| 1. |
- Serhan, Charles N., et al.
(författare)
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The Atlas of Inflammation Resolution (AIR)
- 2020
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Ingår i: Molecular Aspects of Medicine. - : Elsevier. - 0098-2997 .- 1872-9452. ; 74
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Tidskriftsartikel (refereegranskat)abstract
- Acute inflammation is a protective reaction by the immune system in response to invading pathogens or tissue damage. Ideally, the response should be localized, self-limited, and returning to homeostasis. If not resolved, acute inflammation can result in organ pathologies leading to chronic inflammatory phenotypes. Acute inflammation and inflammation resolution are complex coordinated processes, involving a number of cell types, interacting in space and time. The biomolecular complexity and the fact that several biomedical fields are involved, make a multi- and interdisciplinary approach necessary. The Atlas of Inflammation Resolution (AIR) is a web-based resource capturing an essential part of the state-of-the-art in acute inflammation and inflammation resolution research. The AIR provides an interface for users to search thousands of interactions, arranged in inter-connected multi-layers of process diagrams, covering a wide range of clinically relevant phenotypes. By mapping experimental data onto the AIR, it can be used to elucidate drug action as well as molecular mechanisms underlying different disease phenotypes. For the visualization and exploration of information, the AIR uses the Minerva platform, which is a well-established tool for the presentation of disease maps. The molecular details of the AIR are encoded using international standards. The AIR was created as a freely accessible resource, supporting research and education in the fields of acute inflammation and inflammation resolution. The AIR connects research communities, facilitates clinical decision making, and supports research scientists in the formulation and validation of hypotheses. The AIR is accessible through https://air.bio.informatik.uni-rostock.de.
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| 2. |
- Blanchet, Xavier, et al.
(författare)
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Inflammatory role and prognostic value of platelet chemokines in acute coronary syndrome
- 2014
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 112:6, s. 1277-1287
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Tidskriftsartikel (refereegranskat)abstract
- Activated platelets and neutrophils exacerbate atherosclerosis. Platelets release the chemokines CXCL4, CXCL4L1 and CCL5, whereas myeloperoxidase (MPO) and azurocidin are neutrophil-derived. We investigated whether plasma levels of these platelet and neutrophil mediators are affected by the acute coronary syndrome (ACS), its medical treatment, concomitant clinical or laboratory parameters, and predictive for the progression of coronary artery disease (CAD). In an observational study, the association of various factors with plasma concentrations of platelet chemokines and neutrophil mediators in 204 patients, either upon admission with ACS and 6 hours later or without ACS or CAD, was determined by multiple linear regression. Mediator release was further analysed after activation of blood with ACS-associated triggers such as plaque material. CXCL4, CXCL4L1, CCL5, MPO and azurocidin levels were elevated in ACS. CXCL4 and CCL5 but not CXCL4L1 or MPO were associated with platelet counts and CRP. CXCL4 (in association with heparin treatment) and MPO declined over 6 hours during ACS. Elevated CCL5 was associated with a progression of CAD. Incubating blood with plaque material, PAR1 and PAR4 activation induced a marked release of CXCL4 and CCL5, whereas CXCL4L1 and MPO were hardly or not altered. Platelet chemokines and neutrophil products are concomitantly elevated in ACS and differentially modulated by heparin treatment. CCL5 levels during ACS predict a progression of preexisting CAD. Platelet-derived products appear to dominate the inflammatory response during ACS, adding to the emerging evidence that ACS per se may promote vascular inflammation.
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| 3. |
- d'Alessandro, Elisa, et al.
(författare)
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Thrombo-Inflammation in Cardiovascular Disease : An Expert Consensus Document from the Third Maastricht Consensus Conference on Thrombosis
- 2020
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Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 120:4, s. 538-564
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Tidskriftsartikel (refereegranskat)abstract
- Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, and clinical scientists to discuss the origin and potential consequences of thrombo-inflammation in the etiology, diagnostics, and management of patients with cardiovascular disease, including myocardial infarction, stroke, and peripheral artery disease. This article presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following topics: (1) challenges of the endothelial cell barrier; (2) circulating cells and thrombo-inflammation, focused on platelets, neutrophils, and neutrophil extracellular traps; (3) procoagulant mechanisms; (4) arterial vascular changes in atherogenesis; attenuating atherosclerosis and ischemia/reperfusion injury; (5) management of patients with arterial vascular disease; and (6) pathogenesis of venous thrombosis and late consequences of venous thromboembolism.
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| 4. |
- Grommes, Jochen, et al.
(författare)
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Disruption of Platelet-derived Chemokine Heteromers Prevents Neutrophil Extravasation in Acute Lung Injury
- 2012
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1535-4970. ; 185:6, s. 628-636
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Acute lung injury (ALI) causes high mortality, but its molecular mechanisms and therapeutic options remain ill-defined. Gram-negative bacterial infections are the main cause of ALI, leading to lung neutrophil infiltration, permeability increases, deterioration of gas exchange, and lung damage. Platelets are activated during ALI, but insights into their mechanistic contribution to neutrophil accumulation in the lung are elusive. Objectives: To determine mechanisms of platelet-mediated neutrophil recruitment in ALI. Methods: Interference with platelet-neutrophil interactions using antagonists to P-selectin and glycoprotein IIb/IIIa or a small peptide antagonist disrupting platelet chemokine heteromer formation in mouse models of ALI. Measurements and Main Results: In a murine model of LPS-induced ALI, we uncover important roles for neutrophils and platelets in permeability changes and subsequent lung damage. Furthermore, platelet depletion abrogated lung neutrophil infiltration, suggesting a sequential participation of platelets and neutrophils. Whereas antagonists to P-selectin and glycoprotein IIb/IIIa had no effects on LPS-mediated ALI, antibodies to the platelet-derived chemokines CCL5 and CXCL4 strongly diminished neutrophil eflux and permeability changes. The two chemokines were found to form heteromers in human and murine ALI samples, positively correlating with leukocyte influx into the lung. Disruption of CCL5-CXCL4 heteromers in LPS-, acid-, and sepsis-induced ALI abolished lung edema, neutrophil infiltration, and tissue damage, thereby revealing a causal contribution. Conclusions: Taken together, our data identify a novel function of platelet-derived chemokine heteromers during ALI and demonstrate means for therapeutic interference.
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| 5. |
- Grommes, Jochen, et al.
(författare)
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Pioglitazone attenuates endotoxin-induced acute lung injury by reducing neutrophil recruitment
- 2012
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 40:2, s. 416-423
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Tidskriftsartikel (refereegranskat)abstract
- Treatment of acute lung injury (ALI) remains an unsolved problem in intensive care medicine. Activation and recruitment of neutrophils are regarded as key mechanisms in the progression of ALI. As pioglitazone holds potent pleiotropic anti-inflammatory effects, we explored its effects during ALI. C57Bl/6 mice were exposed to aerosolised lipopolysaccharides (LPSs) (500 mu g.mL(-1)) and their alveolar, interstitial and intravascular neutrophils were assessed 4 h later. Lung permeability changes were evaluated by fluorescein isothiocyanate-dextran clearance and protein content in the bronchoalveolar lavage fluid. In vitro, human isolated neutrophils were pretreated with piolitazone (10 mu M, for 1 or 3 h) and then activated with N-formyl-L-methionyl-L-leucyl-L-phenylalanine. Neutrophil activation, adhesion, release and formation of reactive oxygen species (ROS) and phagocytosis were measured thereafter. Pioglitazone treatment before or after induction of ALI significantly diminished alveolar (reduction by 73% and 67%, respectively) and interstitial neutrophil influx (reduction by 55% and 63%, respectively) and reduced lung permeability changes (reduction by 64% and 58%, respectively) indicating a protective role of pioglitazone treatment in ALI. Moreover, pioglitazone significantly reduced degranulation and adhesion of neutrophils without affecting ROS formation and release or bacterial phagocytosis. Pioglitazone reduces recruitment and activation of neutrophils thereby preventing LPS-induced ALI. Our results imply a potential role for pioglitazone treatment in the management of ALI.
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| 6. |
- Grommes, Jochen, et al.
(författare)
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Simvastatin Reduces Endotoxin-Induced Acute Lung Injury by Decreasing Neutrophil Recruitment and Radical Formation
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Treatment of acute lung injury (ALI) remains an unsolved problem in intensive care medicine. As simvastatin exerts protective effects in inflammatory diseases we explored its effects on development of ALI and due to the importance of neutrophils in ALI also on neutrophil effector functions. Methods: C57Bl/6 mice were exposed to aerosolized LPS (500 mg/ml) for 30 min. The count of alveolar, interstitial, and intravasal neutrophils were assessed 4 h later by flow cytometry. Lung permeability changes were assessed by FITC-dextran clearance and albumin content in the BAL fluid. In vitro, we analyzed the effect of simvastatin on neutrophil adhesion, degranulation, apoptosis, and formation of reactive oxygen species. To monitor effects of simvastatin on bacterial clearance we performed phagocytosis and bacterial killing studies in vitro as well as sepsis experiments in mice. Results: Simvastatin treatment before and after onset of ALI reduces neutrophil influx into the lung as well as lung permeability indicating the protective role of simvastatin in ALI. Moreover, simvastatin reduces the formation of ROS species and adhesion of neutrophils without affecting apoptosis, bacterial phagocytosis and bacterial clearance. Conclusion: Simvastatin reduces recruitment and activation of neutrophils hereby protecting from LPS-induced ALI. Our results imply a potential role for statins in the management of ALI.
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| 7. |
- Linder, Adam, et al.
(författare)
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Roles of Heparin-Binding Protein in Bacterial Infections.
- 2010
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Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 2, s. 431-438
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Tidskriftsartikel (refereegranskat)abstract
- Infectious diseases remain a major health problem, where sepsis and other severe infectious diseases are common causes of morbidity and mortality. The importance of early and appropriate treatment of sepsis and severe bacterial infections has been underlined by the successes of measures like the Surviving Sepsis Campaign, among others. Thus, there is a need for clinical and laboratory tools to identify a patient with severe infection early and to distinguish between bacterial and non-bacterial conditions. Heparin-binding protein (HBP) is also called azurocidin, or cationic antimicrobial protein of 37 kDa (CAP37). It is a multifunctional granule-associated protein that is rapidly mobilized from migrating polymorphonuclear leukocytes. HBP acts as a chemoattractant, an activator of monocytes and macrophages, and induces vascular leakage and edema formation. The release of HBP is triggered by ligation of neutrophilic beta(2)-integrins, a process that may be initiated by bacterial structures. The overall outcome is powerful vascular leakage. It has been shown that patients with severe sepsis express high levels of HBP in plasma before they develop hypotension. HBP is also involved in the pathophysiology of soft tissue infection. In conclusion, this protein is strongly involved in the pathophysiology of severe bacterial infections, and thus represents a potential diagnostic marker and a target for treatment.
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| 8. |
- Rohwedder, Ina, et al.
(författare)
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Plasma fibronectin deficiency impedes atherosclerosis progression and fibrous cap formation
- 2012
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 4:7, s. 564-576
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Tidskriftsartikel (refereegranskat)abstract
- Atherosclerotic lesions are asymmetric focal thickenings of the intima of arteries that consist of lipids, various cell types and extracellular matrix (ECM). These lesions lead to vascular occlusion representing the most common cause of death in the Western world. The main cause of vascular occlusion is rupture of atheromatous lesions followed by thrombus formation. Fibronectin (FN) is one of the earliest ECM proteins deposited at atherosclerosis-prone sites and was suggested to promote atherosclerotic lesion formation. Here, we report that atherosclerosis-prone apolipoprotein E-null mice lacking hepatocyte-derived plasma FN (pFN) fed with a pro-atherogenic diet display dramatically reduced FN depositions at atherosclerosis-prone areas, which results in significantly smaller and fewer atherosclerotic plaques. However, the atherosclerotic lesions from pFN-deficient mice lacked vascular smooth muscle cells and failed to develop a fibrous cap. Thus, our results demonstrate that while FN worsens the course of atherosclerosis by increasing the atherogenic plaque area, it promotes the formation of the protective fibrous cap, which in humans prevents plaques rupture and vascular occlusion. See accompanying article http://dx.doi.org/10.1002/emmm.201200238
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| 9. |
- Soehnlein, Oliver, et al.
(författare)
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Anesthesia Aggravates Lung Damage and Precipitates Hypotension in Endotoxemic Sheep
- 2010
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Ingår i: Shock. - 1540-0514. ; 34:4, s. 412-419
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Tidskriftsartikel (refereegranskat)abstract
- Beneficial anti-inflammatory properties have been ascribed to volatile anesthetics in septic conditions, but no studies have compared anesthesia to the conscious state in a large-animal model. The aim of this study was to investigate the effect of isoflurane anesthesia on cardiovascular and respiratory function, leukocyte activation, and lung damage in a model of endotoxemia in sheep. Conscious (n = 6) and anesthetized (n = 6) sheep were made endotoxemic by continuous infusion of LPS for 48 h. Central hemodynamics were monitored continuously, and blood samples were collected regularly. Activation of leukocytes was assessed by surface expression of CD11b and plasma myeloperoxidase concentration. Lung damage was determined by electron microscopy, cell count in bronchoalveolar lavage fluid, and analysis of lung vascular permeability. Four additional animals (two conscious and two anesthetized) went through the same protocol but did not receive LPS. LPS infusion induced a hyperdynamic sepsis. The drop in total peripheral resistance was compensated by an increase in heart rate and cardiac output in the conscious group, whereas anesthetized sheep failed to compensate in this way. Endotoxemic isoflurane-anesthetized sheep also showed signs of aggravated lung edema formation and tissue damage together with enhanced neutrophil activation and lung tissue accumulation. Our data suggest that isoflurane in conjunction with mechanical ventilation blunts cardiovascular compensatory mechanisms in sepsis and enhances leukocyte activation, which may contribute to lung edema formation and tissue damage.
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| 10. |
- Soehnlein, Oliver, et al.
(författare)
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Neutrophil primary granule proteins HBP and HNP1-3 boost bacterial phagocytosis by human and murine macrophages.
- 2008
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 118:10, s. 3491-3502
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Tidskriftsartikel (refereegranskat)abstract
- In acute inflammation, infiltrating polymorphonuclear leukocytes (also known as PMNs) release preformed granule proteins having multitudinous effects on the surrounding environment. Here we present what we believe to be a novel role for PMN-derived proteins in bacterial phagocytosis by both human and murine macrophages. Exposure of macrophages to PMN secretion markedly enhanced phagocytosis of IgG-opsonized Staphylococcus aureus both in vitro and in murine models in vivo. PMN secretion activated macrophages, resulting in upregulation of the Fcgamma receptors CD32 and CD64, which then mediated the enhanced phagocytosis of IgG-opsonized bacteria. The phagocytosis-stimulating activity within the PMN secretion was found to be due to proteins released from PMN primary granules; thorough investigation revealed heparin-binding protein (HBP) and human neutrophil peptides 1-3 (HNP1-3) as the mediators of the macrophage response to PMN secretion. The use of blocking antibodies and knockout mice revealed that HBP acts via beta(2) integrins, but the receptor for HNP1-3 remained unclear. Mechanistically, HBP and HNP1-3 triggered macrophage release of TNF-alpha and IFN-gamma, which acted in an autocrine loop to enhance expression of CD32 and CD64 and thereby enhance phagocytosis. Thus, we attribute what may be a novel role for PMN granule proteins in regulating the immune response to bacterial infections.
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