66 results on '"Michaëlsson E"'
Search Results
2. Receptor for α1-Microglobulin on T Lymphocytes: Inhibition of Antigen-Induced Interleukin-2 Production
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WESTER, L., MICHAËLSSON, E., HOLMDAHL, R., OLOFSSON, T., and ÅKERSTRÖM, B.
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- 1998
3. Pharmacological inhibition of myeloperoxidase attenuates nonalcoholic steatohepatitis-induced liver fibrosis in mice
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Koop, A., primary, Thiele, N., additional, Steins, D., additional, Diedrich, T., additional, Michaëlsson, E., additional, Wiesch, J.S.Z., additional, Lohse, A.W., additional, Heeren, J., additional, and Kluwe, J., additional
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- 2018
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4. THU-513 - Pharmacological inhibition of myeloperoxidase attenuates nonalcoholic steatohepatitis-induced liver fibrosis in mice
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Koop, A., Thiele, N., Steins, D., Diedrich, T., Michaëlsson, E., Wiesch, J.S.Z., Lohse, A.W., Heeren, J., and Kluwe, J.
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- 2018
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5. Macrophages, but not dendritic cells, present collagen to T cells
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Michaëlsson, E., Holmdahl, Martin H:son, Engström, Åke, Burkhardt, H., Scheynius, A., Holmdahl, R., Michaëlsson, E., Holmdahl, Martin H:son, Engström, Åke, Burkhardt, H., Scheynius, A., and Holmdahl, R.
- Abstract
Dendritic cells, such as epidermal Langerhans cells, play a crucial role for the antigen-specific priming of T cells. We have addressed the question whether dendritic cells present collagen, a major protein component in tissues through which dendritic cells migrate, i.e. the basement membrane, dermis, and synovial tissue. Langerhans cells, spleen cells and peritoneal macrophages were compared for antigen-presenting capacity using a panel of mouse T cell hybridomas reactive with different determinants on type II collagen, myelin basic protein, ovalbumin and pepsin. Langerhans cells did not present any of the type II collagen determinants, unless the antigen was administered as a 15-mer peptide, but did present myelin basic protein, ovalbumin and pepsin. Spleen cells and peritoneal macrophages, in contrast, presented all type II collagen determinants. This biased antigen presentation was also observed when Langerhans cells were pulsed with antigen in vivo. The inability to present type II collagen is related to the collagen sequence as such, since both native type II collagen, type II collagen alpha chains, as well as a type II collagen determinant incorporated in type I collagen, were not presented by Langerhans cells. In addition, granulocyte/macrophage colony-stimulating factor-expanded blood dendritic cells displayed the same biased antigen presentation, suggesting that the inability to present collagen is not restricted to dendritic cells localized in epidermis. B cell-deficient mice could prime a type II collagen-reactive T cell response, thus excluding B cells as obligatory antigen-presenting cells for the priming of collagen-reactive T cells. We suggest that neither Langerhans cells nor B cells, but macrophages are the primary antigen-presenting cells in the immune response towards type II collagen.
- Published
- 1995
6. Systemic versus cartilage-specific expression of a type II collagen-specific T-cell epitope determines the level of tolerance and susceptibility to arthritis.
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Malmström, V, primary, Michaëlsson, E, additional, Burkhardt, H, additional, Mattsson, R, additional, Vuorio, E, additional, and Holmdahl, R, additional
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- 1996
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7. T cell recognition of carbohydrates on type II collagen.
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Michaëlsson, E, primary, Malmström, V, additional, Reis, S, additional, Engström, A, additional, Burkhardt, H, additional, and Holmdahl, R, additional
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- 1994
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8. CTLA-4 ligation suppresses CD28-induced NF-kappaB and AP-1 activity in mouse T cell blasts.
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Olsson, C, Riesbeck, K, Dohlsten, M, Michaëlsson, E, and Riebeck, K
- Abstract
The effects of cytotoxic lymphocyte antigen 4 (CTLA-4) on CD3/CD28 monoclonal antibody (mAb) activation of CD4(+)/CTLA-4(+) blastoid T cells were studied in an in vitro model system. As previously reported, coligation of CTLA-4 mAb results in suppression of T cell proliferation and cytokine production. The proliferation but not the interleukin 2 (IL-2) production could be restored by addition of exogenous IL-2, suggesting that the inhibitory effect occurred at the level of IL-2 production rather than at the regulation of the IL-2 receptor pathway. To study the effects on nuclear factors critical for T cell activation, we analyzed the levels of the transcription factors NF-kappaB and AP-1. These were potently induced in CD3/CD28 mAb-restimulated T cells. In contrast, CTLA-4 ligation strongly suppressed the induction of both transcription factors. The compositions of NF-kappaB and AP-1 family members were similar, irrespective of stimulation conditions. Analyses of the NF-kappaB regulator IkappaB-alpha revealed similar levels of IkappaB-alpha protein in the preparations. However, a reduced phosphorylation of IkappaB-alpha in CTLA-4 coengaged T cell blasts compared with T cells ligated with CD3/CD28 was found. Previous studies have concluded that CTLA-4 ligation regulates T cell activation by inhibiting the T cell receptor-mediated signals. However, the present findings propose that the major impact of CTLA-4 ligation is inhibition of signals mediated by CD28.
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- 1999
9. Biased dependency of CD80 versus CD86 in the induction of transcription factors regulating the human IL-2 promoter.
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Olsson, C, Michaëlsson, E, Parra, E, Pettersson, U, Lando, P A, and Dohlsten, M
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In addition to the signals obtained by ligation of the TCR, T cells need additional, co-stimulatory signals to be activated. One such co-stimulatory signal is delivered when CD28 on T cells binds to CD80 or CD86 on antigen-presenting cells (APC). In the present study, we analyzed the ability of CD80 and CD86 to co-stimulate human T cells activated by superantigen. Using the Raji B cell lymphoma, which express similar levels of CD80 and CD86, it was found that T cell proliferation was mainly co-stimulated by CD80. To further characterize the consequences of this biased co-stimulatory dependency, we employed a well-defined system of transfected CHO cells expressing human MHC class II together with CD80, CD86 or CD80 and CD86. Proliferation of freshly prepared CD4+ T cells required the presence of either CD80 or CD86. However, IL-2 production reached only suboptimal levels in the presence of CD86 but optimal levels with CD80. To analyze IL-2 transcriptional activity in CD80 and CD86 co-stimulated T cells we used Jurkat T cells transfected with luciferase reporter gene constructs. CD80 induced higher levels of IL-2 promoter-enhancer activity compared to CD86. Furthermore, the activity of transcription factors regulating the IL-2 promoter-enhancer region including activation protein-1, CD28 response element and nuclear factor kappaB were 4-8 times higher after CD80 compared to CD86 ligation. Our results suggest that the eventual appearance of CD80 on recently activated CD86+ APC is important for the superinduction of IL-2 production and to support vigorous T cell proliferation.
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- 1998
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10. Novel Mouse Model of Myocardial Infarction, Plaque Rupture, and Stroke Shows Improved Survival With Myeloperoxidase Inhibition.
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Shamsuzzaman S, Deaton RA, Salamon A, Doviak H, Serbulea V, Milosek VM, Evans MA, Karnewar S, Saibaba S, Alencar GF, Shankman LS, Walsh K, Bekiranov S, Kocher O, Krieger M, Kull B, Persson M, Michaëlsson E, Bergenhem N, Heydarkhan-Hagvall S, and Owens GK
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- Animals, Male, Mice, Diet, Western adverse effects, Disease Models, Animal, Enzyme Inhibitors therapeutic use, Enzyme Inhibitors pharmacology, Mice, Inbred C57BL, Mice, Knockout, Receptors, LDL genetics, Receptors, LDL deficiency, Rupture, Spontaneous, Scavenger Receptors, Class B genetics, Scavenger Receptors, Class B metabolism, Myocardial Infarction pathology, Myocardial Infarction drug therapy, Peroxidase metabolism, Plaque, Atherosclerotic drug therapy, Stroke drug therapy, Stroke prevention & control
- Abstract
Background: Thromboembolic events, including myocardial infarction (MI) or stroke, caused by the rupture or erosion of unstable atherosclerotic plaques are the leading cause of death worldwide. Although most mouse models of atherosclerosis develop lesions in the aorta and carotid arteries, they do not develop advanced coronary artery lesions. Moreover, they do not undergo spontaneous plaque rupture with MI and stroke or do so at such a low frequency that they are not viable experimental models to study late-stage thrombotic events or to identify novel therapeutic approaches for treating atherosclerotic disease. This has stymied the development of more effective therapeutic approaches for reducing these events beyond what has been achieved with aggressive lipid lowering. Here, we describe a diet-inducible mouse model that develops widespread advanced atherosclerosis in coronary, brachiocephalic, and carotid arteries with plaque rupture, MI, and stroke., Methods: We characterized a novel mouse model with a C-terminal mutation in the scavenger receptor class B, type 1 (SR-BI), combined with Ldlr knockout (designated SR-BI
∆CT/∆CT / Ldlr-/- ). Mice were fed Western diet (WD) for 26 weeks and analyzed for MI and stroke. Coronary, brachiocephalic, and carotid arteries were analyzed for atherosclerotic lesions and indices of plaque stability. To validate the utility of this model, SR-BI∆CT/∆CT / Ldlr-/- mice were treated with the drug candidate AZM198, which inhibits myeloperoxidase, an enzyme produced by activated neutrophils that predicts rupture of human atherosclerotic lesions., Results: SR-BI∆CT/∆CT / Ldlr-/- mice show high (>80%) mortality rates after 26 weeks of WD feeding because of major adverse cardiovascular events, including spontaneous plaque rupture with MI and stroke. Moreover, WD-fed SR-BI∆CT/∆CT / Ldlr-/- mice displayed elevated circulating high-sensitivity cardiac troponin I and increased neutrophil extracellular trap formation within lesions compared with control mice. Treatment of WD-fed SR-BI∆CT/∆CT / Ldlr-/- mice with AZM198 showed remarkable benefits, including >90% improvement in survival and >60% decrease in the incidence of plaque rupture, MI, and stroke, in conjunction with decreased circulating high-sensitivity cardiac troponin I and reduced neutrophil extracellular trap formation within lesions., Conclusions: WD-fed SR-BI∆CT/∆CT / Ldlr-/- mice more closely replicate late-stage clinical events of advanced human atherosclerotic disease than previous models and can be used to identify and test potential new therapeutic agents to prevent major adverse cardiac events.- Published
- 2024
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11. Rationale and design of ENDEAVOR: A sequential phase 2b-3 randomized clinical trial to evaluate the effect of myeloperoxidase inhibition on symptoms and exercise capacity in heart failure with preserved or mildly reduced ejection fraction.
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Lund LH, Lam CSP, Pizzato PE, Gabrielsen A, Michaëlsson E, Nelander K, Ericsson H, Holden J, Folkvaljon F, Mattsson A, Collén A, Aurell M, Whatling C, Baldus S, Drelich G, Goudev A, Merkely B, Bergh N, and Shah SJ
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- Humans, Stroke Volume physiology, Exercise Tolerance physiology, Peroxidase pharmacology, Peroxidase therapeutic use, Comorbidity, Heart Failure drug therapy, Heart Diseases
- Abstract
Aims: Mitiperstat (formerly AZD4831) is a novel selective myeloperoxidase inhibitor. Currently, no effective therapies target comorbidity-induced systemic inflammation, which may be a key mechanism underlying heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). Circulating neutrophils secrete myeloperoxidase, causing oxidative stress, microvascular endothelial dysfunction, interstitial fibrosis, cardiomyocyte remodelling and diastolic dysfunction. Mitiperstat may therefore improve function of the heart and other organs, and ameliorate heart failure symptoms and exercise intolerance. ENDEAVOR is a combined, seamless phase 2b-3 study of the efficacy and safety of mitiperstat in patients with HFpEF/HFmrEF., Methods: In phase 2b, approximately 660 patients with heart failure and ejection fraction >40% are being randomized 1:1:1 to mitiperstat 2.5 mg, 5 mg or placebo for 48 weeks. Eligible patients have baseline 6-min walk distance (6MWD) of 30-400 m with a <50 m difference between screening and randomization and Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) ≤90 points at screening and randomization. The dual primary endpoints are change from baseline to week 16 in 6MWD and KCCQ-TSS. The sample size provides 85% power to detect placebo-adjusted improvements of 21 m in 6MWD and 6.0 points in KCCQ-TSS at overall two-sided alpha of 0.05. Safety is monitored throughout treatment, with a focus on maculopapular rash. In phase 3 of ENDEAVOR, approximately 820 patients will be randomized 1:1 to mitiperstat or placebo., Conclusion: ENDEAVOR is the first phase 2b-3 study to evaluate whether myeloperoxidase inhibition can improve symptoms and exercise capacity in patients with HFpEF/HFmrEF., (© 2023 AstraZeneca. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)
- Published
- 2023
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12. Myeloperoxidase Inhibition Reverses Biomarker Profiles Associated With Clinical Outcomes in HFpEF.
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Michaëlsson E, Lund LH, Hage C, Shah SJ, Voors AA, Saraste A, Redfors B, Grove EL, Barasa A, Richards AM, Svedlund S, Lagerström-Fermér M, Gabrielsen A, Garkaviy P, Gan LM, and Lam CSP
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- Humans, Antigens, Neoplasm therapeutic use, Biomarkers, Cell Adhesion Molecules therapeutic use, Peroxidase therapeutic use, Proteomics, Quality of Life, Stroke Volume physiology, Heart Failure
- Abstract
Background: Systemic microvascular dysfunction and inflammation are postulated to play a pathophysiologic role in heart failure with preserved ejection fraction (HFpEF)., Objectives: This study aimed to identify biomarker profiles associated with clinical outcomes in HFpEF and investigate how inhibition of the neutrophil-derived reactive oxygen species-producing enzyme, myeloperoxidase, affects these biomarkers., Methods: Using supervised principal component analyses, the investigators assessed the associations between baseline plasma proteomic Olink biomarkers and clinical outcomes in 3 independent observational HFpEF cohorts (n = 86, n = 216, and n = 242). These profiles were then compared with the biomarker profiles discriminating patients treated with active drug vs placebo in SATELLITE (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure), a double-blind randomized 3-month trial evaluating safety and tolerability of the myeloperoxidase inhibitor AZD4831 in HFpEF (n = 41). Pathophysiological pathways were inferred from the biomarker profiles by interrogation of the Ingenuity Knowledge Database., Results: TNF-R1, TRAIL-R2, GDF15, U-PAR, and ADM were the top individual biomarkers associated with heart failure hospitalization or death, and FABP4, HGF, RARRES2, CSTB, and FGF23 were associated with lower functional capacity and poorer quality of life. AZD4831 downregulated many markers (most significantly CDCP1, PRELP, CX3CL1, LIFR, VSIG2). There was remarkable consistency among pathways associated with clinical outcomes in the observational HFpEF cohorts, the top canonical pathways being associated with tumor microenvironments, wound healing signaling, and cardiac hypertrophy signaling. These pathways were predicted to be downregulated in AZD4831 relative to placebo-treated patients., Conclusions: Biomarker pathways that were most strongly associated with clinical outcomes were also the ones reduced by AZD4831. These results support the further investigation of myeloperoxidase inhibition in HFpEF., Competing Interests: Funding Support and Author Disclosures The KaRen study was supported by grants from the Fédération Française de Cardiologie/Société Française de Cardiologi and Medtronic Bakken Research Center. The PROMIS-HFpEF and SATELLITE studies were funded by AstraZeneca. Drs Michaëlsson, Gabrielsen, and Garkaviy are employees of and Dr Gan is a former employee of and hold shares in AstraZeneca, which is developing AZD4831 for the treatment of HFpEF. Dr Lund has received research grants from AstraZeneca, Novartis, Boehringer Ingelheim, Vifor-Fresenius, and Boston Scientific; has received consulting or speaker fees from AstraZeneca, Novartis, Boehringer Ingelheim, Vifor-Fresenius, Bayer, Sanofi, Merck, Myokardia, Orion Pharma, MedScape, Radcliffe Cardiology, Lexicon, and Respicardia, and has stock ownership in AnaCardio, outside the submitted work. Dr Hage has received consulting fees from Novartis, Roche Diagnostics, and AnaCardio; and has received speaker fees from Novartis and Merck Sharp & Dohme. Dr Shah has received research grant funding and consultant fees from AstraZeneca. The employer of Dr Voors (Univeristy of Groningen) received consultancy fees from Anacardio, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cytokinetics, Merck, Novartis, NovoNordisk, Eli Lilly, Moderna, Roche Diagnostics; and has received research support from NovoNordisk and Roche Diagnostics. Dr Saraste has received speaker or consulting fees from Abbot, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, and Pfizer. Dr Grove has received speaker or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Merck Sharp & Dohme, Lundbeck Pharma, and Organon; is an investigator in clinical studies sponsored by AstraZeneca or Bayer; and has received unrestricted research grants from Boehringer Ingelheim. Dr Richards has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Sphingotec, and Medtronic; has served as consultant to Roche Diagnostics and on the Advisory Board/ Steering Committee/Executive Committee for Roche Diagnostics, Critical Diagnostics, Pfizer, and Novartis. Dr Svedlund has received research grant funding from AstraZeneca. Dr Lam has received research support from NovoNordisk and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and is a co-founder and nonexecutive director of Us2.ai. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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13. Therapeutic inhibition of MPO stabilizes pre-existing high risk atherosclerotic plaque.
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Chen W, Tumanov S, Kong SMY, Cheng D, Michaëlsson E, Bongers A, Power C, Ayer A, and Stocker R
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- Animals, Mice, Disease Models, Animal, Atherosclerosis drug therapy, Cardiovascular Diseases prevention & control, Peroxidase antagonists & inhibitors, Plaque, Atherosclerotic drug therapy, Plaque, Atherosclerotic pathology
- Abstract
Currently there are no established therapies to treat high-risk patients with unstable atherosclerotic lesions that are prone to rupture and can result in thrombosis, abrupt arterial occlusion, and a precipitous infarction. Rather than being stenotic, rupture-prone non-occlusive plaques are commonly enriched with inflammatory cells and have a thin fibrous cap. We reported previously that inhibition of the pro-inflammatory enzyme myeloperoxidase (MPO) with the suicide inhibitor AZM198 prevents formation of unstable plaque in the Tandem Stenosis (TS) mouse model of plaque instability. However, in our previous study AZM198 was administered to animals before unstable plaque was present and hence it did not test the significant unmet clinical need present in high-risk patients with vulnerable atherosclerosis. In the present study we therefore asked whether pharmacological inhibition of MPO with AZM198 can stabilize pre-existing unstable lesions in an interventional setting using the mouse model of plaque instability. In vivo molecular magnetic resonance imaging of arterial MPO activity using bis-5-hydroxytryptamide-DTPA-Gd and histological analyses revealed that arterial MPO activity was elevated one week after TS surgery, prior to the presence of unstable lesions observed two weeks after TS surgery. Animals with pre-existing unstable plaque were treated with AZM198 for one or five weeks. Both short- and long-term intervention effectively inhibited arterial MPO activity and increased fibrous cap thickness, indicative of a more stable plaque phenotype. Plaque stabilization was observed without AZM198 affecting the arterial content of Ly6B.2
+ - and CD68+ -cells and MPO protein. These findings demonstrate that inhibition of arterial MPO activity converts unstable into stable atherosclerotic lesions in a preclinical model of plaque instability and highlight the potential therapeutic potency of MPO inhibition for the management of high-risk patients and the development of novel protective strategies against cardiovascular diseases., Competing Interests: Declaration of competing interest ED is an AstraZeneca employee and holds shares in AstraZeneca, which is developing the myeloperoxidase inhibitor AZD4831 for the treatment of HFpEF. RS has received in-kind support from AstraZeneca. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2022
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14. Association of epicardial adipose tissue with proteomics, coronary flow reserve, cardiac structure and function, and quality of life in heart failure with preserved ejection fraction: insights from the PROMIS-HFpEF study.
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Venkateshvaran A, Faxen UL, Hage C, Michaëlsson E, Svedlund S, Saraste A, Beussink-Nelson L, Fermer ML, Gan LM, Tromp J, Lam CSP, Shah SJ, and Lund LH
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- Humans, Stroke Volume physiology, Quality of Life, Ventricular Function, Left physiology, Prospective Studies, Proteomics, Adipose Tissue diagnostic imaging, Inflammation pathology, Heart Failure
- Abstract
Aim: Epicardial adipose tissue (EAT) may play a role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). We investigated associations of EAT with proteomics, coronary flow reserve (CFR), cardiac structure and function, and quality of life (QoL) in the prospective multinational PROMIS-HFpEF cohort., Methods and Results: Epicardial adipose tissue was measured by echocardiography in 182 patients and defined as increased if ≥9 mm. Proteins were measured using high-throughput proximity extension assays. Microvascular dysfunction was evaluated with Doppler-based CFR, cardiac structural and functional indices with echocardiography and QoL by Kansas City Cardiomyopathy Questionnaire (KCCQ). Patients with increased EAT (n = 54; 30%) had higher body mass index (32 [28-40] vs. 27 [23-30] kg/m
2 ; p < 0.001), lower N-terminal pro-B-type natriuretic peptide (466 [193-1133] vs. 1120 [494-1990] pg/ml; p < 0.001), smaller indexed left ventricular (LV) end-diastolic and left atrial (LA) volumes and tendency to lower KCCQ score. Non-indexed LV/LA volumes did not differ between groups. When adjusted for body mass index, EAT remained associated with LV septal wall thickness (coefficient 1.02, 95% confidence interval [CI] 1.00-1.04; p = 0.018) and mitral E wave deceleration time (coefficient 1.03, 95% CI 1.01-1.05; p = 0.005). Increased EAT was associated with proteomic markers of adipose biology and inflammation, insulin resistance, endothelial dysfunction, and dyslipidaemia but not significantly with CFR., Conclusion: Increased EAT was associated with cardiac structural alterations and proteins expressing adiposity, inflammation, lower insulin sensitivity and endothelial dysfunction related to HFpEF pathology, probably driven by general obesity. Potential local mechanical or paracrine effects mediated by EAT remain to be elucidated., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)- Published
- 2022
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15. Correction to "Discovery of AZD4831, a Mechanism-Based Irreversible Inhibitor of Myeloperoxidase, As a Potential Treatment for Heart Failure with Preserved Ejection Fraction".
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Inghardt T, Antonsson T, Ericsson C, Hovdal D, Johannesson P, Johansson C, Jurva U, Kajanus J, Kull B, Michaëlsson E, Pettersen A, Sjögren T, Sörensen H, Westerlund K, and Lindstedt EL
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- 2022
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16. Discovery of AZD4831, a Mechanism-Based Irreversible Inhibitor of Myeloperoxidase, As a Potential Treatment for Heart Failure with Preserved Ejection Fraction.
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Inghardt T, Antonsson T, Ericsson C, Hovdal D, Johannesson P, Johansson C, Jurva U, Kajanus J, Kull B, Michaëlsson E, Pettersen A, Sjögren T, Sörensen H, Westerlund K, and Lindstedt EL
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- Animals, Humans, Iodide Peroxidase therapeutic use, Peroxidase, Pyrimidines, Pyrroles, Stroke Volume physiology, Heart Failure drug therapy
- Abstract
Myeloperoxidase is a promising therapeutic target for treatment of patients suffering from heart failure with preserved ejection fraction (HFpEF). We aimed to discover a covalent myeloperoxidase inhibitor with high selectivity for myeloperoxidase over thyroid peroxidase, limited penetration of the blood-brain barrier, and pharmacokinetics suitable for once-daily oral administration at low dose. Structure-activity relationship, biophysical, and structural studies led to prioritization of four compounds for in-depth safety and pharmacokinetic studies in animal models. One compound (AZD4831) progressed to clinical studies on grounds of high potency (IC
50 , 1.5 nM in vitro ) and selectivity (>450-fold vs thyroid peroxidase in vitro ), the mechanism of irreversible inhibition, and the safety profile. Following phase 1 studies in healthy volunteers and a phase 2a study in patients with HFpEF, a phase 2 b /3 efficacy study of AZD4831 in patients with HFpEF started in 2021.- Published
- 2022
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17. Inhibiting cardiac myeloperoxidase alleviates the relaxation defect in hypertrophic cardiomyocytes.
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Ramachandra CJA, Kp MMJ, Chua J, Hernandez-Resendiz S, Liehn EA, Knöll R, Gan LM, Michaëlsson E, Jonsson MKB, Ryden-Markinhuhta K, Bhat RV, Fritsche-Danielson R, Lin YH, Sadayappan S, Tang HC, Wong P, Shim W, and Hausenloy DJ
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- Animals, Cardiac Myosins genetics, Cardiac Myosins metabolism, Cardiomyopathy, Hypertrophic enzymology, Cardiomyopathy, Hypertrophic genetics, Cardiomyopathy, Hypertrophic physiopathology, Carrier Proteins genetics, Carrier Proteins metabolism, Cell Line, Disease Models, Animal, Humans, Hypertrophy, Left Ventricular enzymology, Hypertrophy, Left Ventricular genetics, Hypertrophy, Left Ventricular physiopathology, Induced Pluripotent Stem Cells enzymology, Induced Pluripotent Stem Cells pathology, Male, Mice, Inbred C57BL, Mutation, Missense, Myocytes, Cardiac enzymology, Myocytes, Cardiac pathology, Myosin Heavy Chains genetics, Myosin Heavy Chains metabolism, Peroxidase metabolism, Phosphorylation, Reactive Oxygen Species metabolism, Tyrosine analogs & derivatives, Tyrosine metabolism, Mice, Cardiomyopathy, Hypertrophic drug therapy, Enzyme Inhibitors pharmacology, Hypertrophy, Left Ventricular drug therapy, Induced Pluripotent Stem Cells drug effects, Myocardial Contraction drug effects, Myocytes, Cardiac drug effects, Peroxidase antagonists & inhibitors, Ventricular Function, Left drug effects
- Abstract
Aims: Hypertrophic cardiomyopathy (HCM) is characterized by cardiomyocyte hypertrophy and disarray, and myocardial stiffness due to interstitial fibrosis, which result in impaired left ventricular filling and diastolic dysfunction. The latter manifests as exercise intolerance, angina, and dyspnoea. There is currently no specific treatment for improving diastolic function in HCM. Here, we investigated whether myeloperoxidase (MPO) is expressed in cardiomyocytes and provides a novel therapeutic target for alleviating diastolic dysfunction in HCM., Methods and Results: Human cardiomyocytes derived from control-induced pluripotent stem cells (iPSC-CMs) were shown to express MPO, with MPO levels being increased in iPSC-CMs generated from two HCM patients harbouring sarcomeric mutations in the MYBPC3 and MYH7 genes. The presence of cardiomyocyte MPO was associated with higher chlorination and peroxidation activity, increased levels of 3-chlorotyrosine-modified cardiac myosin binding protein-C (MYBPC3), attenuated phosphorylation of MYBPC3 at Ser-282, perturbed calcium signalling, and impaired cardiomyocyte relaxation. Interestingly, treatment with the MPO inhibitor, AZD5904, reduced 3-chlorotyrosine-modified MYBPC3 levels, restored MYBPC3 phosphorylation, and alleviated the calcium signalling and relaxation defects. Finally, we found that MPO protein was expressed in healthy adult murine and human cardiomyocytes, and MPO levels were increased in diseased hearts with left ventricular hypertrophy., Conclusion: This study demonstrates that MPO inhibition alleviates the relaxation defect in hypertrophic iPSC-CMs through MYBPC3 phosphorylation. These findings highlight cardiomyocyte MPO as a novel therapeutic target for improving myocardial relaxation associated with HCM, a treatment strategy which can be readily investigated in the clinical setting, given that MPO inhibitors are already available for clinical testing., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2022
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18. Early Clinical Experience With AZD4831, A Novel Myeloperoxidase Inhibitor, Developed for Patients With Heart Failure With Preserved Ejection Fraction.
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Nelander K, Lagerstrom-Fermer M, Amilon C, Michaëlsson E, Heijer M, Kjaer M, Russell M, Han D, Lindstedt EL, Whatling C, Gan LM, and Ericsson H
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- Administration, Oral, Adult, Dose-Response Relationship, Drug, Double-Blind Method, Healthy Volunteers, Humans, Male, Middle Aged, Pyrimidines administration & dosage, Pyrimidines pharmacokinetics, Pyrroles administration & dosage, Pyrroles pharmacokinetics, Single-Blind Method, Stroke Volume, Ventricular Function, Left, Young Adult, Heart Failure drug therapy, Peroxidase antagonists & inhibitors, Pyrimidines adverse effects, Pyrroles adverse effects
- Abstract
We evaluated safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics of AZD4831, a novel oral myeloperoxidase (MPO) inhibitor, in a randomized, single-blind, placebo-controlled study, following once-daily multiple ascending dosing to steady-state in healthy subjects. Target engagement was measured as specific MPO activity in plasma following ex vivo zymosan stimulation of whole blood. Except for generalized maculopapular rash in 4 of 13 subjects receiving the 2 highest doses, 15 and 45 mg AZD4831, no clinically relevant safety and tolerability findings were observed. AZD4831 was rapidly absorbed and plasma concentrations declined slowly with an elimination half-life of ~ 60 hours. A dose/concentration-effect relationship between MPO inhibition vs. AZD4831 exposure was established with > 50% MPO inhibition in plasma at concentrations in the low nanomolar range. Steady-state levels were achieved within 10 days. Taken together, the PK profile, the sustained dose/concentration-dependent MPO inhibition, and available clinical data support further clinical development of AZD4831 in patients with heart failure with preserved ejection fraction., (© 2020 AstraZeneca. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2021
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19. Myeloperoxidase and related biomarkers are suggestive footprints of endothelial microvascular inflammation in HFpEF patients.
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Hage C, Michaëlsson E, Kull B, Miliotis T, Svedlund S, Linde C, Donal E, Daubert JC, Gan LM, and Lund LH
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- Aged, Biomarkers, Female, Humans, Inflammation, Male, Middle Aged, Stroke Volume, Heart Failure diagnosis, Peroxidase
- Abstract
Aims: In heart failure (HF) with preserved ejection fraction (HFpEF), microvascular inflammation is proposed as an underlying mechanism. Myeloperoxidase (MPO) is associated with vascular dysfunction and prognosis in congestive HF., Methods and Results: MPO, MPO-related biomarkers, and echocardiography were assessed in 86 patients, 4-8 weeks after presentation with acute HF (EF ≥ 45%), and in 46 healthy controls. Patients were followed up for median 579 days (Q1;Q3 276;1178) regarding the composite endpoint all-cause mortality or HF hospitalization. Patients were 73 years old, 51% were female, EF was 64% (Q1;Q3 58;68), E/e' was ratio 10.8 (8.3;14.0), and left atrial volume index (LAVI) was 43 mL/m
2 (38;52). Controls were 60 (57;62) years old (vs. patients; P < 0.001), 24% were female (P = 0.005), and left ventricular EF was 63% (59;66; P = 0.790). MPO was increased in HFpEF compared with controls, 101 (81;132) vs. 86 (74;101 ng/mL, P = 0.015), as was uric acid 369 (314;439) vs. 289 (252;328 μmol/L, P < 0.001), calprotectin, asymmetric dimethyl arginine (ADMA), and symmetric dimethyl arginine (SDMA), while arginine was decreased. MPO correlated with uric acid (r = 0.26; P = 0.016). In patients with E/e' > 14, uric acid and SDMA were elevated (421 vs. 344 μM, P = 0.012; 0.54 vs. 0.47 μM, P = 0.039, respectively), and MPO was 121 vs. 98 ng/mL (P = 0.090). The ratios of arginine/ADMA (112 vs. 162; P < 0.001) and ADMA/SDMA (1.36 vs. 1.17; P = 0.002) were decreased in HFpEF patients, suggesting reduced NO availability and increased enzymatic clearance of ADMA, respectively. Uric acid independently predicted the endpoint [hazard ratio (HR) 3.76 (95% CI 1.19-11.85; P = 0.024)] but not MPO [HR 1.48 (95% CI 0.70-3.14; P = 0.304)] or the other biomarkers., Conclusions: In HFpEF, MPO-dependent oxidative stress reflected by uric acid and calprotectin is increased, and SDMA is associated with diastolic dysfunction and uric acid with outcome. This suggests microvascular neutrophil involvement mirroring endothelial dysfunction, a central component of the HFpEF syndrome and a potential treatment target., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)- Published
- 2020
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20. Therapeutic Targeting of Myeloperoxidase Attenuates NASH in Mice.
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Koop AC, Thiele ND, Steins D, Michaëlsson E, Wehmeyer M, Scheja L, Steglich B, Huber S, Schulze Zur Wiesch J, Lohse AW, Heeren J, and Kluwe J
- Abstract
Myeloperoxidase (MPO) activity has been associated with the metabolic syndrome, cardiovascular and liver disease. Here, we evaluate the therapeutic potential of MPO inhibition on nonalcoholic steatohepatitis (NASH) and NASH-induced fibrosis, the main determinant of outcomes. MPO plasma levels were elevated in patients with nonalcoholic fatty liver disease (NAFLD) compared with healthy controls. In a second cohort, hepatic MPO messenger RNA expression correlated with higher body mass index and hemoglobin A1c, both being risk factors for NAFLD. We could establish by immunohistochemistry that MPO-positive cells were recruited to the liver in various mouse models of fibrogenic liver injury, including bile duct ligation, carbon tetrachloride (CCl
4 ) treatment, spontaneous liver fibrogenesis in multidrug resistance 2 knockout (MDR2 KO) mice, and NASH-inducing diet. Comparison of MPO-deficient mice and their wild-type littermates exposed to a high-caloric diet revealed that MPO deficiency protects against NASH-related liver injury and fibrosis. In line with this, hepatic gene expression analysis demonstrated a MPO-dependent activation of pathways relevant for wound healing, inflammation, and cell death in NASH. MPO deficiency did not affect NAFLD-independent liver injury and fibrosis in MDR2 KO or CCl4 -treated mice. Finally, we treated wild-type mice exposed to NASH-inducing diet with an oral MPO inhibitor. Pharmacological MPO inhibition not only reduced markers of MPO-mediated liver damage, serum alanine aminotransferase levels, and hepatic steatosis, but also significantly decreased NASH-induced liver fibrosis. MPO inhibitor treatment, but not MPO deficiency, significantly altered gut microbiota including a significant expansion of Akkermansia muciniphila . Conclusions: MPO specifically promotes NASH-induced liver fibrosis. Pharmacological MPO inhibition attenuates NASH progression and NASH-induced liver fibrosis in mice and is associated with beneficial changes of intestinal microbiota., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)- Published
- 2020
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21. Myeloperoxidase inhibition decreases morbidity and oxidative stress in mice with cystic fibrosis-like lung inflammation.
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Dickerhof N, Huang J, Min E, Michaëlsson E, Lindstedt EL, Pearson JF, Kettle AJ, and Day BJ
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- Animals, Bronchoalveolar Lavage Fluid, Burkholderia, Inflammation, Lung metabolism, Mice, Morbidity, Oxidative Stress, Peroxidase metabolism, Cystic Fibrosis drug therapy, Pneumonia drug therapy
- Abstract
Background: Cystic fibrosis (CF) lung disease is characterized by severe bacterial infections, excessive neutrophilic inflammation and oxidative stress. The neutrophil enzyme myeloperoxidase (MPO), which produces hypochlorous acid, is associated with worse disease outcomes. Therefore, pharmacological inhibition of MPO in the airways has therapeutic potential. We investigated whether treating mice with an MPO inhibitor during pulmonary infection decreases oxidative stress and improves infection outcomes in mice with CF-like lung inflammation without impacting on bacterial clearance., Methods: Transgenic β-epithelial sodium channel (βENaC)-overexpressing mice (n = 10) were infected with Burkholderia multivorans and treated twice daily with the MPO inhibitor AZM198 (125 μmol/kg) or vehicle administered by oral gavage for two days. Bodyweight was recorded daily. MPO activity, markers of oxidative stress, inflammatory cytokines and leukocytes numbers were measured in bronchoalveolar lavage fluid (BALF). Bacterial burden was determined in lung tissue homogenates., Results: During the course of infection, mice treated with AZM198 lost less weight than vehicle-treated mice (p < 0.01). MPO activity and glutathione sulfonamide, a hypochlorous acid-specific glutathione oxidation product, were significantly lower in BALF from AZM198-treated mice (p < 0.05). The inflammatory cytokines CXCL1 and TNF-α in BALF and bacterial burden in the lung were not significantly different between treated and control mice., Conclusions: Orally administered AZM198 inhibits MPO activity in epithelial lining fluid. Blocking hypochlorous acid production in epithelial lining fluid during pulmonary infections through inhibition of MPO improves morbidity in mice with CF-like lung inflammation without interfering with clearance of bacteria. Pharmacological inhibition of MPO is an approach to limit destructive oxidative stress in cystic fibrosis lung disease in humans., Competing Interests: Declaration of competing interest EM and EL are AstraZeneca employees, own AZ shares and a patent for an MPO inhibitor. AZ has an MPO inhibitor program in clinical development. AJK has a patent for novel MPO inhibitors pending. Other authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2020
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22. RNA sequencing data describing transcriptional changes in aorta of ApoE-/- mice after alpha 7 nicotinic acetylcholine receptor (α7nAChR) stimulation.
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Ulleryd MA, Mjörnstedt F, Panagaki D, Yang LJ, Engevall K, Gutierrez S, Wang Y, Gan LM, Nilsson H, Michaëlsson E, and Johansson ME
- Abstract
This manuscript is a companion paper to Ulleryd M.U. et al., "Stimulation of alpha 7 nicotinic acetylcholine receptor (α7nAChR) inhibits atherosclerosis via immunomodulatory effects on myeloid cells" Atherosclerosis, 2019 [1]. Data shown here include RNA sequencing data from whole aorta of ApoE-/- mice fed high fat diet and treated with the alpha 7 nicotinic acetylcholine receptor (α7nAChR) agonist AZ6983 for 8 weeks using subcutaneously implanted osmotic minipumps. Here we present the top gene networks affected by treatment with AZ6983, as well as the up- and down-regulated genes in aorta after treatment. Further, a URL link to the RNA sequencing datasets submitted to GEO is included., (© 2020 The Authors.)
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- 2020
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23. Therapeutic Myeloperoxidase Inhibition Attenuates Neutrophil Activation, ANCA-Mediated Endothelial Damage, and Crescentic GN.
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Antonelou M, Michaëlsson E, Evans RDR, Wang CJ, Henderson SR, Walker LSK, Unwin RJ, and Salama AD
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- Adaptive Immunity drug effects, Animals, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis drug therapy, Cell Degranulation drug effects, Extracellular Traps drug effects, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Peroxidase blood, Peroxidase metabolism, Antibodies, Antineutrophil Cytoplasmic immunology, Endothelial Cells pathology, Glomerulonephritis drug therapy, Neutrophil Activation drug effects, Peroxidase antagonists & inhibitors
- Abstract
Background: Myeloperoxidase released after neutrophil and monocyte activation can generate reactive oxygen species, leading to host tissue damage. Extracellular glomerular myeloperoxidase deposition, seen in ANCA-associated vasculitis, may enhance crescentic GN through antigen-specific T and B cell activation. Myeloperoxidase-deficient animals have attenuated GN early on, but augmented T cell responses. We investigated the effect of myeloperoxidase inhibition, using the myeloperoxidase inhibitor AZM198, to understand its potential role in treating crescentic GN., Methods: We evaluated renal biopsy samples from patients with various forms of crescentic GN for myeloperoxidase and neutrophils, measured serum myeloperoxidase concentration in patients with ANCA-associated vasculitis and controls, and assessed neutrophil extracellular trap formation, reactive oxygen species production, and neutrophil degranulation in ANCA-stimulated neutrophils in the absence and presence of AZM198. We also tested the effect of AZM198 on ANCA-stimulated neutrophil-mediated endothelial cell damage in vitro , as well as on crescentic GN severity and antigen-specific T cell reactivity in the murine model of nephrotoxic nephritis., Results: All biopsy specimens with crescentic GN had extracellular glomerular myeloperoxidase deposition that correlated significantly with eGFR and crescent formation. In vitro , AZM198 led to a significant reduction in neutrophil extracellular trap formation, reactive oxygen species production, and released human neutrophil peptide levels, and attenuated neutrophil-mediated endothelial cell damage. In vivo , delayed AZM198 treatment significantly reduced proteinuria, glomerular thrombosis, serum creatinine, and glomerular macrophage infiltration, without increasing adaptive T cell responses., Conclusions: Myeloperoxidase inhibition reduced neutrophil degranulation and neutrophil-mediated endothelial cell damage in patients with ANCA-associated vasculitis. In preclinical crescentic GN, delayed myeloperoxidase inhibition suppressed kidney damage without augmenting adaptive immune responses, suggesting it might offer a novel adjunctive therapeutic approach in crescentic GN., (Copyright © 2020 by the American Society of Nephrology.)
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- 2020
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24. Pharmacological myeloperoxidase (MPO) inhibition in an obese/hypertensive mouse model attenuates obesity and liver damage, but not cardiac remodeling.
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Piek A, Koonen DPY, Schouten EM, Lindtstedt EL, Michaëlsson E, de Boer RA, and Silljé HHW
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- Angiotensin II administration & dosage, Angiotensin II toxicity, Animals, Diet, High-Fat adverse effects, Disease Models, Animal, Heart Ventricles drug effects, Heart Ventricles immunology, Heart Ventricles pathology, Humans, Hypertension blood, Hypertension diagnosis, Hypertension etiology, Hypertrophy, Left Ventricular blood, Hypertrophy, Left Ventricular diagnosis, Hypertrophy, Left Ventricular etiology, Intra-Abdominal Fat drug effects, Intra-Abdominal Fat immunology, Liver drug effects, Liver immunology, Liver pathology, Male, Mice, Non-alcoholic Fatty Liver Disease blood, Non-alcoholic Fatty Liver Disease diagnosis, Non-alcoholic Fatty Liver Disease etiology, Obesity blood, Obesity diagnosis, Obesity etiology, Peroxidase blood, Peroxidase metabolism, Severity of Illness Index, Ventricular Remodeling drug effects, Ventricular Remodeling immunology, Hypertension drug therapy, Hypertrophy, Left Ventricular drug therapy, Non-alcoholic Fatty Liver Disease drug therapy, Obesity drug therapy, Peroxidase antagonists & inhibitors, Thioxanthenes administration & dosage
- Abstract
Lifestyle factors are important drivers of chronic diseases, including cardiovascular syndromes, with low grade inflammation as a central player. Attenuating myeloperoxidase (MPO) activity, an inflammatory enzyme associated with obesity, hypertension and heart failure, could have protective effects on multiple organs. Herein, the effects of the novel oral available MPO inhibitor AZM198 were studied in an obese/hypertensive mouse model which displays a cardiac phenotype. Eight week old male C57BL6/J mice received 16 weeks of high fat diet (HFD) combined with angiotensin II (AngII) infusion during the last 4 weeks, with low fat diet and saline infusion as control. Treated animals showed therapeutic AZM198 levels (2.1 µM), corresponding to 95% MPO inhibition. AZM198 reduced elevated circulating MPO levels in HFD/AngII mice to normal values. Independent of food intake, bodyweight increase and fat accumulation were attenuated by AZM198, alongside with reduced visceral adipose tissue (VAT) inflammation and attenuated severity of nonalcoholic steatohepatitis. The HFD/AngII perturbation caused impaired cardiac relaxation and contraction, and increased cardiac hypertrophy and fibrosis. AZM198 treatment did, however, not improve these cardiac parameters. Thus, AZM198 had positive effects on the main lipid controlling tissues in the body, namely adipose tissue and liver. This did, however, not directly result in improved cardiac function.
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- 2019
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25. Inhibiting myeloperoxidase prevents onset and reverses established high-fat diet-induced microvascular insulin resistance.
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Chai W, Aylor K, Liu Z, Gan LM, Michaëlsson E, and Barrett E
- Subjects
- Animals, Aorta metabolism, Blood Flow Velocity drug effects, Diet, High-Fat, Glucose Clamp Technique, Male, Microcirculation drug effects, Microvessels metabolism, Mitogen-Activated Protein Kinase 1 drug effects, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 drug effects, Mitogen-Activated Protein Kinase 3 metabolism, Muscle, Skeletal blood supply, Muscle, Skeletal metabolism, Nitric Oxide Synthase Type III drug effects, Nitric Oxide Synthase Type III metabolism, Rats, Rats, Sprague-Dawley, Aorta drug effects, Enzyme Inhibitors pharmacology, Insulin Resistance, Microvessels drug effects, Muscle, Skeletal drug effects, Peroxidase antagonists & inhibitors
- Abstract
A high-fat diet (HFD) can rapidly recruit neutrophils to insulin target tissues and within days induce microvascular insulin resistance (IR). Myeloperoxidase (MPO) is highly enriched in neutrophils, can inhibit nitric oxide-mediated vasorelaxation in vitro and is associated with increased cardiovascular disease risk. AZD5904 irreversibly inhibits MPO and in human clinical trials. MPO knockout, or chemical inhibition, blunts HFD-induced metabolic IR in mice. Whether MPO affects microvascular IR or muscle metabolic insulin sensitivity in vivo is unknown. We used contrast-enhanced ultrasound and the euglycemic insulin clamp to test whether inhibiting MPO could prevent the development or reverse established HFD-induced metabolic and/or microvascular IR in Sprague-Dawley rats. Two weeks of HFD feeding blocked insulin-mediated skeletal muscle capillary recruitment, inhibited glucose utilization, and insulin signaling to muscle. Continuous subcutaneous AZD5904 infusion during the 2 wk selectively blocked HFD's microvascular effect. Furthermore, AZD5904 infusion during the last 2 of 4 wk of HFD feeding restored microvascular insulin sensitivity but not metabolic IR. We conclude that inhibiting MPO selectively improves vascular IR. This selective microvascular effect may connote a therapeutic potential for MPO inhibition in the prevention of vascular disease/dysfunction seen in IR humans.
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- 2019
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26. Stimulation of alpha 7 nicotinic acetylcholine receptor (α7nAChR) inhibits atherosclerosis via immunomodulatory effects on myeloid cells.
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Ulleryd MA, Mjörnstedt F, Panagaki D, Yang LJ, Engevall K, Gutiérrez S, Wang Y, Gan LM, Nilsson H, Michaëlsson E, and Johansson ME
- Subjects
- Animals, Aorta, Thoracic pathology, Apoptosis, Atherosclerosis pathology, Cytokines metabolism, Disease Models, Animal, Female, Humans, Inflammation immunology, Inflammation pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells immunology, Myeloid Cells metabolism, alpha7 Nicotinic Acetylcholine Receptor agonists, Aorta, Thoracic metabolism, Atherosclerosis metabolism, Inflammation metabolism, Myeloid Cells pathology, alpha7 Nicotinic Acetylcholine Receptor metabolism
- Abstract
Background and Aims: Alpha 7 nicotinic acetylcholine receptor (α7nAChR) stimulation can regulate acute inflammation, and lack of α7nAChR accelerates atherosclerosis in mice. In this study, we aimed to investigate the effects of the novel α7nAChR agonist, AZ6983, on atherosclerosis and assess its possible immunomodulating effects., Methods: AZ6983 was tested in vitro in LPS-challenged mouse and human blood and in vivo using the acute inflammatory air pouch model. Thereafter, long-term effects of AZ6983 treatment on atherosclerosis and immune responses were assessed in apoE
-/- mice after 8 and 12 weeks. Atherosclerosis was investigated in the aortic root and thoracic aorta, serum levels of cytokines were analysed and RNAseq was used to study aortic gene expression. Further, bone-marrow-derived macrophages were used to assess phagocytosis in vitro., Results: α7nAChR activation by AZ6983 decreased pro-inflammatory cytokines in acute stimulations of human and mouse blood in vitro, as well as in vivo using the air pouch model. Treating apoE-/- mice with AZ6983 decreased atherosclerosis by 37-49% and decreased serum cytokine levels. RNAseq analysis of aortae suggested the involvement of several specific myeloid cell functions, including phagocytosis. In line with this, AZ6983 significantly increased phagocytosis in bone marrow-derived macrophages., Conclusions: This study demonstrates that activation of α7nAChR with AZ6983 inhibits atherosclerosis in apoE-/- mice and that immunomodulating effects on myeloid cells, such as enhanced phagocytosis and suppression of inflammatory cytokines, could be part of the athero-protective mechanisms. The observed anti-inflammatory effect in human blood supports the idea that AZ6983 may decrease disease also in humans., (Copyright © 2019. Published by Elsevier B.V.)- Published
- 2019
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27. Inhibition of MPO (Myeloperoxidase) Attenuates Endothelial Dysfunction in Mouse Models of Vascular Inflammation and Atherosclerosis.
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Cheng D, Talib J, Stanley CP, Rashid I, Michaëlsson E, Lindstedt EL, Croft KD, Kettle AJ, Maghzal GJ, and Stocker R
- Subjects
- Animals, Apolipoproteins E physiology, Atherosclerosis physiopathology, Disease Models, Animal, Endothelial Cells physiology, Enzyme Inhibitors pharmacology, Inflammation physiopathology, Male, Mice, Mice, Inbred C57BL, Peroxidase physiology, Vascular Diseases physiopathology, Atherosclerosis drug therapy, Endothelial Cells drug effects, Inflammation drug therapy, Peroxidase antagonists & inhibitors, Vascular Diseases drug therapy
- Abstract
Objective- Inflammation-driven endothelial dysfunction initiates and contributes to the progression of atherosclerosis, and MPO (myeloperoxidase) has been implicated as a potential culprit. On release by circulating phagocytes, MPO is thought to contribute to endothelial dysfunction by limiting NO bioavailability via formation of reactive oxidants including hypochlorous acid. However, it remains largely untested whether specific pharmacological inhibition of MPO attenuates endothelial dysfunction. We, therefore, tested the ability of a mechanism-based MPO inhibitor, AZM198, to inhibit endothelial dysfunction in models of vascular inflammation. Approach and Results- Three models of inflammation were used: femoral cuff, the tandem stenosis model of plaque rupture in Apoe
-/- mice, and C57BL/6J mice fed a high-fat, high-carbohydrate diet as a model of insulin resistance. Endothelial dysfunction was observed in all 3 models, and oral administration of AZM198 significantly improved endothelial function in the femoral cuff and tandem stenosis models only. Improvement in endothelial function was associated with decreased arterial MPO activity, determined by the in vivo conversion of hydroethidine to 2-chloroethidium, without affecting circulating inflammatory cytokines or arterial MPO content. Mechanistic studies in Mpo-/- mice confirmed the contribution of MPO to endothelial dysfunction and revealed oxidation of sGC (soluble guanylyl cyclase) as the underlying cause of the observed limited NO bioavailability. Conclusions- Pharmacological inhibition of MPO is a potential strategy to limit endothelial dysfunction in vascular inflammation. Visual Overview- An online visual overview is available for this article.- Published
- 2019
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28. Safety, tolerability, pharmacokinetics and effect on serum uric acid of the myeloperoxidase inhibitor AZD4831 in a randomized, placebo-controlled, phase I study in healthy volunteers.
- Author
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Gan LM, Lagerström-Fermér M, Ericsson H, Nelander K, Lindstedt EL, Michaëlsson E, Kjaer M, Heijer M, Whatling C, and Fuhr R
- Subjects
- Administration, Oral, Adult, Area Under Curve, Cardiovascular Diseases prevention & control, Drug Administration Schedule, Enzyme Inhibitors adverse effects, Enzyme Inhibitors pharmacokinetics, Half-Life, Healthy Volunteers, Humans, Male, Middle Aged, Placebos, Pyrimidines adverse effects, Pyrimidines pharmacokinetics, Pyrroles adverse effects, Pyrroles pharmacokinetics, Single-Blind Method, Young Adult, Enzyme Inhibitors administration & dosage, Peroxidase antagonists & inhibitors, Pyrimidines administration & dosage, Pyrroles administration & dosage, Uric Acid blood
- Abstract
Aims: Myeloperoxidase activity can contribute to impaired vascular endothelial function and fibrosis in chronic inflammation-related cardiovascular disease. Here, we investigated the safety, tolerability and pharmacokinetics of the myeloperoxidase inhibitor, AZD4831., Methods: In this randomized, single-blind, placebo-controlled, phase I, first-in-human study, healthy men in five sequential cohorts were randomized 3:1 to receive a single oral dose of AZD4831 (5, 15, 45, 135 or 405 mg) or placebo, after overnight fasting. After at least 7 days' washout, one cohort additionally received AZD4831 45 mg after a high-calorie meal., Results: Forty men participated in the study (eight per cohort: AZD4831, n = 6; placebo, n = 2). AZD4831 distributed rapidly into plasma, with a half-life of 38.2-50.0 hours. The area under the plasma concentration-time curve (AUC) increased proportionally with dose (AUC
0-∝ slope estimate 1.060; 95% confidence interval [CI] 0.9943, 1.127). Increases in maximum plasma concentration were slightly more than dose proportional (slope estimate 1.201; 95% CI 1.071, 1.332). Food intake reduced AZD4831 absorption rate but did not substantially affect overall exposure or plasma half-life (n = 4). Serum uric acid concentrations decreased by 71.77 (95% CI 29.15, 114.39) and 84.42 (58.90, 109.94) μmol L-1 with AZD4831 135 mg and 405 mg, respectively. Maculopapular rash (moderate intensity) occurred in 4/30 participants receiving AZD4831 (13.3%). No other safety concerns were identified., Conclusions: AZD4831 was generally well tolerated, rapidly absorbed, had a long plasma half-life and lowered uric acid concentrations after single oral doses in healthy men. These findings support the further clinical development of AZD4831., (© 2019 AstraZeneca. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2019
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29. Promoting intestinal lymphatic transport targets a liver-X receptor (LXR) agonist (WAY-252,623) to lymphocytes and enhances immunomodulation.
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Cao E, Lindgren A, Martinsson S, Hu L, Lindfors L, Sigfridsson K, Skantze U, Michaëlsson E, Trevaskis NL, and Porter CJH
- Subjects
- ATP Binding Cassette Transporter 1 genetics, Administration, Oral, Animals, Female, Forkhead Transcription Factors genetics, Gene Expression drug effects, Immunomodulation drug effects, Indazoles blood, Indazoles pharmacokinetics, Lymphocytes drug effects, Lymphocytes immunology, Male, Rats, Inbred Lew, Rats, Sprague-Dawley, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory immunology, Indazoles administration & dosage, Intestines immunology, Liver X Receptors agonists, Lymphatic Vessels immunology, Nanoparticles administration & dosage
- Abstract
Lymphocytes play a central role in the pathology of a range of chronic conditions such as autoimmune disease, transplant rejection, leukemia, lymphoma HIV/AIDs and cardiometabolic diseases such as atherosclerosis. Current treatments for lymphocyte-associated conditions are incompletely effective and/or complicated by a range of off-target toxicities. One major challenge is poor drug access to lymphocytes via the systemic blood and this may be attributed, at least in part, to the fact that lymphocytes are concentrated within lymph fluid and lymphoid tissues, particularly in gut-associated lymphatics. Here we demonstrate that promoting drug uptake into the intestinal lymphatics with a long chain fatty acid, thereby increasing lymphocyte access, enhances the pharmacodynamic effect of a highly lipophilic liver X receptor (LXR) agonist, WAY-252623, that has been suggested as a potential treatment for atherosclerosis. This has been exemplified by: (1) increased mRNA expression of key markers of LXR activation (ABCA1) and regulatory T cells (Foxp3) in local lymphatic lymphocytes and (2) enhanced numbers of CD4
+ CD25+ Foxp3+ regulatory T cells in the systemic circulation, after administration of a 5-fold lower dose with a lymph directing lipid formulation when compared with a non-lipid containing formulation. These data suggest that combining lipophilic, lymphotropic drug candidates such as WAY-252,623, with lymph-directing long chain lipid based formulations can enhance drug targeting to, and activity on, lymphocytes in lymph and that this effect persists through to the systemic circulation. This presents a promising approach to achieve more selective and effective therapeutic outcomes for the treatment of lymphocyte associated diseases., (Copyright © 2019 Elsevier B.V. All rights reserved.)- Published
- 2019
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30. Extracellular volume by cardiac magnetic resonance is associated with biomarkers of inflammation in hypertensive heart disease.
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Pan JA, Michaëlsson E, Shaw PW, Kuruvilla S, Kramer CM, Gan LM, Keeley EC, and Salerno M
- Subjects
- Biomarkers blood, Humans, Inflammation, Myocardium pathology, Heart diagnostic imaging, Hypertension blood, Hypertension epidemiology, Hypertension metabolism, Hypertension pathology, Hypertrophy, Left Ventricular diagnostic imaging, Hypertrophy, Left Ventricular pathology, Magnetic Resonance Imaging
- Abstract
Objectives: Cardiac magnetic resonance (CMR) provides a unique approach to the characterization of hypertensive heart disease (HHD), enabling the measurement of left ventricular mass and expansion of extracellular volume (ECV). Combining plasma biomarkers with CMR could provide potential insights into the pathophysiological mechanisms in ventricular remodelling., Methods: In this study, we estimated correlations between plasma biomarkers and CMR parameters of HHD. Patients with a history of hypertension with or without left ventricular hypertrophy (LVH) and healthy volunteers (17 hypertensive non-LVH, 13 hypertensive LVH and 11 controls) underwent CMR on a Siemens 1.5T Avanto. T1 mapping was performed before (native T1) and serially after injection of 0.15 mmol/kg gadolinium-DTPA. Mean ECV and left ventricular mass index (LVMI) were determined. Blood samples were obtained and analysed using the Olink CVD 92-plex biomarker panel., Results: Individual groups were compared on the basis of 91 plasma biomarkers using partial least squares discriminant analysis (PLS-DA). ECV and LVMI were correlated with the 91 distinct plasma biomarkers via orthogonal projection to latent structures by partial least square (OPLS) analysis. A two-dimensional PLS-DA explained 49% of the differences between the three groups. OPLS analysis showed that four plasma biomarkers were significantly correlated to both ECV and LVMI, eight were significantly correlated with LVMI only and 11 were significantly correlated to ECV only., Conclusion: ECV and LVMI correlate differentially in plasma biomarker patterns. Top predictors of ECV consisted of well established biomarkers of systemic inflammation and metabolic function.
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- 2019
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31. Myeloperoxidase is a potential molecular imaging and therapeutic target for the identification and stabilization of high-risk atherosclerotic plaque.
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Rashid I, Maghzal GJ, Chen YC, Cheng D, Talib J, Newington D, Ren M, Vajandar SK, Searle A, Maluenda A, Lindstedt EL, Jabbour A, Kettle AJ, Bongers A, Power C, Michaëlsson E, Peter K, and Stocker R
- Subjects
- Animals, Disease Models, Animal, Fibrin metabolism, Hemosiderin metabolism, Mass Spectrometry, Mice, Knockout, Peroxidase antagonists & inhibitors, Thioxanthenes pharmacology, Atherosclerosis diagnostic imaging, Atherosclerosis enzymology, Magnetic Resonance Imaging methods, Molecular Imaging, Peroxidase metabolism, Plaque, Atherosclerotic diagnostic imaging, Plaque, Atherosclerotic enzymology
- Abstract
Aims: As the inflammatory enzyme myeloperoxidase (MPO) is abundant in ruptured human atherosclerotic plaques, we aimed to investigate the role of MPO as a potential diagnostic and therapeutic target for high-risk plaque., Methods and Results: We employed the tandem stenosis model of atherosclerotic plaque instability in apolipoprotein E gene knockout (Apoe-/-) mice. To test the role of MPO, we used Mpo-/-Apoe-/- mice and the 2-thioxanthine MPO inhibitor AZM198. In vivo MPO activity was assessed by liquid chromatography-tandem mass spectrometry detection of 2-chloroethidium generation from hydroethidine and by bis-5HT-DTPA-Gd (MPO-Gd) molecular magnetic resonance imaging (MRI), while plaque phenotype was verified histologically. Myeloperoxidase activity was two-fold greater in plaque with unstable compared with stable phenotype. Genetic deletion of MPO significantly increased fibrous cap thickness, and decreased plaque fibrin and haemosiderin content in plaque with unstable phenotype. AZM198 inhibited MPO activity and it also increased fibrous cap thickness and decreased fibrin and haemosiderin in plaque with unstable phenotype, without affecting lesion monocytes and red blood cell markers or circulating leukocytes and lipids. MPO-Gd MRI demonstrated sustained enhancement of plaque with unstable phenotype on T1-weighted imaging that was two-fold greater than stable plaque and was significantly attenuated by both AZM198 treatment and deletion of the Mpo gene., Conclusion: Our data implicate MPO in atherosclerotic plaque instability and suggest that non-invasive imaging and pharmacological inhibition of plaque MPO activity hold promise for clinical translation in the management of high-risk coronary artery disease.
- Published
- 2018
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32. Myeloperoxidase aggravates pulmonary arterial hypertension by activation of vascular Rho-kinase.
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Klinke A, Berghausen E, Friedrichs K, Molz S, Lau D, Remane L, Berlin M, Kaltwasser C, Adam M, Mehrkens D, Mollenhauer M, Manchanda K, Ravekes T, Heresi GA, Aytekin M, Dweik RA, Hennigs JK, Kubala L, Michaëlsson E, Rosenkranz S, Rudolph TK, Hazen SL, Klose H, Schermuly RT, Rudolph V, and Baldus S
- Subjects
- Adult, Amides administration & dosage, Animals, Cohort Studies, Disease Models, Animal, Female, Humans, Hypertension, Pulmonary blood, Hypertension, Pulmonary mortality, Hypertension, Pulmonary physiopathology, Hypoxia blood, Hypoxia etiology, Infusions, Intravenous, Kaplan-Meier Estimate, Lung pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Peroxidase administration & dosage, Peroxidase blood, Pulmonary Artery physiopathology, Pyridines administration & dosage, Rats, Rats, Sprague-Dawley, Recombinant Proteins administration & dosage, Recombinant Proteins blood, Recombinant Proteins metabolism, Vascular Remodeling drug effects, Vascular Remodeling physiology, Vasoconstriction drug effects, Vasoconstriction physiology, rho-Associated Kinases antagonists & inhibitors, Hypertension, Pulmonary pathology, Hypoxia pathology, Peroxidase metabolism, Pulmonary Artery pathology, rho-Associated Kinases metabolism
- Abstract
Pulmonary arterial hypertension (PAH) remains a disease with limited therapeutic options and dismal prognosis. Despite its etiologic heterogeneity, the underlying unifying pathophysiology is characterized by increased vascular tone and adverse remodeling of the pulmonary circulation. Myeloperoxidase (MPO), an enzyme abundantly expressed in neutrophils, has potent vasoconstrictive and profibrotic properties, thus qualifying as a potential contributor to this disease. Here, we sought to investigate whether MPO is causally linked to the pathophysiology of PAH. Investigation of 2 independent clinical cohorts revealed that MPO plasma levels were elevated in subjects with PAH and predicted adverse outcome. Experimental analyses showed that, upon hypoxia, right ventricular pressure was less increased in Mpo-/- than in WT mice. The hypoxia-induced activation of the Rho-kinase pathway, a critical subcellular signaling pathway yielding vasoconstriction and structural vascular remodeling, was blunted in Mpo-/- mice. Mice subjected to i.v. infusion of MPO revealed activation of Rho-kinase and increased right ventricular pressure, which was prevented by coinfusion of the Rho-kinase inhibitor Y-27632. In the Sugen5416/hypoxia rat model, PAH was attenuated by the MPO inhibitor AZM198. The current data demonstrate a tight mechanistic link between MPO, the activation of Rho-kinase, and adverse pulmonary vascular function, thus pointing toward a potentially novel avenue of treatment.
- Published
- 2018
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33. Evaluation of pharmacokinetic and pharmacodynamic profiles of liposomes for the cell type-specific delivery of small molecule drugs.
- Author
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Dasa SSK, Suzuki R, Mugler E, Chen L, Jansson-Löfmark R, Michaëlsson E, Lindfors L, Klibanov AL, French BA, and Kelly KA
- Subjects
- Animals, Drug Delivery Systems, Mice, Myocardial Infarction complications, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic etiology, Peptide Library, Phthalazines pharmacokinetics, Phthalazines therapeutic use, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors therapeutic use, Pyridines pharmacokinetics, Pyridines therapeutic use, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors, Liposomes chemistry, Peptides chemistry, Phthalazines administration & dosage, Protein Kinase Inhibitors administration & dosage, Pyridines administration & dosage
- Abstract
Liposome-based drug formulations represent an exciting avenue of research as they increase efficacy to toxicity ratios. Current formulations rely on passive accumulation to the disease site where drug is taken up by the cells. Ligand mediated targeting increases the net accumulation of liposomes, however, an unexplored benefit is to potentially refine pharmacodynamics (PD) of a drug specifically to different cell types within diseased tissue. As a model system, we engineered cardiomyocyte- (I-1) and endothelial-targeted (B-40) liposomes to carry a VEGFR2 inhibitor (PTK787), and examined the effect of cell type-specific delivery on both pharmacokinetics (PK) and PD. Neovascularization in post-myocardial infarction was significantly reduced by B-40 liposomes loaded with PTK787 as compared to animals injected with I-1 liposomes, and profoundly more as compared to free PTK787. This study thus shows that the intraorgan targeting of drugs through cell type-specific delivery holds substantial promise towards lowering the minimal efficacious dose administered systemically., (Published by Elsevier Inc.)
- Published
- 2017
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34. Determining myeloperoxidase activity and protein concentration in a single assay: Utility in biomarker and therapeutic studies.
- Author
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Russell M, Prokoph N, Henderson N, Eketjäll S, Balendran CA, Michaëlsson E, Fidock M, and Hughes G
- Subjects
- Humans, Peroxidase metabolism, Biomarkers blood, Blood Proteins analysis, Enzyme-Linked Immunosorbent Assay methods, Peroxidase blood
- Abstract
Myeloperoxidase (MPO) is predominantly expressed by neutrophils and is an important enzyme used by the immune system for the neutralisation of bacteria and other microorganisms. The strong oxidative activity of MPO has been linked to pro-inflammatory responses in surrounding cells and tissues with implication in the pathophysiology of cardiovascular, neuroscience and inflammatory diseases. This broad disease association has made MPO an attractive biomarker and therapeutic target. Here we describe the construction and validation of a single combined MPO activity and protein concentration assay using commercially available reagents. This method offers the investigative laboratory the ability to generate results from blood plasma samples in a single analytical run using the same sample aliquot., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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35. Nanocrystal formulations of a poorly soluble drug. 2. Evaluation of nanocrystal liver uptake and distribution after intravenous administration to mice.
- Author
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Sigfridsson K, Skantze P, Skantze U, Svensson L, Löfgren L, Nordell P, Michaëlsson E, Smedsrød B, Fuglesteg B, Elvevold K, and Lindfors L
- Subjects
- Administration, Intravenous, Animals, Endothelial Cells metabolism, Female, Kupffer Cells metabolism, Liver cytology, Male, Mice, Mice, Inbred C57BL, Tissue Distribution, Liver metabolism, Nanoparticles metabolism, Phosphatidylethanolamines pharmacokinetics, Polyethylene Glycols pharmacokinetics
- Abstract
A stabilized high drug load intravenous formulation could allow compounds with less optimal pharmacokinetic profiles to be developed. Polyethylene glycol (PEG)-ylation is a frequently used strategy for particle delivery systems to avoid the liver, thereby extending blood circulation time. The present work reports the mouse in vivo distribution after i.v. administration of a series of nanocrystals prepared with the bead milling technique and PEG-ylated with DSPE-PEG2000 and Pluronic F127, with and without polyvinylpyrrolidone K30 (PVP)/Aerosol OT (AOT) as primary stabilizers. While all formulations were cleared significantly faster than expected from nanocrystal dissolution alone, purely DSPE-PEG2000 PEG-ylated particles displayed prolonged circulation time (particles elimination half-life of 9min) compared to DSPE-PEG2000/PVP/AOT formulation (half-life of 3min). The two Pluronic F127 stabilized formulations displayed similar half-lives (9min with and without PVP/AOT, respectively). Whole tissue kinetics shows that clearance of particles could be attributed to accumulation in the liver. A separate in vivo study addressed the liver cell distribution after administration. Dissolved compound accumulated in hepatocytes only, while particles were distributed between liver sinusoidal endothelial cells and Kupffer cells. More DSPE-PEG2000/PVP/AOT stabilized particles accumulated in the liver, preferably in Kupffer cells, compared to Pluronic F127/PVP/AOT stabilized particles. The present study extends the understanding of PEG-ylation and "stealth" behaviour to also include nanocrystals., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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36. Determinants of coronary flow reserve in non-diabetic patients with chest pain without myocardial perfusion defects.
- Author
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Westergren HU, Michaëlsson E, Blomster JI, Miliotis T, Svedlund S, and Gan LM
- Subjects
- Adult, Aged, Chest Pain diagnostic imaging, Female, Humans, Male, Middle Aged, Myocardial Perfusion Imaging, Sex Characteristics, Chest Pain physiopathology, Fractional Flow Reserve, Myocardial
- Abstract
Background: Microvascular dysfunction could be responsible for chest pain in patients without myocardial perfusion defects. We evaluated microvascular function using ultrasound-assessed coronary flow reserve (CFR) in patients with chest pain and normal myocardial perfusion scintigram. Secondly, we investigated association between cardiovascular parameters and decreased CFR in a sex specific manner., Methods: A total of 202 (128 women) non-diabetic patients with chest pain and suspected myocardial ischemia, but without myocardial perfusion defects on myocardial perfusion scintigram, were enrolled and underwent CFR examination and blood sampling. All patients were followed-up for cardiovascular events. We used a supervised principal component analysis including 66 variables such as clinical parameters, ongoing medication, coronary artery disease history, lipids, metabolic parameters, inflammatory and other cardiovascular parameters., Results: During a median follow-up time of 5.4 years, 25 cardiovascular events occurred; (men;18, women;7). Average CFR of the study cohort was 2.7±1.2 and 14% showed impaired CFR<2.0. In an adjusted Cox regression analysis, CFR<2.0 independently predicted event-free survival (HR:2.5, p = 0.033). In the supervised principal component analysis high insulin resistance assessed by Homeostatic model assessment for insulin resistance was the strongest biochemical marker associated with decreased CFR. Interestingly, upon sex specific multivariable linear regression analysis, the association was only significant in men (β = -0.132, p = 0.041) while systolic blood pressure remained an independent predictor in women (β = -0.009, p = 0.011)., Conclusions: In non-diabetic patients with chest pain without myocardial perfusion defects, low CFR has prognostic value for future cardiovascular events. Insulin resistance appears to be a marker for decreased CFR in men. Indeed, in the context of contribution of traditional risk factors in this patient population, the value of systolic blood pressure seems to be important in the women.
- Published
- 2017
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37. Inflammatory Biomarkers Predict Heart Failure Severity and Prognosis in Patients With Heart Failure With Preserved Ejection Fraction: A Holistic Proteomic Approach.
- Author
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Hage C, Michaëlsson E, Linde C, Donal E, Daubert JC, Gan LM, and Lund LH
- Subjects
- Aged, Aged, 80 and over, Biomarkers blood, Databases, Protein, Echocardiography, Female, France, Heart Failure blood, Heart Failure mortality, Heart Failure physiopathology, Humans, Least-Squares Analysis, Male, Multivariate Analysis, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Prospective Studies, Risk Factors, Severity of Illness Index, Sweden, Heart Failure diagnosis, Inflammation Mediators blood, Proteomics methods, Stroke Volume, Ventricular Function, Left
- Abstract
Background: Underlying mechanisms in heart failure (HF) with preserved ejection fraction remain unknown. We investigated cardiovascular plasma biomarkers in HF with preserved ejection fraction and their correlation to diastolic dysfunction, functional class, pathophysiological processes, and prognosis., Methods and Results: In 86 stable patients with HF and EF ≥45% in the Karolinska Rennes (KaRen) biomarker substudy, biomarkers were quantified by a multiplex immunoassay. Orthogonal projection to latent structures by partial least square analysis was performed on 87 biomarkers and 240 clinical variables, ranking biomarkers associated with New York Heart Association (NYHA) Functional class and the composite outcome (all-cause mortality and HF hospitalization). Biomarkers significantly correlated with outcome were analyzed by multivariable Cox regression and correlations with echocardiographic measurements performed. The orthogonal partial least square outcome-predicting biomarker pattern was run against the Ingenuity Pathway Analysis (IPA) database, containing annotated data from the public domain. The orthogonal partial least square analyses identified 32 biomarkers correlated with NYHA class and 28 predicting outcomes. Among outcome-predicting biomarkers, growth/differentiation factor-15 was the strongest and an additional 7 were also significant in Cox regression analyses when adjusted for age, sex, and N-terminal probrain natriuretic peptide: adrenomedullin (hazard ratio per log increase 2.53), agouti-related protein; (1.48), chitinase-3-like protein 1 (1.35), C-C motif chemokine 20 (1.35), fatty acid-binding protein (1.33), tumor necrosis factor receptor 1 (2.29), and TNF-related apoptosis-inducing ligand (0.34). Twenty-three of them correlated with diastolic dysfunction (E/e') and 5 with left atrial volume index. The IPA suggested that increased inflammation, immune activation with decreased necrosis and apoptosis preceded poor outcome., Conclusions: In HF with preserved ejection fraction, novel biomarkers of inflammation predict HF severity and prognosis that may complement or even outperform traditional markers, such as N-terminal probrain natriuretic peptide. These findings lend support to a hypothesis implicating global systemic inflammation in HF with preserved ejection fraction., Clinical Trial Registration: URL: http://www.clinicaltrials.gov; Unique identifier: NCT00774709., (© 2017 American Heart Association, Inc.)
- Published
- 2017
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38. Suppression of abdominal aortic aneurysm formation by AR-R17779, an agonist for the α7 nicotinic acetylcholine receptor.
- Author
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Watanabe A, Ichiki T, Kojima H, Takahara Y, Hurt-Camejo E, Michaëlsson E, Sankoda C, Ikeda J, Inoue E, Tokunou T, Kitamoto S, and Sunagawa K
- Subjects
- Animals, Aortic Aneurysm, Abdominal genetics, Aortic Aneurysm, Abdominal metabolism, Blotting, Western, Cytokines biosynthesis, Cytokines genetics, Disease Models, Animal, Disease Progression, Gene Expression Regulation drug effects, Matrix Metalloproteinases biosynthesis, Matrix Metalloproteinases genetics, Mice, Mice, Inbred C57BL, RNA genetics, Reverse Transcriptase Polymerase Chain Reaction, Aortic Aneurysm, Abdominal prevention & control, Bridged-Ring Compounds pharmacology, Spiro Compounds pharmacology, alpha7 Nicotinic Acetylcholine Receptor agonists
- Abstract
Objective: Activation of vagal nerve suppresses inflammatory responses through activation of α7 nicotinic acetylcholine receptor (nAchR). We sought to determine whether AR-R17779, a selective agonist of α7nAchR, affects the development of abdominal aortic aneurysm (AAA)., Methods and Results: AAA was induced by topical application of calcium chloride (CaCl2) to abdominal aorta (AAA group). NaCl (0.9%) was substituted for CaCl2 as a sham operation (SHAM group). AR-R17779 was administered in drinking water (AAA/AR-R group). One and 6 weeks after the operation, aortic tissue was excised for histological and molecular analyses. Aortic diameter and macrophage infiltration into the aortic adventitia were increased in AAA group compared with SHAM group at 6 weeks. Treatment with AR-R17779 reduced the diameter of the aorta and macrophage infiltration compared with AAA group. Wavy morphology of the elastic lamellae was lost in AAA group while it was preserved in AAA/AR-R group. Expression of inflammatory cytokines and matrix metalloproteinase (MMP) activities were enhanced in AAA group, which was suppressed in AAA/AR-R group. AR-R17779 treatment suppressed CaCl2-induced expression of cytokines, activities of MMPs and NF-κB activation at 1 week when aortic dilatation had not developed., Conclusion: Treatment with AR-R17779 prevented the enlargement of abdominal aorta induced by CaCl2 in association with reduced inflammation and extracellular matrix disruption. These findings suggest therapeutic potential of α7nAchR activation for prevention of AAA development., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2016
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39. Neutrophil NET formation is regulated from the inside by myeloperoxidase-processed reactive oxygen species.
- Author
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Björnsdottir H, Welin A, Michaëlsson E, Osla V, Berg S, Christenson K, Sundqvist M, Dahlgren C, Karlsson A, and Bylund J
- Subjects
- Flow Cytometry, Humans, Hydrogen Peroxide metabolism, NADPH Oxidases metabolism, Oxidation-Reduction, Tetradecanoylphorbol Acetate pharmacology, Extracellular Traps metabolism, Neutrophils metabolism, Peroxidase metabolism, Reactive Oxygen Species metabolism
- Abstract
Aim: Neutrophil extracellular traps (NETs) are mesh-like DNA fibers clad with intracellular proteins that are cast out from neutrophils in response to certain stimuli. The process is thought to depend on reactive oxygen species (ROS) generated by the phagocyte NADPH-oxidase and the ROS-modulating granule enzyme myeloperoxidase (MPO), but when, how, and where these factors contribute is so far uncertain. The neutrophil NADPH-oxidase can be activated at different cellular sites and ROS may be produced and processed by MPO within intracellular granules, even in situations where a phagosome is not formed, e.g., upon stimulation with phorbol myristate acetate (PMA)., Objectives: We investigated the subcellular location of ROS production and processing by MPO in the context of PMA-induced NET formation., Results: Complete neutralization of extracellular ROS was not sufficient to block NET formation triggered by PMA, indicating that intragranular ROS are critical for NETosis. Employing a set of novel MPO-inhibitors, inhibition of NET formation correlated with inhibition of intragranular MPO activity. Also, extracellular addition of MPO was not sufficient to rescue NET formation in completely MPO-deficient neutrophils and specific neutralization by luminol of MPO-processed ROS within intracellular granules led to a complete block of PMA-triggered NET formation., Conclusion: We show for the first time that inhibition of intragranular MPO activity, or neutralization of intragranular MPO-processed ROS by luminol effectively block NET formation. Our data demonstrate that ROS must be formed and processed by MPO in order to trigger NET formation, and that these events have to occur within intracellular granules., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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40. Stimulation of α7 nicotinic acetylcholine receptor by AR-R17779 suppresses atherosclerosis and aortic aneurysm formation in apolipoprotein E-deficient mice.
- Author
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Hashimoto T, Ichiki T, Watanabe A, Hurt-Camejo E, Michaëlsson E, Ikeda J, Inoue E, Matsuura H, Tokunou T, Kitamoto S, and Sunagawa K
- Subjects
- Animals, Anti-Inflammatory Agents pharmacology, Apolipoproteins E genetics, Blood Pressure drug effects, Disease Models, Animal, Lipids blood, Male, Mice, Mice, Knockout, Rats, Rats, Sprague-Dawley, alpha7 Nicotinic Acetylcholine Receptor metabolism, Aortic Aneurysm prevention & control, Atherosclerosis prevention & control, Bridged-Ring Compounds pharmacology, Spiro Compounds pharmacology, alpha7 Nicotinic Acetylcholine Receptor agonists
- Abstract
Atherosclerosis is a chronic inflammatory disease. It has been appreciated that vagus nerve inhibits macrophage activation via α7 nicotinic acetylcholine receptor (nAChR), termed the cholinergic anti-inflammatory pathway. We explored the effects of AR-R17779, a selective α7nAChR agonist, on atherosclerosis and aneurysm formation in apolipoprotein E (ApoE)-deficient mice. ApoE-deficient mice were fed a high-fat diet (HFD) and angiotensin II (Ang II) was infused by osmotic minipumps from 10-week-old for 4weeks. AR-R17779 was given in drinking water ad libitum. Oil red O staining of the aorta showed that combined loading of HFD and Ang II induced marked atherosclerosis compared with control mice fed a normal chow. Treatment with AR-R17779 significantly reduced atherosclerotic plaque area and improved survival of mice. Treatment with AR-R17779 also suppressed abdominal aortic aneurysm formation. Quantitative RT-PCR of the aorta revealed that mRNA expression levels of interleukin-1β, interleukin-6 and NOX2 were significantly decreased in AR-R17779-treated mice compared with Ang II+HFD mice. AR-R17779 treatment also reduced blood pressure and serum lipid levels. In conclusion, α7nAChR activation attenuates atherogenesis and aortic abdominal aneurysm formation in ApoE-deficient mice possibly through an anti-inflammatory effect and reduction of blood pressure and lipid levels. Pharmacological activation of α7nAChR may have a therapeutic potential against atherosclerotic vascular diseases through multiple mechanisms., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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41. Modelling of mouse experimental colitis by global property screens: a holistic approach to assess drug effects in inflammatory bowel disease.
- Author
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Gottfries J, Melgar S, and Michaëlsson E
- Subjects
- Animals, Colitis chemically induced, Colitis drug therapy, Colon drug effects, Colon metabolism, Colon pathology, Cytokines blood, Dextran Sulfate, Female, Haptoglobins metabolism, Holistic Health, Humans, Inflammation Mediators blood, Inflammatory Bowel Diseases diagnosis, Inflammatory Bowel Diseases drug therapy, Liver X Receptors, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Orphan Nuclear Receptors agonists, PPAR alpha agonists, PPAR gamma agonists, Principal Component Analysis, Biomarkers blood, Colitis blood, Disease Models, Animal, Inflammatory Bowel Diseases blood
- Abstract
Preclinical disease models play an important role in the establishment of new treatment paradigms, identification of biomarkers and assessment of drug efficacy and safety. However, the accuracy of these models in context of the human disease are sometimes questioned, e.g. due to trials failing to confirm efficacy in humans. We suggest that one reason behind this gap in predictability may relate to how the preclinical data is analyzed and interpreted. In the present paper, we introduce a holistic approach to analyze and illustrate data in context of one of the most commonly used colitis models, i.e. the mouse dextran sulphate sodium (DSS) colitis model. Diseased mice were followed over time along disease progression and by use of tool pharmacological compounds activating nuclear hormone receptors, respectively. A new multivariate statistics approach was applied including principal component analysis (PCA) with treatment prediction subsequent to establishing the principal component analysis model. Thus, several studies could be overlaid and compared to each other in a new, comprehensive and holistic way. This method, named mouse colitis global property screening, appears applicable not only to any animal modelling series of studies but also to human clinical studies. The prerequisites for the study set up and calculations are delineated and examples of new learnings from the global property screening will be presented.
- Published
- 2012
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42. Intestinal, adipose, and liver inflammation in diet-induced obese mice.
- Author
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Li H, Lelliott C, Håkansson P, Ploj K, Tuneld A, Verolin-Johansson M, Benthem L, Carlsson B, Storlien L, and Michaëlsson E
- Subjects
- Animals, Body Weight physiology, Cytokines blood, Cytokines metabolism, Diet, Atherogenic, Female, Gastroenteritis blood, Gastroenteritis pathology, Gastroenteritis veterinary, Hepatitis, Animal blood, Hepatitis, Animal pathology, Intestinal Mucosa metabolism, Intestines pathology, Intra-Abdominal Fat metabolism, Intra-Abdominal Fat pathology, Liver metabolism, Liver pathology, Mice, Mice, Inbred C57BL, Mice, Obese, Obesity etiology, Obesity pathology, Obesity veterinary, Organ Size, Panniculitis, Peritoneal blood, Panniculitis, Peritoneal pathology, Panniculitis, Peritoneal veterinary, Gastroenteritis complications, Hepatitis, Animal complications, Obesity complications, Panniculitis, Peritoneal complications
- Abstract
Chronic inflammation and increased visceral adipose tissue (VAT) are key elements of the metabolic syndrome. Both are considered to play a pathogenic role in the development of liver steatosis and insulin resistance. The aim of the present study was to investigate the hypothesis that an inflamed intestine, induced both by diet and chemical irritation, could induce persistent inflammation in VAT. Female C57BL/6JOlaHsd mice were used. In study I, groups of mice (n = 6 per group) were given an obesity-inducing cafeteria diet (diet-induced obesity) or regular chow only (control) for 14 weeks. In study II, colitis in mice (n = 8) was induced by 3% dextran sulfate sodium in tap water for 5 days followed by 21 days of tap water alone. Healthy control mice (n = 8) had tap water only. At the end of the studies, all mice were killed; and blood and tissues were sampled and processed for analysis. Body weight of diet-induced obese mice was greatly increased, with evidence of systemic inflammation, insulin resistance, and liver steatosis. Tissue inflammation indexed by proinflammatory cytokine expression was recorded in liver, mesenteric fat, and proximal colon/distal ileum, but not in subcutaneous or perigonadal fat. In dextran sulfate sodium-induced colitis mice, mesenteric fat was even more inflamed than the colon, whereas a much milder inflammation was seen in liver and subcutaneous fat. The studies showed both diet- and colitis-initiated inflammation in mesenteric fat. Fat depots contiguous with intestine and their capacity for exaggerated inflammatory responses to conditions of impaired gut barrier function may account for the particularly pathogenic role of VAT in obesity-induced metabolic disorders.
- Published
- 2008
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43. Validation of murine dextran sulfate sodium-induced colitis using four therapeutic agents for human inflammatory bowel disease.
- Author
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Melgar S, Karlsson L, Rehnström E, Karlsson A, Utkovic H, Jansson L, and Michaëlsson E
- Subjects
- Acute Disease, Animals, Antibodies administration & dosage, Antibodies therapeutic use, Chronic Disease, Cyclosporine administration & dosage, Cyclosporine therapeutic use, Dextran Sulfate, Female, Humans, Immunosuppressive Agents administration & dosage, Interleukin-12 Subunit p40 immunology, Methotrexate administration & dosage, Methotrexate therapeutic use, Mice, Mice, Inbred C57BL, CD3 Complex immunology, Colitis chemically induced, Colitis drug therapy, Disease Models, Animal, Immunosuppressive Agents therapeutic use, Inflammatory Bowel Diseases drug therapy, Interleukin-12 Subunit p40 metabolism
- Abstract
Dextran sulfate sodium (DSS)-induced colitis is one of the most frequently used rodent models for inflammatory bowel disease (IBD). The aim of this study was to validate the murine DSS-induced colitis model using four therapeutic agents for IBD. C57BL/6 mice were exposed to 3% DSS for 5days followed by 7-9 days of water (acute inflammation) or 20-31 days of water (chronic phase). Clinical symptoms, plasma and colonic inflammatory markers and histology were assessed for the efficacy of cyclosporine A (CsA), methotrexate or anti-IL-12p40 in acute colitis and of anti-IL-12p40 or an agonistic anti-CD3 antibody in chronic colitis. Cyclosporine A and anti-IL-12p40 (in the acute phase) and anti-CD3 (in the chronic phase) treatment attenuated local cytokine levels, improved clinical symptoms (CsA and anti-IL-12p40) and histology (CsA and anti-CD3). Further, anti-IL-12p40 treatment was partly efficacious in the chronic phase, whereas methotrexate showed no efficacy in the acute colitis. Thus, three of the current tested agents showed efficacy in the disease model, arguing that DSS-induced colitis can be used as a relevant model for the translation of mice data to human disease.
- Published
- 2008
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44. Intra-colonic administration of the TLR7 agonist R-848 induces an acute local and systemic inflammation in mice.
- Author
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Karlsson A, Jägervall K, Utkovic H, Karlsson L, Rehnström E, Fredin MF, Gillberg PG, Jansson L, Michaëlsson E, and Melgar S
- Subjects
- Animals, Cytokines immunology, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Immunity, Innate immunology, Immunologic Factors immunology, Inflammation pathology, Mice, Mice, Inbred BALB C, Colon drug effects, Colon immunology, Imidazoles administration & dosage, Immunity, Innate drug effects, Inflammation chemically induced, Inflammation immunology, Membrane Glycoproteins antagonists & inhibitors, Toll-Like Receptor 7 antagonists & inhibitors
- Abstract
Imidazoquinoline compounds, such as resiquimod (R-848), are well known topically active immune modifiers that bind to toll-like receptor 7 (TLR7). The aim of this study was to characterize the R-848 induced inflammatory response in mice and to validate the response using methyl-prednisolone and anti-TNF antibody. Intra-colonic application of R-848 to BALB/c mice induced a systemic transient elevation of TNF, CXCL1, IL-6, and IL-12p40 and a colonic elevation of cytokines/chemokines and iNOS, without infiltration of immune cells or epithelial destruction. Treatment with methyl-prednisolone or anti-TNF antibody attenuated the systemic (TNF, IL-6, IL-12p40, and CXCL1) and local (colonic TNF and iNOS mRNA expression) response induced by R-848. In summary, intra-colonic administration of R-848 induces an acute systemic and local inflammatory response, which can be attenuated by steroids or anti-TNF antibody. We suggest that the R-848 inflammatory model can be useful in future validation of new drugs for gastrointestinal inflammatory conditions.
- Published
- 2008
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45. Mice with experimental colitis show an altered metabolism with decreased metabolic rate.
- Author
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Melgar S, Bjursell M, Gerdin AK, Svensson L, Michaëlsson E, and Bohlooly-Y M
- Subjects
- Alanine Transaminase blood, Animals, Body Composition, Cholesterol blood, Colitis blood, Colitis drug therapy, Colon metabolism, Colon physiopathology, Dextran Sulfate, Disease Models, Animal, Inflammatory Bowel Diseases, Male, Methylprednisolone therapeutic use, Mice, Mice, Inbred C57BL, Triglycerides blood, Colitis metabolism
- Abstract
Patients with inflammatory bowel disease (IBD) suffer from body weight loss, malnutrition, and several other metabolic alterations affecting their quality of life. The aim of this study was to investigate the metabolic changes that may occur during acute and chronic colonic inflammation induced by dextran sulfate sodium (DSS) in mice. Clinical symptoms and inflammatory markers revealed the presence of an ongoing inflammatory response in the DSS-treated mice. Mice with acute inflammation had decreased body weight, respiratory exchange ratios (RER), food intake, and body fat content. Mice with chronic inflammation had decreased nutrient uptake, body fat content, locomotor activity, metabolic rates, and bone mineral density. Despite this, the body weight, food and water intake, lean mass, and RER of these mice returned to values similar to those in healthy controls. Thus, murine experimental colitis is associated with significant metabolic alterations similar to IBD patients. Our data show that the metabolic responses during acute and chronic inflammation are different, although the metabolic rate is reduced in both phases. These observations suggest compensatory metabolic alterations in chronic colitis resulting in a healthy appearance despite gross colon pathology.
- Published
- 2007
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46. Local production of chemokines and prostaglandin E2 in the acute, chronic and recovery phase of murine experimental colitis.
- Author
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Melgar S, Drmotova M, Rehnström E, Jansson L, and Michaëlsson E
- Subjects
- Acute Disease, Animals, Anticoagulants toxicity, Chemokines immunology, Chronic Disease, Colitis chemically induced, Colitis immunology, Colitis pathology, Colitis rehabilitation, Dextran Sulfate toxicity, Dinoprostone immunology, Down-Regulation drug effects, Down-Regulation immunology, Humans, Inflammation chemically induced, Inflammation immunology, Inflammation metabolism, Inflammation rehabilitation, Inflammatory Bowel Diseases immunology, Inflammatory Bowel Diseases metabolism, Inflammatory Bowel Diseases pathology, Mice, Mice, Inbred BALB C, Up-Regulation drug effects, Up-Regulation immunology, Chemokines biosynthesis, Colitis metabolism, Dinoprostone biosynthesis
- Abstract
Increased levels of chemokines and prostaglandins have been reported in patients with inflammatory bowel disease, although their changes during disease development are less understood. The aim of this study was to investigate the local production of nine selected chemokines and prostaglandin E(2) (PGE(2)) to elucidate their role in colitis progression in BALB/c and C57BL/6 mice exposed to dextran sulphate sodium. The acute inflammation in both strains was accompanied by a significant up-regulation of CXCL1, CXCL2/3, CXCL10, CCL2, CCL4 and CCL22 and a downregulation of PGE(2). In the recovery phase in BALB/c, one-week post-DSS, PGE(2) levels were significantly increased with a concomitant downregulation of CXCL1, CXCL2/3, CXCL10, CCL2, and CCL4. In contrast, in C57BL/6 mice CXCL1, CXCL2/3, CXCL10, CCL2, CCL3 and CCL4 production remained high during the chronic phase, without any up-regulation of PGE(2). In addition, CCL5 was significantly increased at d26 and 33 compared to d5. Interestingly, the number of macrophages was significantly increased during the acute phase, whereas T cells were significantly increased in both the acute and chronic phase in C57BL/6 mice. Thus, our results show that chemokines are produced in a dynamic manner during colitis progression.
- Published
- 2006
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47. Magnetic resonance imaging of experimental mouse colitis and association with inflammatory activity.
- Author
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Larsson AE, Melgar S, Rehnström E, Michaëlsson E, Svensson L, Hockings P, and Olsson LE
- Subjects
- Animals, Biomarkers, Colitis pathology, Colon anatomy & histology, Colon metabolism, Colon pathology, Disease Models, Animal, Female, Haptoglobins metabolism, Mice, Mice, Inbred C57BL, Sensitivity and Specificity, Colitis diagnosis, Magnetic Resonance Imaging
- Abstract
Background: Ulcerative colitis and Crohn's disease are the major chronic inflammatory bowel diseases affecting the gastrointestinal tract in humans. Imaging techniques such as endoscopy and computed tomography are used to monitor disease activity. Magnetic resonance imaging (MRI) is emerging as a diagnostic modality, and studies have shown that MRI can be used in the diagnostic procedure of patients with inflammatory bowel disease. The aim of the present study was to investigate the role of MRI in quantitatively reflecting inflammation in an experimental mouse colitis model., Methods: Colonic inflammation was induced by exposing mice to dextran sulfate sodium. MRI was used to assess colon wall thickness, T2-weighted (T2w) signal, and contrast-enhanced T1-weighted (T1w) signal in inflamed and healthy animals in vivo. Haptoglobin and interleukin-1beta served as systemic and local inflammatory markers, and macroscopic ex vivo scoring of the colon was performed to assess colonic inflammation., Results: Dextran sulfate sodium-exposed animals displayed increased levels of inflammatory markers and higher inflammatory score compared with healthy animals. Colon wall thickness and contrast-enhanced T1w signal were significantly increased in dextran sulfate sodium-exposed compared with healthy animals. In addition, the T2w signal was positively correlated with haptoglobin levels and colon wall thickness in the inflamed animals., Conclusions: Our results show that MRI can be used to depict healthy and inflamed mouse colon and that the T2w signal, contrast-enhanced T1w signal, and colon wall thickness may be used to characterize inflammation in experimental colitis. These potential biomarkers may be useful in the evaluation of putative drugs in longitudinal studies in both mice and humans.
- Published
- 2006
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48. Acute colitis induced by dextran sulfate sodium progresses to chronicity in C57BL/6 but not in BALB/c mice: correlation between symptoms and inflammation.
- Author
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Melgar S, Karlsson A, and Michaëlsson E
- Subjects
- Acute Disease, Animals, Anticoagulants administration & dosage, Chronic Disease, Colitis chemically induced, Colitis veterinary, Cytokines analysis, Cytokines biosynthesis, Dextran Sulfate administration & dosage, Female, Haptoglobins analysis, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Anticoagulants adverse effects, Colitis physiopathology, Dextran Sulfate adverse effects, Disease Models, Animal, Inflammation
- Abstract
Exposure to dextran sulfate sodium (DSS) induces acute colitis, which is normally resolved after DSS removal. To study chronicity, mice are typically subjected to three to five cycles of weekly DSS exposures, each followed by a 1- to 2-wk rest period. Here, we describe a novel and convenient way of inducing chronic, progressive colitis by a single exposure to DSS. C57BL/6 mice exposed to DSS for 5 days developed acute colitis that progressed to severe chronic inflammation. The plasma haptoglobin levels remained high during the chronic phase, showing that the inflammation was active. Surprisingly, the mice regained their original weight along with the progression of colitis, and the only apparent symptom was loose feces. Histopathological changes 4 wk after DSS removal were dense infiltrates of mononuclear cells, irregular epithelial structure, and persistent deposits of collagen. A progressive production of the cytokines IL-1beta, IL-12 p70, and IL-17 correlated with the extensive cellular infiltration, whereas high IFN-gamma production was mainly found late in the chronic phase. Similar to C57BL/6 mice, BALB/c mice exposed to 5 days of DSS developed acute colitis as previously described. The acute colitis was accompanied by elevated plasma levels of haptoglobin and increased colonic levels of IL-1alpha/beta, IL-6, IL-18, and granulocyte colony-stimulating factor. However, soon after DSS removal, BALB/c mice recovered and were symptom free within 2 wk and completely recovered 4 wk after DSS removal in terms of histopathology, haptoglobin levels, and local cytokine production. In summary, these data stress the effect of genetic background on the outcome of DSS provocation. We believe that the present protocol to induce chronic colitis in C57BL/6 mice offers a robust model for validating future therapies for treatment of inflammatory bowel disease.
- Published
- 2005
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49. Interference with CD28, CD80, CD86 or CD152 in collagen-induced arthritis. Limited role of IFN-gamma in anti-B7-mediated suppression of disease.
- Author
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Tellander AC, Pettersson U, Runström A, Andersson M, and Michaëlsson E
- Subjects
- Abatacept, Animals, Antibodies, Blocking pharmacology, Antibodies, Monoclonal administration & dosage, B7-2 Antigen, CD28 Antigens metabolism, CTLA-4 Antigen, Immunoglobulin G blood, Injections, Intraperitoneal, Lymphocyte Activation immunology, Male, Membrane Glycoproteins antagonists & inhibitors, Mice, Mice, Inbred BALB C, Mice, Inbred DBA, Signal Transduction immunology, T-Lymphocytes immunology, Antibodies, Monoclonal pharmacology, Antigens, CD immunology, Antigens, Differentiation immunology, Arthritis, Experimental immunology, B7-1 Antigen immunology, CD28 Antigens immunology, Collagen immunology, Immune Tolerance physiology, Immunoconjugates, Interferon-gamma physiology, Membrane Glycoproteins immunology
- Abstract
We have investigated interference with co-stimulation by administering mAbs towards CD28, CD80, CD86, and CD152 in mice immunized for the development of collagen-induced arthritis (CIA). Anti-CD80 and anti-CD86 treatment inhibited disease score and incidence, whereas anti-CD28 treatment led only to a delayed disease onset. Administration of anti-CD152 had no effect. The CII-specific Ab-response was suppressed by the co-stimulatory blockade, with a stronger effect on IgG1 than on IgG2a. The CII-driven T cell proliferation, on the other hand, was not affected. Furthermore, T cells primed in the presence of either anti-B7 or anti-CD28 produced markedly increased amounts of IFN-gamma in response to CII. To investigate whether this increase in IFN-gamma was related to disease suppression, IFN-gamma-deficient mice were immunized with CII, treated with anti-B7 and followed for the development of arthritis. As in the wild-type mice, administration of anti-B7 to IFN-gamma-deficient mice led to a reduced disease incidence and severity as well as reduced anti-CII IgG titers. Collectively, these data stress the importance of co-stimulation for the delivery of B cell help rather than for production of Th1 cytokines. We also demonstrate that the enhanced production of IFN-gamma observed after B7-blockade is not accountable for the anti-B7 mediated inhibition of CIA., (Copyright 2001 Academic Press.)
- Published
- 2001
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50. Potent adjuvant effect by anti-CD40 in collagen-induced arthritis. Enhanced disease is accompanied by increased production of collagen type-II reactive IgG2a and IFN-gamma.
- Author
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Tellander AC, Michaëlsson E, Brunmark C, and Andersson M
- Subjects
- Animals, Antibodies, Monoclonal pharmacology, Antibody Specificity, Antigens, CD biosynthesis, Antigens, CD immunology, Arthritis, Experimental immunology, B7-1 Antigen biosynthesis, B7-1 Antigen immunology, B7-2 Antigen, CD40 Antigens biosynthesis, Cattle, Freund's Adjuvant pharmacology, Immunization, Immunoglobulin G immunology, Male, Membrane Glycoproteins biosynthesis, Membrane Glycoproteins immunology, Mice, Mice, Inbred DBA, T-Lymphocytes immunology, T-Lymphocytes metabolism, Up-Regulation, Antibodies, Monoclonal immunology, Arthritis, Experimental metabolism, CD40 Antigens immunology, Collagen immunology, Immunoglobulin G biosynthesis, Interferon-gamma biosynthesis
- Abstract
Collagen type II-induced arthritis (CIA) is an experimental model of rheumatoid arthritis, an autoimmune inflammatory disease of the peripheral joints in humans. CD40 interaction with its ligand CD154 (CD40L) has been shown to be an obligatory step in the initiation of autoimmune disease in several animal models. In this study we report on the effect of CD40 stimulation in CIA induced by immunization with type II collagen (CII) in CFA or IFA. We found that the administration of stimulatory anti-CD40 mAb resulted in earlier onset and more severe disease in IFA-CII-immunized mice. The mAb treatment resulted in markedly elevated titers of CII-specific IgG2a antibodies whereas CII-specific IgG1 titers were unaffected. Draining lymph node cell cultures from mice treated with anti-CD40 exhibited significantly increased IFN-gamma production compared to cultures from control antibody-treated mice. In conclusion, our results indicate that the level of CD40 activation during the induction of an autoimmune response may determine the severity of the resulting disease.
- Published
- 2000
- Full Text
- View/download PDF
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