of numerous vascular ailments. Our previous work establishing that specific transcriptional responses of cultured endothelial cells treated with human serum can reveal relative circulating inflammatory potential in a manner responsive to pollutant exposures, providing a model to assess responses associated with exposure to these waste materials in this population. To investigate a potential link between exposures to AUM and serum inflammatory potential in affected communities, primary human coronary artery endothelial cells were treated for 4 h with serum provided by Navajo study participants (n=145). Endothelial transcriptional responses of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and chemokine ligand 2 (CCL2) were measured. These transcriptional responses were then linked to AUM exposure metrics, including surface area-weighted AUM proximity and estimated oral intake of metals. AUM proximity strongly predicted endothelial transcriptional responses to serum including CCL2, VCAM-1 and ICAM-1 (P<0.0001 for each), whereas annual water intakes of arsenic and uranium did not, even after controlling for all major effect modifiers. Inflammatory potential associated with proximity to AUMs, but not oral intake of specific metals, additionally suggests a role for inhalation exposure as a contributor to cardiovascular disease.

Clots Are Potent Triggers of Inflammatory Cell Gene Expression: Indications for Timely Fibrinolysis.

PubMed

Campbell, Robert A; Vieira-de-Abreu, Adriana; Rowley, Jesse W; Franks, Zechariah G; Manne, Bhanu Kanth; Rondina, Matthew T; Kraiss, Larry W; Majersik, Jennifer J; Zimmerman, Guy A; Weyrich, Andrew S

2017-10-01

Blood vessel wall damage often results in the formation of a fibrin clot that traps inflammatory cells, including monocytes. The effect of clot formation and subsequent lysis on the expression of monocyte-derived genes involved in the development and progression of ischemic stroke and other vascular diseases, however, is unknown. Determine whether clot formation and lysis regulates the expression of human monocyte-derived genes that modulate vascular diseases. We performed next-generation RNA sequencing on monocytes extracted from whole blood clots and using a purified plasma clot system. Numerous mRNAs were differentially expressed by monocytes embedded in clots compared with unclotted controls, and IL-8 (interleukin 8) and MCP-1 (monocyte chemoattractant protein-1) were among the upregulated transcripts in both models. Clotted plasma also increased expression of IL-8 and MCP-1, which far exceeded responses observed in lipopolysaccharide-stimulated monocytes. Upregulation of IL-8 and MCP-1 occurred in a thrombin-independent but fibrin-dependent manner. Fibrinolysis initiated shortly after plasma clot formation (ie, 1-2 hours) reduced the synthesis of IL-8 and MCP-1, whereas delayed fibrinolysis was far less effective. Consistent with these in vitro models, monocytes embedded in unresolved thrombi from patients undergoing thrombectomy stained positively for IL-8 and MCP-1. These findings demonstrate that clots are potent inducers of monocyte gene expression and that timely fibrinolysis attenuates inflammatory responses, specifically IL-8 and MCP-1. Dampening of inflammatory gene expression by timely clot lysis may contribute to the clinically proven efficacy of fibrinolytic drug treatment within hours of stroke onset. © 2017 American Heart Association, Inc.

The formation of inflammatory demyelinated lesions in cerebral white matter

PubMed Central

Maggi, Pietro; Cummings Macri, Sheila M.; Gaitán, María I.; Leibovitch, Emily; Wholer, Jillian E; Knight, Heather L.; Ellis, Mary; Wu, Tianxia; Silva, Afonso C.; Massacesi, Luca; Jacobson, Steven; Westmoreland, Susan; Reich, Daniel S.

2016-01-01

Objective Vascular permeability and inflammatory demyelination are intimately linked in the brain, but what is their temporal relationship? We aimed to determine the radiological correlates of the earliest tissue changes accompanying demyelination in a primate model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) in the common marmoset. Methods At 7 tesla MRI, T1 maps, proton density and T2-weighted images were acquired before and after EAE induction in 5 marmosets (every other week before lesions appeared, weekly thereafter). From scans before and after intravenous injection of contrast material, we measured the evolution of lesional blood-brain-barrier (BBB) permeability, comparing in vivo MRI to postmortem tissue examination. Results On average, BBB permeability increased 3.5 fold (p<0.0001) over the 4 weeks prior to lesion appearance. Permeability gradually decreased after lesion appearance, with attendant changes in the distribution of inflammatory cells (predominantly macrophages and microglia) and demyelination. On tissue analysis, we also identified small perivascular foci of microglia and T cells without blood-derived macrophages or demyelination. These foci had no visible MRI correlates, though permeability within the foci, but not outside, increased in the weeks before the animals died (p<0.0001). Interpretation This study provides compelling evidence that in marmoset EAE, which forms lesions strongly resembling those of MS, early changes in vascular permeability are associated with perivascular inflammatory cuffing and parenchymal microglial activation but precede the arrival of blood-derived monocytes that accompany demyelination. Prospective detection of transient permeability changes could afford an opportunity for early intervention to forestall tissue damage in newly forming lesions. PMID:25088017

The formation of inflammatory demyelinated lesions in cerebral white matter.

PubMed

Maggi, Pietro; Macri, Sheila M Cummings; Gaitán, María I; Leibovitch, Emily; Wholer, Jillian E; Knight, Heather L; Ellis, Mary; Wu, Tianxia; Silva, Afonso C; Massacesi, Luca; Jacobson, Steven; Westmoreland, Susan; Reich, Daniel S

2014-10-01

Vascular permeability and inflammatory demyelination are intimately linked in the brain, but what is their temporal relationship? We aimed to determine the radiological correlates of the earliest tissue changes accompanying demyelination in a primate model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) in the common marmoset. By 7T magnetic resonance imaging (MRI), T1 maps, proton density, and T2-weighted images were acquired before and after EAE induction in 5 marmosets (every other week before lesions appeared, weekly thereafter). From scans before and after intravenous injection of contrast material, we measured the evolution of lesional blood-brain barrier (BBB) permeability, comparing in vivo MRI to postmortem tissue examination. On average, BBB permeability increased 3.5-fold (p < 0.0001) over the 4 weeks prior to lesion appearance. Permeability gradually decreased after lesion appearance, with attendant changes in the distribution of inflammatory cells (predominantly macrophages and microglia) and demyelination. On tissue analysis, we also identified small perivascular foci of microglia and T cells without blood-derived macrophages or demyelination. These foci had no visible MRI correlates, although permeability within the foci, but not outside, increased in the weeks before the animals died (p < 0.0001). This study provides compelling evidence that in marmoset EAE, which forms lesions strongly resembling those of MS, early changes in vascular permeability are associated with perivascular inflammatory cuffing and parenchymal microglial activation but precede the arrival of blood-derived monocytes that accompany demyelination. Prospective detection of transient permeability changes could afford an opportunity for early intervention to forestall tissue damage in newly forming lesions. © 2014 American Neurological Association.

Evaluation of vascular space involvement in endometrial adenocarcinomas: laparoscopic vs abdominal hysterectomies.

PubMed

Folkins, Ann K; Nevadunsky, Nicole S; Saleemuddin, A; Jarboe, Elke A; Muto, Michael G; Feltmate, Colleen M; Crum, Chris P; Hirsch, Michelle S

2010-08-01

Recent reports have described 'vascular pseudoinvasion' in total laparoscopic hysterectomies with endometrial carcinoma. To better understand this phenomenon, we compared pathologic findings in these laparoscopic and total abdominal hysterectomies performed for uterine endometrioid adenocarcinoma. Reports from 58 robotically assisted laparoscopic and 39 abdominal hysterectomies with grade 1 or 2 endometrioid endometrial adenocarcinomas were reviewed for stage, depth of invasion, vascular space involvement, uterine weight, and lymph node metastases. In addition, attention was given to possible procedural artifacts, including vertical endomyometrial clefts, and inflammatory debris, benign endometrial glands, and disaggregated tumor cells in vascular spaces. All foci with vascular involvement were reviewed by three gynecologic pathologists. Nine of the 58 (16%) laparoscopic and 3 of the 39 (7%) abdominal hysterectomies contained vascular space involvement based on the original pathology reports (P-value=0.0833). No one histologic feature consistently distinguished laparoscopic from abdominal cases on blind review of the available cases. Disaggregated intravascular tumor cells were significantly associated with reported vascular involvement in both procedures (P-values<0.001 and 0.016), most of which were corroborated on review. Laparoscopic procedures tend to have a higher index of vascular involvement, which is associated with lower stage, fewer lymph node metastases, and less myometrial invasion; however, pathologists cannot consistently determine the procedure on histologic findings alone. Moreover, there is significant inter-observer variability in distinguishing true from artifactual vascular space involvement, even among pathologists at the same institution. The clinical significance of apparent true vascular space involvement seen adjacent to artifacts is unclear, as is the impact of laparoscopic hysterectomy on recurrence risk.

Extracorporeal membrane oxygenation and cytokine adsorption

PubMed Central

Träger, Karl

2018-01-01

Extracorporeal membrane oxygenation (ECMO) is an increasingly used technology for mechanical support of respiratory and cardio-circulatory failure. Excessive systemic inflammatory response is observed during sepsis and after cardiopulmonary bypass (CPB) with similar clinical features. The overwhelming inflammatory response is characterized by highly elevated pro- and anti-inflammatory cytokine levels. The excessive cytokine release during the overwhelming inflammatory response may result in multiple organ damage and failure. During ECMO therapy activation of complement and contact systems occur which may be followed by cytokine release. Controlling excessively increased cytokines may be considered as a valuable treatment option. Hemoadsorption therapy may be used to decrease cytokine levels in case of excessive inflammatory response and due to its unspecific adsorptive characteristics also substances like myoglobin, free hemoglobin or bilirubin. Controlling pro-inflammatory response with hemoadsorption may have positive impact on the endothelial glycocalix and also may be advantageous for maintenance of the vascular barrier function which plays a pivotal role in the development of tissue edema and oxygen mismatch. Hemoadsorption therapy seems to offer a promising new option for the treatment of patients with overwhelming inflammatory response leading to faster hemodynamic and metabolic stabilization finally resulting in preserved organ functions. PMID:29732183

Extracorporeal membrane oxygenation and cytokine adsorption.

PubMed

Datzmann, Thomas; Träger, Karl

2018-03-01

Extracorporeal membrane oxygenation (ECMO) is an increasingly used technology for mechanical support of respiratory and cardio-circulatory failure. Excessive systemic inflammatory response is observed during sepsis and after cardiopulmonary bypass (CPB) with similar clinical features. The overwhelming inflammatory response is characterized by highly elevated pro- and anti-inflammatory cytokine levels. The excessive cytokine release during the overwhelming inflammatory response may result in multiple organ damage and failure. During ECMO therapy activation of complement and contact systems occur which may be followed by cytokine release. Controlling excessively increased cytokines may be considered as a valuable treatment option. Hemoadsorption therapy may be used to decrease cytokine levels in case of excessive inflammatory response and due to its unspecific adsorptive characteristics also substances like myoglobin, free hemoglobin or bilirubin. Controlling pro-inflammatory response with hemoadsorption may have positive impact on the endothelial glycocalix and also may be advantageous for maintenance of the vascular barrier function which plays a pivotal role in the development of tissue edema and oxygen mismatch. Hemoadsorption therapy seems to offer a promising new option for the treatment of patients with overwhelming inflammatory response leading to faster hemodynamic and metabolic stabilization finally resulting in preserved organ functions.

Characterization of vascular permeability using a biomimetic microfluidic blood vessel model

PubMed Central

Thomas, Antony; Wang, Shunqiang; Sohrabi, Salman; Orr, Colin; He, Ran; Shi, Wentao; Liu, Yaling

2017-01-01

The inflammatory response in endothelial cells (ECs) leads to an increase in vascular permeability through the formation of gaps. However, the dynamic nature of vascular permeability and external factors involved is still elusive. In this work, we use a biomimetic blood vessel (BBV) microfluidic model to measure in real-time the change in permeability of the EC layer under culture in physiologically relevant flow conditions. This platform studies the dynamics and characterizes vascular permeability when the EC layer is triggered with an inflammatory agent using tracer molecules of three different sizes, and the results are compared to a transwell insert study. We also apply an analytical model to compare the permeability data from the different tracer molecules to understand the physiological and bio-transport significance of endothelial permeability based on the molecule of interest. A computational model of the BBV model is also built to understand the factors influencing transport of molecules of different sizes under flow. The endothelial monolayer cultured under flow in the BBV model was treated with thrombin, a serine protease that induces a rapid and reversible increase in endothelium permeability. On analysis of permeability data, it is found that the transport characteristics for fluorescein isothiocyanate (FITC) dye and FITC Dextran 4k Da molecules are similar in both BBV and transwell models, but FITC Dextran 70k Da molecules show increased permeability in the BBV model as convection flow (Peclet number > 1) influences the molecule transport in the BBV model. We also calculated from permeability data the relative increase in intercellular gap area during thrombin treatment for ECs in the BBV and transwell insert models to be between 12% and 15%. This relative increase was found to be within range of what we quantified from F-actin stained EC layer images. The work highlights the importance of incorporating flow in in vitro vascular models, especially in studies involving transport of large size objects such as antibodies, proteins, nano/micro particles, and cells. PMID:28344727

The relationship between components of tumour inflammatory cell infiltrate and clinicopathological factors and survival in patients with primary operable invasive ductal breast cancer

PubMed Central

Mohammed, Z MA; Going, J J; Edwards, J; Elsberger, B; Doughty, J C; McMillan, D C

2012-01-01

Background: The importance of the components of host local inflammatory response in determining outcome in primary operable ductal invasive breast cancer is not clear. The aim of this study was to examine the relationship between components of the tumour inflammatory cell infiltrate and standard clinicopathological factors including hormone status (oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER)-2), Ki-67 and survival in patients with primary operable invasive ductal breast cancer. Methods: Tumour inflammatory cell infiltrate, hormone status (ER, PR and HER-2), Ki-67 and standard clinicopathological factors were determined using routine pathological and immuno-histochemical techniques in 468 patients. Results: The large majority (94%) of ductal tumours had evidence of inflammatory cell infiltrate. The general inflammatory cell infiltrate was positively associated with high grade (P<0.001), the absence of ER (P<0.001), the absence of PR (P<0.01), the presence of vascular invasion (P<0.05) and high lymphocytic infiltrate, plasma cell infiltrate, other inflammatory cell infiltrate and macrophage infiltrate (all P<0.001). The median follow-up of the survivors was 165 months. During this period, 93 patients died of their cancer. On univariate analysis, stratified for ER status, tumour size (P<0.01), lymph node involvement (P<0.001), tumour plasma cell infiltrate (P<0.001), other inflammatory cell infiltrate (P<0.05) and treatment (P<0.05) were associated with poorer cancer-specific survival whereas lymphocyte infiltrate (P<0.001) was associated with improved cancer-specific survival. On multivariate analysis, stratified for ER status, lymph node involvement (P<0.05) was independently associated with poorer cancer-specific survival whereas increased tumour lymphocyte infiltrate (P<0.001) was independently associated with improved cancer-specific survival. Conclusion: The results of this study show that, using routine histology, the general inflammatory cell infiltrate was a common feature and was positively associated with high grade, the absence of ER, the absence of PR, the presence of vascular invasion and high-grade infiltration of lymphocytes, plasma cells, other inflammatory cells and macrophages. Also, that within a mature cohort of patients, a high lymphocytic infiltrate was associated with improved survival, independent of clinicopathological characteristics including ER status, in primary operable ductal invasive breast cancer. These results rationalise previous work and provide a sound basis for future studies in this important area of breast cancer research. PMID:22878371

Participation of blood vessel cells in human adaptive immune responses.

PubMed

Pober, Jordan S; Tellides, George

2012-01-01

Circulating T cells contact blood vessels either when they extravasate across the walls of microvessels into inflamed tissues or when they enter into the walls of larger vessels in inflammatory diseases such as atherosclerosis. The blood vessel wall is largely composed of three cell types: endothelial cells lining the entire vascular tree; pericytes supporting the endothelium of microvessels; and smooth muscle cells forming the bulk of large vessel walls. Each of these cell types interacts with and alters the behavior of infiltrating T cells in different ways, making these cells active participants in the processes of immune-mediated inflammation. In this review, we compare and contrast what is known about the nature of these interactions in humans. Copyright © 2011 Elsevier Ltd. All rights reserved.

TAM Receptor Signaling in Immune Homeostasis

PubMed Central

Rothlin, Carla V.; Carrera-Silva, Eugenio A.; Bosurgi, Lidia; Ghosh, Sourav

2015-01-01

The TAM receptor tyrosine kinases (RTKs)—TYRO3, AXL, and MERTK—together with their cognate agonists GAS6 and PROS1 play an essential role in the resolution of inflammation. Deficiencies in TAM signaling have been associated with chronic inflammatory and autoimmune diseases. Three processes regulated by TAM signaling may contribute, either independently or collectively, to immune homeostasis: the negative regulation of the innate immune response, the phagocytosis of apoptotic cells, and the restoration of vascular integrity. Recent studies have also revealed the function of TAMs in infectious diseases and cancer. Here, we review the important milestones in the discovery of these RTKs and their ligands and the studies that underscore the functional importance of this signaling pathway in physiological immune settings and disease. PMID:25594431

Antiartherosclerotic Effects of Plant Flavonoids

PubMed Central

Gunasekaran, Baskaran; Shukor, Mohd Yunus

2014-01-01

Atherosclerosis is the process of hardening and narrowing the arteries. Atherosclerosis is generally associated with cardiovascular diseases such as strokes, heart attacks, and peripheral vascular diseases. Since the usage of the synthetic drug, statins, leads to various side effects, the plants flavonoids with antiartherosclerotic activity gained much attention and were proven to reduce the risk of atherosclerosis in vitro and in vivo based on different animal models. The flavonoids compounds also exhibit lipid lowering effects and anti-inflammatory and antiatherogenic properties. The future development of flavonoids-based drugs is believed to provide significant effects on atherosclerosis and its related diseases. This paper discusses the antiatherosclerotic effects of selected plant flavonoids such as quercetin, kaempferol, myricetin, rutin, naringenin, catechin, fisetin, and gossypetin. PMID:24971331

Occipital Neuralgia in Chiari I Malformation: Two Different Events or Two Different Faces of the Same Event?

PubMed

Tondo, Giacomo; De Marchi, Fabiola; Mittino, Daniela; Cantello, Roberto

2017-11-29

Occipital neuralgia (ON) is characterized by severe pain in the occipital region due to an irritation of the occipital nerves. Traumatic injuries, mass or vascular compression, and infective and inflammatory processes could cause ON. The dislocation of a nerve/muscle/tendon, as can happen in malformations such as the Chiari I malformation (CIM), also can be responsible. Usually, headaches associated with CIM and ON are distinguishable based on specific features of pain. However, the diagnosis is not easy in some cases, especially if a clear medical history cannot be accurately collected. Determining if the pain is related to ON rather than to CIM is important because the treatments may be different.

Occipital Neuralgia in Chiari I Malformation: Two Different Events or Two Different Faces of the Same Event?

PubMed Central

De Marchi, Fabiola; Mittino, Daniela; Cantello, Roberto

2017-01-01

Occipital neuralgia (ON) is characterized by severe pain in the occipital region due to an irritation of the occipital nerves. Traumatic injuries, mass or vascular compression, and infective and inflammatory processes could cause ON. The dislocation of a nerve/muscle/tendon, as can happen in malformations such as the Chiari I malformation (CIM), also can be responsible. Usually, headaches associated with CIM and ON are distinguishable based on specific features of pain. However, the diagnosis is not easy in some cases, especially if a clear medical history cannot be accurately collected. Determining if the pain is related to ON rather than to CIM is important because the treatments may be different. PMID:29392103

Vascular Proteomics Reveal Novel Proteins Involved in SMC Phenotypic Change: OLR1 as a SMC Receptor Regulating Proliferation and Inflammatory Response

PubMed Central

Kang, Dong Hoon; Choi, Mina; Chang, Soyoung; Lee, Min Young; Lee, Doo Jae; Choi, Kyungsun; Park, Junseong; Han, Eun Chun; Hwang, Daehee; Kwon, Kihwan; Jo, Hanjoong; Choi, Chulhee; Kang, Sang Won

2015-01-01

Neointimal hyperplasia of vascular smooth muscle cells (VSMC) plays a critical role in atherosclerotic plaque formation and in-stent restenosis, but the underlying mechanisms are still incompletely understood. We performed a proteomics study to identify novel signaling molecules organizing the VSMC hyperplasia. The differential proteomics analysis in a balloon-induced injury model of rat carotid artery revealed that the expressions of 44 proteins are changed within 3 days post injury. The combination of cellular function assays and a protein network analysis further demonstrated that 27 out of 44 proteins constitute key signaling networks orchestrating the phenotypic change of VSMC from contractile to epithelial-like synthetic. Among the list of proteins, the in vivo validation specifically revealed that six proteins (Rab15, ITR, OLR1, PDHβ, PTPε) are positive regulators for VSMC hyperplasia. In particular, the OLR1 played dual roles in the VSMC hyperplasia by directly mediating oxidized LDL-induced monocyte adhesion via NF-κB activation and by assisting the PDGF-induced proliferation/migration. Importantly, OLR1 and PDGFRβ were associated in close proximity in the plasma membrane. Thus, this study elicits the protein network organizing the phenotypic change of VSMC in the vascular injury diseases such as atherosclerosis and discovers OLR1 as a novel molecular link between the proliferative and inflammatory responses of VSMCs. PMID:26305474

Upregulation of angiogenesis in oral lichen planus.

PubMed

Al-Hassiny, A; Friedlander, L T; Parachuru, V P B; Seo, B; Hussaini, H M; Rich, A M

2018-02-01

As angiogenesis is fundamental to the pathogenesis of many chronic inflammatory disorders, this study investigated the expression of various vascular markers in oral lichen planus and non-specific oral mucosal inflammatory tissues. Archival specimens of oral lichen planus (n = 15) and inflamed tissues (n = 13) were stained using immunohistochemistry with antibodies to CD34, vascular endothelial growth factor, vascular endothelial growth factor receptor and vasohibin. Nine representative sites at the epithelial-connective tissue junction and through the fibrous connective tissue were selected, and automated analysis techniques were used to determine the extent of positivity expressed as the percentage of positive cells. Significance was denoted when P < .05. The expression of pro-angiogenic factors was higher in lichen planus samples compared with inflamed controls. A higher level of CD34 was observed in the deeper parts of the connective tissue of Oral lichen planus (OLP) (P = .04), whereas VEGF and VEGFR2 expressions were higher all through the tissues (respectively, P < .02 and P < .01). The expression of the anti-angiogenic VASH1 was higher in inflamed tissue compared with lichen planus in all sites evaluated (P < .01). The findings indicate that angiogenic factors are differentially expressed in oral lichen planus compared with inflamed controls, with increased expression of pro-angiogenic factors and decreased anti-angiogenic expression. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Vascular endothelial-targeted therapy combined with cytotoxic chemotherapy induces inflammatory intratumoral infiltrates and inhibits tumor relapses after surgery.

PubMed

Judy, Brendan F; Aliperti, Louis A; Predina, Jarrod D; Levine, Daniel; Kapoor, Veena; Thorpe, Philip E; Albelda, Steven M; Singhal, Sunil

2012-04-01

Surgery is the most effective therapy for cancer in the United States, but disease still recurs in more than 40% of patients within 5 years after resection. Chemotherapy is given postoperatively to prevent relapses; however, this approach has had marginal success. After surgery, recurrent tumors depend on rapid neovascular proliferation to deliver nutrients and oxygen. Phosphatidylserine (PS) is exposed on the vascular endothelial cells in the tumor microenvironment but is notably absent on blood vessels in normal tissues. Thus, PS is an attractive target for cancer therapy after surgery. Syngeneic mice bearing TC1 lung cancer tumors were treated with mch1N11 (a novel mouse chimeric monoclonal antibody that targets PS), cisplatin (cis), or combination after surgery. Tumor relapses and disease progression were decreased 90% by combination therapy compared with a 50% response rate for cis alone (P = .02). Mice receiving postoperative mch1N11 had no wound-related complications or added systemic toxicity in comparison to control animals. Mechanistic studies demonstrated that the effects of mch1N11 were associated with a dense infiltration of inflammatory cells, particularly granulocytes. This strategy was independent of the adaptive immune system. Together, these data suggest that vascular-targeted strategies directed against exposed PS may be a powerful adjunct to postoperative chemotherapy in preventing relapses after cancer surgery.

Adipose Extracellular Matrix/Stromal Vascular Fraction Gel Secretes Angiogenic Factors and Enhances Skin Wound Healing in a Murine Model.

PubMed

Sun, Mingliang; He, Yunfan; Zhou, Tao; Zhang, Pan; Gao, Jianhua; Lu, Feng

2017-01-01

Mesenchymal stem cells are an attractive cell type for cytotherapy in wound healing. The authors recently developed a novel, adipose-tissue-derived, injectable extracellular matrix/stromal vascular fraction gel (ECM/SVF-gel) for stem cell therapy. This study was designed to assess the therapeutic effects of ECM/SVF-gel on wound healing and potential mechanisms. ECM/SVF-gel was prepared for use in nude mouse excisional wound healing model. An SVF cell suspension and phosphate-buffered saline injection served as the control. The expression levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and monocyte chemotactic protein-1 (MCP-1) in ECM/SVF-gel were analyzed at different time points. Angiogenesis (tube formation) assays of ECM/SVF-gel extracts were evaluated, and vessels density in skin was determined. The ECM/SVF-gel extract promoted tube formation in vitro and increased the expression of the angiogenic factors VEGF and bFGF compared with those in the control. The expression of the inflammatory chemoattractant MCP-1 was high in ECM/SVF-gel at the early stage and decreased sharply during the late stage of wound healing. The potent angiogenic effects exerted by ECM/SVF-gel may contribute to the improvement of wound healing, and these effects could be related to the enhanced inflammatory response in ECM/SVF-gel during the early stage of wound healing.

[Anatomy typological and clinical parallels in case of disturbance of soft tissue formations of shoulder girdle].

PubMed

Volkov, A V; Shutov, Iu M; Shutova, M Z

2012-01-01

The influence of anthropology on topographical anatomical structure peculiarities of soft tissue formations of shoulder girdle has been investigated. The dependence of anatomical structure and topography of muscles, ligaments, tendon sheaths, synovial bursae, rotator cuffs on patient's body constitution type has been examined. The influence of a somatotype on topical damage of soft tissue structures of shoulder girdle has been proved. The so-called "holes" or weak areas, joint capsules, places where ligaments attach to bones and cartilages, where vascular formations also take place have been revealed. It is in these areas that degenerative inflammatory process begins. First of all this process influences hemolymph circulation, then it results in disturbance in production and resorption of synovial fluid and causes destructive processes in ligaments, tendons and osteochondral tissue. Due to research the ability to conduct differential diagnosis has been determined, methods of modality treatment and prevention of periarticular tissue diseases have been optimized.

A Computational Model Predicting Disruption of Blood Vessel Development

PubMed Central

Kleinstreuer, Nicole; Dix, David; Rountree, Michael; Baker, Nancy; Sipes, Nisha; Reif, David; Spencer, Richard; Knudsen, Thomas

2013-01-01

Vascular development is a complex process regulated by dynamic biological networks that vary in topology and state across different tissues and developmental stages. Signals regulating de novo blood vessel formation (vasculogenesis) and remodeling (angiogenesis) come from a variety of biological pathways linked to endothelial cell (EC) behavior, extracellular matrix (ECM) remodeling and the local generation of chemokines and growth factors. Simulating these interactions at a systems level requires sufficient biological detail about the relevant molecular pathways and associated cellular behaviors, and tractable computational models that offset mathematical and biological complexity. Here, we describe a novel multicellular agent-based model of vasculogenesis using the CompuCell3D (http://www.compucell3d.org/) modeling environment supplemented with semi-automatic knowledgebase creation. The model incorporates vascular endothelial growth factor signals, pro- and anti-angiogenic inflammatory chemokine signals, and the plasminogen activating system of enzymes and proteases linked to ECM interactions, to simulate nascent EC organization, growth and remodeling. The model was shown to recapitulate stereotypical capillary plexus formation and structural emergence of non-coded cellular behaviors, such as a heterologous bridging phenomenon linking endothelial tip cells together during formation of polygonal endothelial cords. Molecular targets in the computational model were mapped to signatures of vascular disruption derived from in vitro chemical profiling using the EPA's ToxCast high-throughput screening (HTS) dataset. Simulating the HTS data with the cell-agent based model of vascular development predicted adverse effects of a reference anti-angiogenic thalidomide analog, 5HPP-33, on in vitro angiogenesis with respect to both concentration-response and morphological consequences. These findings support the utility of cell agent-based models for simulating a morphogenetic series of events and for the first time demonstrate the applicability of these models for predictive toxicology. PMID:23592958

Pre-vascularization Enhances Therapeutic Effects of Human Mesenchymal Stem Cell Sheets in Full Thickness Skin Wound Repair.

PubMed

Chen, Lei; Xing, Qi; Zhai, Qiyi; Tahtinen, Mitchell; Zhou, Fei; Chen, Lili; Xu, Yingbin; Qi, Shaohai; Zhao, Feng

2017-01-01

Split thickness skin graft (STSG) implantation is one of the standard therapies for full thickness wound repair when full thickness autologous skin grafts (FTG) or skin flap transplants are inapplicable. Combined transplantation of STSG with dermal substitute could enhance its therapeutic effects but the results remain unsatisfactory due to insufficient blood supply at early stages, which causes graft necrosis and fibrosis. Human mesenchymal stem cell (hMSC) sheets are capable of accelerating the wound healing process. We hypothesized that pre-vascularized hMSC sheets would further improve regeneration by providing more versatile angiogenic factors and pre-formed microvessels. In this work, in vitro cultured hMSC cell sheets (HCS) and pre-vascularized hMSC cell sheets (PHCS) were implanted in a rat full thickness skin wound model covered with an autologous STSG. Results demonstrated that the HCS and the PHCS implantations significantly reduced skin contraction and improved cosmetic appearance relative to the STSG control group. The PHCS group experienced the least hemorrhage and necrosis, and lowest inflammatory cell infiltration. It also induced the highest neovascularization in early stages, which established a robust blood micro-circulation to support grafts survival and tissue regeneration. Moreover, the PHCS grafts preserved the largest amount of skin appendages, including hair follicles and sebaceous glands, and developed the smallest epidermal thickness. The superior therapeutic effects seen in PHCS groups were attributed to the elevated presence of growth factors and cytokines in the pre-vascularized cell sheet, which exerted a beneficial paracrine signaling during wound repair. Hence, the strategy of combining STSG with PHCS implantation appears to be a promising approach in regenerative treatment of full thickness skin wounds.

Vascular Smooth Muscle-Specific EP4 Receptor Deletion in Mice Exacerbates Angiotensin II-Induced Renal Injury.

PubMed

Thibodeau, Jean-Francois; Holterman, Chet E; He, Ying; Carter, Anthony; Cron, Gregory O; Boisvert, Naomi C; Abd-Elrahman, Khaled S; Hsu, Karolynn J; Ferguson, Stephen S G; Kennedy, Christopher R J

2016-10-20

Cyclooxygenase inhibition by non-steroidal anti-inflammatory drugs is contraindicated in hypertension, as it may reduce glomerular filtration rate (GFR) and renal blood flow. However, the identity of the specific eicosanoid and receptor underlying these effects is not known. We hypothesized that vascular smooth muscle prostaglandin E2 (PGE2) E-prostanoid 4 (EP4) receptor deletion predisposes to renal injury via unchecked vasoconstrictive actions of angiotensin II (AngII) in a hypertension model. Mice with inducible vascular smooth muscle cell (VSMC)-specific EP4 receptor deletion were generated and subjected to AngII-induced hypertension. EP4 deletion was verified by PCR of aorta and renal vessels, as well as functionally by loss of PGE2-mediated mesenteric artery relaxation. Both AngII-treated groups became similarly hypertensive, whereas albuminuria, foot process effacement, and renal hypertrophy were exacerbated in AngII-treated EP4 VSMC-/- but not in EP4 VSMC+/+ mice and were associated with glomerular scarring, tubulointerstitial injury, and reduced GFR. AngII-treated EP4 VSMC-/- mice exhibited capillary damage and reduced renal perfusion as measured by fluorescent bead microangiography and magnetic resonance imaging, respectively. NADPH oxidase 2 (Nox2) expression was significantly elevated in AngII-treated EP4 -/- mice. EP4-receptor silencing in primary VSMCs abolished PGE2 inhibition of AngII-induced Nox2 mRNA and superoxide production. These data suggest that vascular EP4 receptors buffer the actions of AngII on renal hemodynamics and oxidative injury. EP4 agonists may, therefore, protect against hypertension-associated kidney damage. Antioxid. Redox Signal. 25, 642-656.

The Unconventional Role of Acid Sphingomyelinase in Regulation of Retinal Microangiopathy in Diabetic Human and Animal Models

PubMed Central

Opreanu, Madalina; Tikhonenko, Maria; Bozack, Svetlana; Lydic, Todd A.; Reid, Gavin E.; McSorley, Kelly M.; Sochacki, Andrew; Perez, Gloria I.; Esselman, Walter J.; Kern, Timothy; Kolesnick, Richard; Grant, Maria B.; Busik, Julia V.

2011-01-01

OBJECTIVE Acid sphingomyelinase (ASM) is an important early responder in inflammatory cytokine signaling. The role of ASM in retinal vascular inflammation and vessel loss associated with diabetic retinopathy is not known and represents the goal of this study. RESEARCH DESIGN AND METHODS Protein and gene expression profiles were determined by quantitative RT-PCR and Western blot. ASM activity was determined using Amplex Red sphingomyelinase assay. Caveolar lipid composition was analyzed by nano-electrospray ionization tandem mass spectrometry. Streptozotocin-induced diabetes and retinal ischemia-reperfusion models were used in in vivo studies. RESULTS We identify endothelial caveolae-associated ASM as an essential component in mediating inflammation and vascular pathology in in vivo and in vitro models of diabetic retinopathy. Human retinal endothelial cells (HREC), in contrast with glial and epithelial cells, express the plasma membrane form of ASM that overlaps with caveolin-1. Treatment of HREC with docosahexaenoic acid (DHA) specifically reduces expression of the caveolae-associated ASM, prevents a tumor necrosis factor-α–induced increase in the ceramide-to-sphingomyelin ratio in the caveolae, and inhibits cytokine-induced inflammatory signaling. ASM is expressed in both vascular and neuroretina; however, only vascular ASM is specifically increased in the retinas of animal models at the vasodegenerative phase of diabetic retinopathy. The absence of ASM in ASM−/− mice or inhibition of ASM activity by DHA prevents acellular capillary formation. CONCLUSIONS This is the first study demonstrating activation of ASM in the retinal vasculature of diabetic retinopathy animal models. Inhibition of ASM could be further explored as a potential therapeutic strategy in treating diabetic retinopathy. PMID:21771974

Brain-mediated dysregulation of the bone marrow activity in angiotensin II-induced hypertension.

PubMed

Jun, Joo Yun; Zubcevic, Jasenka; Qi, Yanfei; Afzal, Aqeela; Carvajal, Jessica Marulanda; Thinschmidt, Jeffrey S; Grant, Maria B; Mocco, J; Raizada, Mohan K

2012-11-01

Oxidative stress in the brain is implicated in increased sympathetic drive, inflammatory status, and vascular dysfunctions, associated with development and establishment of hypertension. However, little is known about the mechanism of this impaired brain-vascular communication. Here, we tested the hypothesis that increased oxidative stress in the brain cardioregulatory areas, such as the paraventricular nucleus of the hypothalamus, is driven by mitochondrial reactive oxygen species and leads to increased inflammatory cells (ICs) and decreased/dysfunctional endothelial progenitor cells (EPCs), thereby compromising vasculature repair and accelerating hypertension. Chronic angiotensin II infusion resulted in elevated blood pressure and sympathetic vasomotor drive, decreased spontaneous baroreflex gain, and increased microglia activation in the paraventricular nucleus. This was associated with 46% decrease in bone marrow (BM)-derived EPCs and 250% increase in BM ICs, resulting in 5-fold decrease of EPC/IC ratio in the BM. Treatment with mitochondrial-targeted antioxidant, a scavenger of mitochondrial O(2)(-·), intracerebroventricularly but not subcutaneously attenuated angiotensin II-induced hypertension, decreased activation of microglia in the paraventricular nucleus, and normalized EPCs/ICs. This functional communication between the brain and BM was confirmed by retrograde neuronal labeling from the BM with green fluorescent protein-tagged pseudorabies virus. Administration of green fluorescent protein-tagged pseudorabies virus into the BM resulted in predominant labeling of paraventricular nucleus neurons within 3 days, with some fluorescence in the nucleus tractus solitarius, the rostral ventrolateral medulla, and subfornical organ. Taken together, these data demonstrate that inhibition of mitochondrial reactive oxygen species attenuates angiotensin II-induced hypertension and corrects the imbalance in EPCs/ICs in the BM. They suggest that an imbalance in vascular reparative and ICs may perpetuate vascular pathophysiology in this model of hypertension.

Brain-Mediated Dysregulation of the Bone Marrow Activity in Angiotensin II-induced Hypertension

PubMed Central

Jun, Joo Yun; Zubcevic, Jasenka; Qi, Yanfei; Afzal, Aqeela; Carvajal, Jessica Marulanda; Thinschmidt, Jeffrey S; Grant, Maria B.; Mocco, J; Raizada, Mohan K

2012-01-01

Oxidative stress in the brain is implicated in increased sympathetic drive, inflammatory status and vascular dysfunctions, associated with development and establishment of hypertension. However, little is known about the mechanism of this impaired brain-vascular communication. Here, we tested the hypothesis that increased oxidative stress in the brain cardioregulatory areas, such as the paraventricular nucleus (PVN) of the hypothalamus, is driven by mitochondrial reactive oxygen species (ROS) and leads to increased inflammatory cells (ICs) and decreased/dysfunctional endothelial progenitor cells (EPCs), thereby compromising vasculature repair and accelerating hypertension. Chronic angiotensin II (Ang II) infusion resulted in elevated blood pressure and sympathetic vasomotor drive, decreased spontaneous baroreflex gain, and increased microglia activation in the PVN. This was associated with 46% decrease in BM EPCs and 250% increase in BM ICs, resulting in 5 fold decrease of EPCs/ICs ratio in the BM. Treatment with mitoTEMPO, a scavenger of mitochondrial O2−• intracerebroventricularly but not subcutaneously, attenuated Ang II-induced hypertension, decreased activation of microglia in the PVN, and normalized EPCs/ICs. This functional communication between the brain and BM was confirmed by retrograde neuronal labeling from the BM with GFP-tagged pseudorabies virus (PRV). Administration of GFP-PRV into the BM resulted in predominant labeling of PVN neurons within 3 days, with some fluorescence in the NTS, RVLM and SFO. Taken together, these data demonstrate that inhibition of mitochondrial ROS attenuates Ang II-induced hypertension and corrects the imbalance in EPCs/ICs in the BM. They suggest that an imbalance in vascular reparative and ICs may perpetuate vascular pathophysiology in this model of hypertension. PMID:23045460

Central and peripheral haemodynamic effects of non-steroidal anti-inflammatory drugs in man.

PubMed

Wennmalm, A; Carlsson, I; Edlund, A; Eriksson, S; Kaijser, L; Nowak, J

1984-01-01

The haemodynamic effects of non-steroidal anti-inflammatory (NSAI) drugs can be attributed either to their common property of inhibiting the formation of prostaglandins (PG) in the cardiovascular system, or to direct actions on the tone and sensitivity of the resistance vessels in various regions. Indomethacin (IND) is the most frequently studied NSAI drug, in animals and in man. Its cardiovascular effects differ somewhat from those of other NSAI, due to the fact that, besides inhibiting PG formation, IND acts as a direct vasoconstrictor. The stimulatory effect of IND in vascular smooth muscle results in an increased systemic vascular resistance which, although partially compensated by a decreased cardiac output, gives rise to a moderate increase in systemic blood pressure. The vasoconstrictor effect of IND is of particular interest in patients with ischemic heart disease, since it lowers their already decreased coronary flow, and may thereby accentuate the risk of myocardial infarction. Administration of IND also leads to a decreased blood flow in the splanchnic region, the kidneys, and the brain. The cerebral blood flow is lowered by 25-35%; in addition, IND almost entirely erases the hyperemic flow response to hypercapnia. Of other NSAI drugs, at least aspirin and naproxen are completely devoid of such actions on the cerebral circulation. A common vascular effect of all NSAI drugs is a diminution of reactive hyperemia, the local hyperemia that develops in a tissue subjected to a short period of arterial occlusion. Part of this hyperemic response is dependent on an intact vascular PG formation and consequently it is inhibited when PG formation is blocked. In contrast, NSAI drugs do not affect the functional increase in the blood flow in working skeletal muscle.

Hypertension-Induced Cerebral Small Vessel Disease Leading to Cognitive Impairment.

PubMed

Liu, Yang; Dong, Yan-Hong; Lyu, Pei-Yuan; Chen, Wei-Hong; Li, Rui

2018-03-05

Alzheimer's disease and vascular dementia are responsible for more than 80% of dementia cases. These two conditions share common risk factors including hypertension. Cerebral small vessel disease (CSVD) is strongly associated with both hypertension and cognitive impairment. In this review, we identify the pathophysiological changes in CSVD that are caused by hypertension and further explore the relationship between CSVD and cognitive impairment. We searched and scanned the PubMed database for recently published literatures up to December 2017. We used the keywords of "hypertension", "cerebral small vessel disease", "white matter lesions", "enlarged perivascular spaces", "lacunar infarcts", "cerebral microbleeds", and "cognitive impairment" in the database of PubMed. Articles were obtained and reviewed to analyze the hypertension-induced pathophysiological changes that occur in CSVD and the correlation between CSVD and cognitive impairment. In recent years, studies have demonstrated that hypertension-related changes (e.g., small vascular lesions, inflammatory reactions, hypoperfusion, oxidative stress, damage to autoregulatory processes and the blood-brain barrier, and cerebral amyloid angiopathy) can occur over time in cerebral small vessels, potentially leading to lower cognitive function when blood pressure (BP) control is poor or lacking. Both isolated and co-occurrent CSVD can lead to cognitive deterioration, and this effect may be attributable to a dysfunction in either the cholinergic system or the functionality of cortical and subcortical tracts. We explore the currently available evidence about the hypertensive vasculopathy and inflammatory changes that occur in CSVD. Both are vital prognostic indicators of the development of cognitive impairment. Future studies should be performed to validate the relationship between BP levels and CSVD progression and between the numbers, volumes, and anatomical locations of CSVD and cognitive impairment.

Angiogenesis and inflammation signaling are targets of beer polyphenols on vascular cells.

PubMed

Negrão, Rita; Costa, Raquel; Duarte, Delfim; Taveira Gomes, Tiago; Mendanha, Mário; Moura, Liane; Vasques, Luísa; Azevedo, Isabel; Soares, Raquel

2010-12-01

Emerging evidence indicates that chronic inflammation and oxidative stress cluster together with angiogenic imbalance in a wide range of pathologies. In general, natural polyphenols present health-protective properties, which are likely attributed to their effect on oxidative stress and inflammation. Hops used in beer production are a source of polyphenols such as xanthohumol (XN), and its metabolites isoxanthohumol (IXN) and phytoestrogen 8-prenylnaringenin (8PN). Our study aimed to evaluate XN, IXN, and 8PN effects on angiogenesis and inflammation processes. Opposite in vitro effects were observed between 8PN, stimulating endothelial and smooth muscle cell (SMC) growth, motility, invasion and capillary-like structures formation, and XN and IXN, which inhibited them. Mouse matrigel plug and rat skin wound-healing assays confirmed that XN and IXN treatments reduced vessel number as well as serum macrophage enzymatic activity, whereas 8PN increased blood vessels formation in both assays and enzyme activity in the wound-healing assay. A similar profile was found for serum inflammatory interleukin-1β quantification, in the wound-healing assay. Our data indicate that whereas 8PN stimulates angiogenesis, XN and IXN manifested anti-angiogenic and anti-inflammatory effects in identical conditions. These findings suggest that the effects observed for individual compounds on vascular wall cells must be carefully taken into account, as these polyphenols are metabolized after in vivo administration. The modulation of SMC proliferation and migration is also of special relevance, given the role of these cells in many pathological conditions. Furthermore, these results may provide clues for developing useful therapeutic agents against inflammation- and angiogenesis-associated pathologies. Copyright © 2010 Wiley-Liss, Inc.

Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice.

PubMed

Arumugam, Paritha I; Mullins, Eric S; Shanmukhappa, Shiva Kumar; Monia, Brett P; Loberg, Anastacia; Shaw, Maureen A; Rizvi, Tilat; Wansapura, Janaka; Degen, Jay L; Malik, Punam

2015-10-08

Sickle cell disease (SCD) results in vascular occlusions, chronic hemolytic anemia, and cumulative organ damage. A conspicuous feature of SCD is chronic inflammation and coagulation system activation. Thrombin (factor IIa [FIIa]) is both a central protease in hemostasis and a key modifier of inflammatory processes. To explore the hypothesis that reduced prothrombin (factor II [FII]) levels in SCD will limit vaso-occlusion, vasculopathy, and inflammation, we used 2 strategies to suppress FII in SCD mice. Weekly administration of FII antisense oligonucleotide "gapmer" to Berkeley SCD mice to selectively reduce circulating FII levels to ∼10% of normal for 15 weeks significantly diminished early mortality. More comprehensive, long-term comparative studies were done using mice with genetic diminution of circulating FII. Here, cohorts of FII(lox/-) mice (constitutively carrying ∼10% normal FII) and FII(WT) mice were tracked in parallel for a year following the imposition of SCD via hematopoietic stem cell transplantation. This genetically imposed suppression of FII levels resulted in an impressive reduction in inflammation (reduction in leukocytosis, thrombocytosis, and circulating interleukin-6 levels), reduced endothelial cell dysfunction (reduced endothelial activation and circulating soluble vascular cell adhesion molecule), and a significant improvement in SCD-associated end-organ damage (nephropathy, pulmonary hypertension, pulmonary inflammation, liver function, inflammatory infiltration, and microinfarctions). Notably, all of these benefits were achieved with a relatively modest 1.25-fold increase in prothrombin times, and in the absence of hemorrhagic complications. Taken together, these data establish that prothrombin is a powerful modifier of SCD-induced end-organ damage, and present a novel therapeutic target to ameliorate SCD pathologies. © 2015 by The American Society of Hematology.

Cobra CRISP functions as an inflammatory modulator via a novel Zn2+- and heparan sulfate-dependent transcriptional regulation of endothelial cell adhesion molecules.

PubMed

Wang, Yu-Ling; Kuo, Je-Hung; Lee, Shao-Chen; Liu, Jai-Shin; Hsieh, Yin-Cheng; Shih, Yu-Tsung; Chen, Chun-Jung; Chiu, Jeng-Jiann; Wu, Wen-Guey

2010-11-26

Cysteine-rich secretory proteins (CRISPs) have been identified as a toxin family in most animal venoms with biological functions mainly associated with the ion channel activity of cysteine-rich domain (CRD). CRISPs also bind to Zn(2+) at their N-terminal pathogenesis-related (PR-1) domain, but their function remains unknown. Interestingly, similar the Zn(2+)-binding site exists in all CRISP family, including those identified in a wide range of organisms. Here, we report that the CRISP from Naja atra (natrin) could induce expression of vascular endothelial cell adhesion molecules, i.e. intercellular adhesion molecule-1, vascular adhesion molecule-1, and E-selectin, to promote monocytic cell adhesion in a heparan sulfate (HS)- and Zn(2+)-dependent manner. Using specific inhibitors and small interfering RNAs, the activation mechanisms are shown to involve both mitogen-activated protein kinases and nuclear factor-κB. Biophysical characterization of natrin by using fluorescence, circular dichroism, and x-ray crystallographic methods further reveals the presence of two Zn(2+)-binding sites for natrin. The strong binding site is located near the putative Ser-His-Glu catalytic triad of the N-terminal domain. The weak binding site remains to be characterized, but it may modulate HS binding by enhancing its interaction with long chain HS. Our results strongly suggest that natrin may serve as an inflammatory modulator that could perturb the wound-healing process of the bitten victim by regulating adhesion molecule expression in endothelial cells. Our finding uncovers a new aspect of the biological role of CRISP family in immune response and is expected to facilitate future development of new therapeutic strategy for the envenomed victims.