Mechanisms of Resolution of Inflammation A Focus on Cardiovascular Disease

Lipidomic Research Facility, UHI Department of Diabetes and Cardiovascular Science, Highland Diabetes Institute, Centre for Health Science, Old Perth Road, Inverness IV2 3JH, Scotland.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 05/2011; 31(5):1001-6. DOI: 10.1161/ATVBAHA.110.213850
Source: PubMed


The inflammatory response is an integral part of the innate immune mechanism that is triggered in response to a real or perceived threat to tissue homeostasis, with a primary aim of neutralizing infectious agents and initiating repair to damaged tissue. By design, inflammation is a finite process that resolves as soon as the threat of infection abates and sufficient repair to the tissue is complete. Resolution of inflammation involves apoptosis and subsequent clearance of activated inflammatory cells--a tightly regulated event. Chronic inflammation is a characteristic feature in virtually all inflammatory diseases, including atherosclerosis, and it is becoming increasingly clear that derangement of the processes usually involved in resolution of inflammation is an underlying feature of chronic inflammatory conditions. This review will draw on evidence from a range of diseases in which dysregulated inflammation is important, with particular emphasis on cardiovascular disease.

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    • "Pro-inflammatory effects of oxLDL have been attributed mainly to its chemotactic activity contributing to increased recruitment of monocyte/macrophages during atherogenesis [5]. Beyond, oxLDL can injure endothelial cells and vascular smooth muscle cells (VSMC) enhancing by this way vascular inflammation [6] [7]. High concentrations of oxLDL are cytotoxic [8]. "
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    ABSTRACT: The pathogenesis of atherosclerosis involves an imbalanced lipid metabolism and a deregulated immune response culminating in chronic inflammation of the arterial wall. Recent studies show that endogenous ligands, such as modified plasma lipoproteins, can trigger pattern recognition receptors (PRR) of innate immunity for cellular and humoral reactions. The underlying molecular pathways remain less explored. In this study, we investigated the mechanisms of inflammatory effects of oxidized low-density lipoproteins (oxLDL) on human primary coronary artery smooth muscle cells (VSMC). We show that already low concentration of oxLDL initiated atherogenic signals triggering VSMC transition to proinflammatory phenotype. oxLDL impaired the expression of contractile proteins and myocardin in VSMC and initiated changes in cell functional responses, including expression of proinflammatory molecules. The effects of oxLDL were abolished by downregulation of the multifunctional urokinase receptor (uPAR). In response to oxLDL uPAR associated with CD36 and TLR4, the two main PRR for both pathogen and endogenous ligands. We demonstrate that uPAR association with CD36 and TLR4 mediated oxLDL-induced and NF-κB-dependent G-CSF and GM-CSF expression and changes in VSMC contractile proteins. uPAR-mediated release of G-CSF and GM-CSF by VSMC affected macrophage behavior and production of MCP-1. We provide evidence for functional relevance of our in vitro findings to in vivo human atherosclerotic tissues. Our data imply uPAR as a part of a PRR cluster interfering structurally and functionally with CD36 and TLR4 and responding to endogenous atherogenic ligands. They further point to specific function of each component of this cluster in mediating the ultimate signaling pattern.
    Journal of Molecular and Cellular Cardiology 11/2013; 66. DOI:10.1016/j.yjmcc.2013.11.005 · 4.66 Impact Factor
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    • "Thus, in addition to plasma lipid lowering strategies, we should also aim at achieving resolution of the ongoing inflammatory activation in the diseased valves. Since some of the promising novel anti-inflammatory mediators are derivatives of the polyunsaturated fatty acids, including arachidonic acid [75], we face a difficult, but hopefully an ultimately rewarding challenge of resolving the lipid-dependent proinflammatory state in the valves and switching it into a lipid-dependent anti-inflammatory state. "
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    ABSTRACT: In aortic stenosis plasma lipoprotein-derived lipids accumulate in aortic valves. Here, we first compared the lipid compositions of stenotic aortic valves and atherosclerotic plaque cores. Both pathological tissues were found to be enriched in cholesteryl linoleate, a marker of extracellularly accumulated lipoproteins. In addition, a large proportion of the phospholipids were found to contain arachidonic acid, the common precursor of a number of proinflammatory lipid mediators. Next, we isolated and characterized extracellular lipid particles from human stenotic and non-stenotic control valves, and compared them to plasma lipoproteins from the same subjects. The extracellular valvular lipid particles were isolated from 15 stenotic and 14 non-stenotic aortic valves. Significantly more apoB-100-containing lipid particles were found in the stenotic than in the non-stenotic valves. The majority of the lipid particles isolated from the non-stenotic valves had sizes (23±6.2 nm in diameter) similar to those of plasma low density lipoprotein (LDL) (22±1.5 nm), while the lipid particles from stenotic valves were not of uniform size, their sizes ranging from 18 to more than 500 nm. The lipid particles showed signs of oxidative modifications, and when compared to isolated plasma LDL particles, the lipid particles isolated from the stenotic valves had a higher sphingomyelin/phosphatidylcholine -ratio, and also higher contents of lysophosphatidylcholine and unesterified cholesterol. The findings of the present study reveal, for the first time, that in stenotic human aortic valves, infiltrated plasma lipoproteins have undergone oxidative and lipolytic modifications, and become fused and aggregated. The generated large lipid particles may contribute to the pathogenesis of human aortic stenosis.
    PLoS ONE 06/2013; 8(6):e65810. DOI:10.1371/journal.pone.0065810 · 3.23 Impact Factor
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    • "It has been proposed that inhaled particles and gaseous air pollutants cause the release of reactive oxygen species from cells in the lung and circulating immune cells (4), which in turn trigger the release of inflammatory mediators into the systemic circulation to affect other body organs (5). Such an increase in systemic inflammation has been shown to increase cardiovascular disease (CVD) risk (6). Extremes of age, obesity, and underlying respiratory, cardiovascular, and metabolic disorders (diabetes) seem to increase vulnerability and susceptibility to the harmful effects of air pollution (7), and the systemic inflammatory response may further worsen the disease state (6). "
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    ABSTRACT: OBJECTIVE To study the association between ambient air pollutants and serum C-reactive protein (CRP) concentration in 1,392 type 2 diabetic patients in Pune, India.RESEARCH DESIGN AND METHODSA cross-sectional study was conducted that linked daily time series of ambient air pollution data (obtained from central monitoring sites) and plasma CRP concentration in type 2 diabetic patients from the Wellcome Trust Genetic (WellGen) Study, recruited between March 2005 and May 2007. Air pollution effects on CRP concentration were investigated with delays (lags) of 0-7 days and multiday averaging spans of 7, 14, and 30 days before blood collection adjusted for age, sex, BMI, hemoglobin, fasting plasma glucose, treatment with agents with anti-inflammatory action, season, air temperature, and relative humidity.RESULTSMedian CRP concentration was 3.49 mg/L. For 1 SD increase in SO(2) and oxides of nitrogen (NO(x)) concentrations in ambient air, a day before blood collection (lag(1)), we observed a significant increase in CRP (9.34 and 7.77%, respectively). The effect was higher with lag(2) (12.42% for SO(2) and 11.60% for NO(x)) and wore off progressively thereafter. We also found a significant association with multiday averaging times of up to 30 and 7 days for SO(2) and NO(x), respectively. No significant associations were found between particulate matter with an aerodynamic profile ≤10 µm (PM(10)) and CRP concentration except in summer. The association was significantly higher among patients with a shorter duration of diabetes, and in those not on statin and thiazolidinedione treatment.CONCLUSION We demonstrate, for the first time, a possible contribution of ambient air pollution to systemic inflammation in Indian type 2 diabetic patients. This may have implications for vascular complications of diabetes.
    Diabetes care 11/2012; 36(3). DOI:10.2337/dc12-0388 · 8.42 Impact Factor
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