Search

Your search keyword '"Timoteo Marchini"' showing total 22 results
Start Over Author "Timoteo Marchini" Language english
22 results on '"Timoteo Marchini"'

1. Serotonin transporter-deficient mice display enhanced adipose tissue inflammation after chronic high-fat diet feeding

Author

Johannes Hoch, Niklas Burkhard, Shanshan Zhang, Marina Rieder, Timoteo Marchini, Vincent Geest, Krystin Krauel, Timm Zahn, Nicolas Schommer, Muataz Ali Hamad, Carolina Bauer, Nadine Gauchel, Daniela Stallmann, Claus Normann, Dennis Wolf, Rüdiger Eberhard Scharf, Daniel Duerschmied, and Nancy Schanze

Subjects
serotonin, metabolic syndrome, obesity, adipose tissue, inflammation, serotonin transporter, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionSerotonin is involved in leukocyte recruitment during inflammation. Deficiency of the serotonin transporter (SERT) is associated with metabolic changes in humans and mice. A possible link and interaction between the inflammatory effects of serotonin and metabolic derangements in SERT-deficient mice has not been investigated so far.MethodsSERT-deficient (Sert-/-) and wild type (WT) mice were fed a high-fat diet, starting at 8 weeks of age. Metabolic phenotyping (metabolic caging, glucose and insulin tolerance testing, body and organ weight measurements, qPCR, histology) and assessment of adipose tissue inflammation (flow cytometry, histology, qPCR) were carried out at the end of the 19-week high-fat diet feeding period. In parallel, Sert-/- and WT mice received a control diet and were analyzed either at the time point equivalent to high-fat diet feeding or as early as 8-11 weeks of age for baseline characterization.ResultsAfter 19 weeks of high-fat diet, Sert-/- and WT mice displayed similar whole-body and fat pad weights despite increased relative weight gain due to lower starting body weight in Sert-/-. In obese Sert-/- animals insulin resistance and liver steatosis were enhanced as compared to WT animals. Leukocyte accumulation and mRNA expression of cytokine signaling mediators were increased in epididymal adipose tissue of obese Sert-/- mice. These effects were associated with higher adipose tissue mRNA expression of the chemokine monocyte chemoattractant protein 1 and presence of monocytosis in blood with an increased proportion of pro-inflammatory Ly6C+ monocytes. By contrast, Sert-/- mice fed a control diet did not display adipose tissue inflammation.DiscussionOur observations suggest that SERT deficiency in mice is associated with inflammatory processes that manifest as increased adipose tissue inflammation upon chronic high-fat diet feeding due to enhanced leukocyte recruitment.

Published
2023
Full Text
View/download PDF

2. Circulating Autoantibodies Recognizing Immunodominant Epitopes From Human Apolipoprotein B Associate With Cardiometabolic Risk Factors, but Not With Atherosclerotic Disease

Author

Timoteo Marchini, Sara Malchow, Lourdes Caceres, Abed Al Hadi El Rabih, Sophie Hansen, Timothy Mwinyella, Lisa Spiga, Sven Piepenburg, Hauke Horstmann, Tijani Olawale, Xiaowei Li, Lucia Sol Mitre, Mark Colin Gissler, Heiko Bugger, Andreas Zirlik, Timo Heidt, Ingo Hilgendorf, Peter Stachon, Constantin von zur Muehlen, Christoph Bode, and Dennis Wolf

Subjects
atherosclerosis, cardiovascular disease, ApoB, auto-antibodies, immunity, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

RationaleAtherosclerosis is a chronic inflammatory disease of large arteries that involves an autoimmune response with autoreactive T cells and auto-antibodies recognizing Apolipoprotein B (ApoB), the core protein of low-density lipoprotein (LDL). Here, we aimed to establish a clinical association between circulating human ApoB auto-antibodies with atherosclerosis and its clinical risk factors using a novel assay to detect auto-antibodies against a pool of highly immunogenic ApoB-peptides.Methods and ResultsTo detect polyclonal IgM- and IgG-antibodies recognizing ApoB, we developed a chemiluminescent sandwich ELISA with 30 ApoB peptides selected by an in silico assay for a high binding affinity to MHC-II, which cover more than 80% of known MHC-II variants in a Caucasian population. This pre-selection of immunogenic self-peptides accounted for the high variability of human MHC-II, which is fundamental to allow T cell dependent generation of IgG antibodies. We quantified levels of ApoB-autoantibodies in a clinical cohort of 307 patients that underwent coronary angiography. Plasma anti-ApoB IgG and IgM concentrations showed no differences across healthy individuals (n = 67), patients with coronary artery disease (n = 179), and patients with an acute coronary syndrome (n = 61). However, plasma levels of anti-ApoB IgG, which are considered pro-inflammatory, were significantly increased in patients with obesity (p = 0.044) and arterial hypertension (p < 0.0001). In addition, patients diagnosed with the metabolic syndrome showed significantly elevated Anti-ApoB IgG (p = 0.002). Even when normalized for total plasma IgG, anti-ApoB IgG remained highly upregulated in hypertensive patients (p < 0.0001). We observed no association with triglycerides, total cholesterol, VLDL, or LDL plasma levels. However, total and normalized anti-ApoB IgG levels negatively correlated with HDL. In contrast, total and normalized anti-ApoB IgM, that have been suggested as anti-inflammatory, were significantly lower in diabetic patients (p = 0.012) and in patients with the metabolic syndrome (p = 0.005).ConclusionUsing a novel ELISA method to detect auto-antibodies against ApoB in humans, we show that anti-ApoB IgG associate with cardiovascular risk factors but not with the clinical appearance of atherosclerosis, suggesting that humoral immune responses against ApoB are shaped by cardiovascular risk factors but not disease status itself. This novel tool will be helpful to develop immune-based risk stratification for clinical atherosclerosis in the future.

Published
2022
Full Text
View/download PDF

3. The Role of Tumor Necrosis Factor Associated Factors (TRAFs) in Vascular Inflammation and Atherosclerosis

Author

Mark Colin Gissler, Peter Stachon, Dennis Wolf, and Timoteo Marchini

Subjects
TRAF, atherosclerosis, immunity, inflammation, TNF, signaling, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

TNF receptor associated factors (TRAFs) represent a family of cytoplasmic signaling adaptor proteins that regulate, bundle, and transduce inflammatory signals downstream of TNF- (TNF-Rs), interleukin (IL)-1-, Toll-like- (TLRs), and IL-17 receptors. TRAFs play a pivotal role in regulating cell survival and immune cell function and are fundamental regulators of acute and chronic inflammation. Lately, the inhibition of inflammation by anti-cytokine therapy has emerged as novel treatment strategy in patients with atherosclerosis. Likewise, growing evidence from preclinical experiments proposes TRAFs as potent modulators of inflammation in atherosclerosis and vascular inflammation. Yet, TRAFs show a highly complex interplay between different TRAF-family members with partially opposing and overlapping functions that are determined by the level of cellular expression, concomitant signaling events, and the context of the disease. Therefore, inhibition of specific TRAFs may be beneficial in one condition and harmful in others. Here, we carefully discuss the cellular expression and signaling events of TRAFs and evaluate their role in vascular inflammation and atherosclerosis. We also highlight metabolic effects of TRAFs and discuss the development of TRAF-based therapeutics in the future.

Published
2022
Full Text
View/download PDF

4. Inflammatory Cell Recruitment in Cardiovascular Disease

Author

Timoteo Marchini, Lucía Sol Mitre, and Dennis Wolf

Subjects
atherosclerosis, myocardial infarction, recruitment, leukocyte, selectin, integrin, Biology (General), QH301-705.5
Abstract

Atherosclerosis, the main underlying pathology for myocardial infarction and stroke, is a chronic inflammatory disease of middle-sized to large arteries that is initiated and maintained by leukocytes infiltrating into the subendothelial space. It is now clear that the accumulation of pro-inflammatory leukocytes drives progression of atherosclerosis, its clinical complications, and directly modulates tissue-healing in the infarcted heart after myocardial infarction. This inflammatory response is orchestrated by multiple soluble mediators that enhance inflammation systemically and locally, as well as by a multitude of partially tissue-specific molecules that regulate homing, adhesion, and transmigration of leukocytes. While numerous experimental studies in the mouse have refined our understanding of leukocyte accumulation from a conceptual perspective, only a few anti-leukocyte therapies have been directly validated in humans. Lack of tissue-tropism of targeted factors required for leukocyte accumulation and unspecific inhibition strategies remain the major challenges to ultimately translate therapies that modulate leukocytes accumulation into clinical practice. Here, we carefully describe receptor and ligand pairs that guide leukocyte accumulation into the atherosclerotic plaque and the infarcted myocardium, and comment on potential future medical therapies.

Published
2021
Full Text
View/download PDF

5. Role of Mitochondria in the Redox Signaling Network and Its Outcomes in High Impact Inflammatory Syndromes

Author

Natalia D. Magnani, Timoteo Marchini, Valeria Calabró, Silvia Alvarez, and Pablo Evelson

Subjects
mitochodria, inflammation, oxidative stress, environmental pollution, reactive oxygen species, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Inflammation is associated with the release of soluble mediators that drive cellular activation and migration of inflammatory leukocytes to the site of injury, together with endothelial expression of adhesion molecules, and increased vascular permeability. It is a stepwise tightly regulated process that has been evolved to cope with a wide range of different inflammatory stimuli. However, under certain physiopathological conditions, the inflammatory response overwhelms local regulatory mechanisms and leads to systemic inflammation that, in turn, might affect metabolism in distant tissues and organs. In this sense, as mitochondria are able to perceive signals of inflammation is one of the first organelles to be affected by a dysregulation in the systemic inflammatory response, it has been associated with the progression of the physiopathological mechanisms. Mitochondria are also an important source of ROS (reactive oxygen species) within most mammalian cells and are therefore highly involved in oxidative stress. ROS production might contribute to mitochondrial damage in a range of pathologies and is also important in a complex redox signaling network from the organelle to the rest of the cell. Therefore, a role for ROS generated by mitochondria in regulating inflammatory signaling was postulated and mitochondria have been implicated in multiple aspects of the inflammatory response. An inflammatory condition that affects mitochondrial function in different organs is the exposure to air particulate matter (PM). Both after acute and chronic pollutants exposure, PM uptake by alveolar macrophages have been described to induce local cell activation and recruitment, cytokine release, and pulmonary inflammation. Afterwards, inflammatory mediators have been shown to be able to reach the bloodstream and induce a systemic response that affects metabolism in distant organs different from the lung. In this proinflammatory environment, impaired mitochondrial function that leads to bioenergetic dysfunction and enhanced production of oxidants have been shown to affect tissue homeostasis and organ function. In the present review, we aim to discuss the latest insights into the cellular and molecular mechanisms that link systemic inflammation and mitochondrial dysfunction in different organs, taking the exposure to air pollutants as a case model.

Published
2020
Full Text
View/download PDF

6. A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense

Author

Dennis Wolf, Nathaly Anto-Michel, Hermann Blankenbach, Ansgar Wiedemann, Konrad Buscher, Jan David Hohmann, Bock Lim, Marina Bäuml, Alex Marki, Maximilian Mauler, Daniel Duerschmied, Zhichao Fan, Holger Winkels, Daniel Sidler, Philipp Diehl, Dirk M Zajonc, Ingo Hilgendorf, Peter Stachon, Timoteo Marchini, Florian Willecke, Maximilian Schell, Björn Sommer, Constantin von zur Muhlen, Jochen Reinöhl, Teresa Gerhardt, Edward F. Plow, Valentin Yakubenko, Peter Libby, Christoph Bode, Klaus Ley, Karlheinz Peter, and Andreas Zirlik

Subjects
Science
Abstract

Integrin-based therapeutics could block inflammatory processes but they also impair host defence, limiting their usefulness. Here the authors report an anti-Mac1 antibody that blocks its interaction with pro-inflammatory ligand CD40L but not other ligands, and show that it can protect against sepsis in mice.

Published
2018
Full Text
View/download PDF

7. ApoB-Specific CD4+ T Cells in Mouse and Human Atherosclerosis

Author

Timoteo Marchini, Sophie Hansen, and Dennis Wolf

Subjects
atherosclerosis, immunity, autoimmunity, apolipoprotein B, LDL, T cells, Cytology, QH573-671
Abstract

Atherosclerosis is a chronic inflammatory condition of the arterial wall that leads to the formation of vessel-occluding plaques within the subintimal space of middle-sized and larger arteries. While traditionally understood as a myeloid-driven lipid-storage disease, growing evidence suggests that the accumulation of low-density lipoprotein cholesterol (LDL-C) ignites an autoimmune response with CD4+ T-helper (TH) cells that recognize self-peptides from Apolipoprotein B (ApoB), the core protein of LDL-C. These autoreactive CD4+ T cells home to the atherosclerotic plaque, clonally expand, instruct other cells in the plaque, and induce clinical plaque instability. Recent developments in detecting antigen-specific cells at the single cell level have demonstrated that ApoB-reactive CD4+ T cells exist in humans and mice. Their phenotypes and functions deviate from classical immunological concepts of distinct and terminally differentiated TH immunity. Instead, ApoB-specific CD4+ T cells have a highly plastic phenotype, can acquire several, partially opposing and mixed transcriptional programs simultaneously, and transit from one TH subset into another over time. In this review, we highlight adaptive immune mechanisms in atherosclerosis with a focus on CD4+ T cells, introduce novel technologies to detect ApoB-specific CD4+ T cells at the single cell level, and discuss the potential impact of ApoB-driven autoimmunity in atherosclerosis.

Published
2021
Full Text
View/download PDF

9. Deficiency of Endothelial CD40 Induces a Stable Plaque Phenotype and Limits Inflammatory Cell Recruitment to Atherosclerotic Lesions in Mice

Author

Peter Stachon, C Wadle, Xiaowei Li, Christian Weber, Natalie Hoppe, Florian Willecke, Andreas Zirlik, Constantin von zur Mühlen, Dennis Wolf, Timoteo Marchini, Norbert Gerdes, Mark Colin Gissler, Esther Lutgens, Lucia Sol Mitre, Carmen Härdtner, Josef Madl, Lisa Füner, Ingo Hilgendorf, Christoph Bode, Nathaly Anto Michel, Philipp Scherrer, Jan Pennig, Medical Biochemistry, ACS - Atherosclerosis & ischemic syndromes, AII - Inflammatory diseases, Biochemie, and RS: Carim - B01 Blood proteins & engineering

Subjects
Male, 0301 basic medicine, Apolipoprotein E, Pathology, Vascular smooth muscle, P-selectin, MONOCLONAL-ANTIBODY, Mice, Knockout, ApoE, Apoptosis, FUNCTIONAL CD40, 030204 cardiovascular system & hematology, ADHESION, Monocytes, 0302 clinical medicine, CD40, Macrophage, CD40L, Aorta, Cells, Cultured, biology, Chemistry, hemic and immune systems, Hematology, Intercellular Adhesion Molecule-1, Intercellular adhesion molecule, Plaque, Atherosclerotic, Chemotaxis, Leukocyte, medicine.symptom, Intravital microscopy, Signal Transduction, EXPRESSION, medicine.medical_specialty, Aortic Diseases, LOW-DENSITY-LIPOPROTEIN, INHIBITION, Vascular Cell Adhesion Molecule-1, Inflammation, 03 medical and health sciences, Cell Adhesion, medicine, Animals, Humans, CD40 Antigens, Macrophages, P-SELECTIN, Endothelial Cells, Coculture Techniques, VASCULAR SMOOTH-MUSCLE, Disease Models, Animal, 030104 developmental biology, inflammation, plaque phenotype, biology.protein, T-CELLS, LIGAND, atherosclerosis
Abstract

Objectives The co-stimulatory CD40L–CD40 dyad exerts a critical role in atherosclerosis by modulating leukocyte accumulation into developing atherosclerotic plaques. The requirement for cell-type specific expression of both molecules, however, remains elusive. Here, we evaluate the contribution of CD40 expressed on endothelial cells (ECs) in a mouse model of atherosclerosis. Methods and Results Atherosclerotic plaques of apolipoprotein E-deficient (Apoe −/− ) mice and humans displayed increased expression of CD40 on ECs compared with controls. To interrogate the role of CD40 on ECs in atherosclerosis, we induced EC-specific (BmxCreERT2-driven) deficiency of CD40 in Apoe −/− mice. After feeding a chow diet for 25 weeks, EC-specific deletion of CD40 (iEC-CD40) ameliorated plaque lipid deposition and lesional macrophage accumulation but increased intimal smooth muscle cell and collagen content, while atherosclerotic lesion size did not change. Leukocyte adhesion to the vessel wall was impaired in iEC-CD40-deficient mice as demonstrated by intravital microscopy. In accord, expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) in the vascular endothelium declined after deletion of CD40. In vitro, antibody-mediated inhibition of human endothelial CD40 significantly abated monocyte adhesion on ECs. Conclusion Endothelial deficiency of CD40 in mice promotes structural features associated with a stable plaque phenotype in humans and decreases leukocyte adhesion. These results suggest that endothelial-expressed CD40 contributes to inflammatory cell migration and consecutive plaque formation in atherogenesis.

Published
2021

10. Role of Mitochondria in the Redox Signaling Network and Its Outcomes in High Impact Inflammatory Syndromes

Author

Pablo Evelson, Natalia Magnani, Valeria Calabró, Silvia Alvarez, and Timoteo Marchini

Subjects
0301 basic medicine, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Inflammation, Environmental pollution, Review, Mitochondrion, Systemic inflammation, medicine.disease_cause, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Proinflammatory cytokine, purl.org/becyt/ford/3.3 [https], 03 medical and health sciences, 0302 clinical medicine, Endocrinology, INFLAMMATION, mitochodria, Macrophages, Alveolar, medicine, Animals, Humans, REACTIVE OXYGEN SPECIES, OXIDATIVE STRESS, Tissue homeostasis, reactive oxygen species, Air Pollutants, lcsh:RC648-665, Chemistry, MITOCHODRIA, Cell biology, Mitochondria, Oxidative Stress, 030104 developmental biology, ENVIRONMENTAL POLLUTION, purl.org/becyt/ford/3 [https], medicine.symptom, environmental pollution, Inflammation Mediators, Cell activation, Oxidation-Reduction, Oxidative stress, Signal Transduction
Abstract

Inflammation is associated with the release of soluble mediators that drive cellular activation and migration of inflammatory leukocytes to the site of injury, together with endothelial expression of adhesion molecules, and increased vascular permeability. It is a stepwise tightly regulated process that has been evolved to cope with a wide range of different inflammatory stimuli. However, under certain physiopathological conditions, the inflammatory response overwhelms local regulatory mechanisms and leads to systemic inflammation that, in turn, might affect metabolism in distant tissues and organs. In this sense, as mitochondria are able to perceive signals of inflammation is one of the first organelles to be affected by a dysregulation in the systemic inflammatory response, it has been associated with the progression of the physiopathological mechanisms. Mitochondria are also an important source of ROS (reactive oxygen species) within most mammalian cells and are therefore highly involved in oxidative stress. ROS production might contribute to mitochondrial damage in a range of pathologies and is also important in a complex redox signaling network from the organelle to the rest of the cell. Therefore, a role for ROS generated by mitochondria in regulating inflammatory signaling was postulated and mitochondria have been implicated in multiple aspects of the inflammatory response. An inflammatory condition that affects mitochondrial function in different organs is the exposure to air particulate matter (PM). Both after acute and chronic pollutants exposure, PM uptake by alveolar macrophages have been described to induce local cell activation and recruitment, cytokine release, and pulmonary inflammation. Afterwards, inflammatory mediators have been shown to be able to reach the bloodstream and induce a systemic response that affects metabolism in distant organs different from the lung. In this proinflammatory environment, impaired mitochondrial function that leads to bioenergetic dysfunction and enhanced production of oxidants have been shown to affect tissue homeostasis and organ function. In the present review, we aim to discuss the latest insights into the cellular and molecular mechanisms that link systemic inflammation and mitochondrial dysfunction in different organs, taking the exposure to air pollutants as a case model. Fil: Magnani, Natalia Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química General e Inorgánica; Argentina Fil: Marchini, Timoteo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química General e Inorgánica; Argentina Fil: Calabró López, María Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química General e Inorgánica; Argentina Fil: Alvarez, Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Evelson, Pablo Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química General e Inorgánica; Argentina

Published
2020

11. A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense

Author

Karlheinz Peter, Valentin P. Yakubenko, Bock Lim, Philipp Diehl, Alex Marki, Klaus Ley, Björn Sommer, Jochen Reinöhl, Jan David Hohmann, Constantin von zur Mühlen, Maximilian Mauler, Peter Stachon, Ansgar Wiedemann, Holger Winkels, Daniel Duerschmied, Peter Libby, Dirk M. Zajonc, Andreas Zirlik, Daniel Sidler, Florian Willecke, Zhichao Fan, Maximilian Schell, Marina Bäuml, Nathaly Anto-Michel, Ingo Hilgendorf, Christoph Bode, Teresa Gerhardt, Dennis Wolf, Timoteo Marchini, Konrad Buscher, Hermann Blankenbach, and Edward F. Plow

Subjects
0301 basic medicine, Male, Neutrophils, General Physics and Astronomy, Integrin, 030204 cardiovascular system & hematology, 0302 clinical medicine, Leukocytes, Medicine, Molecular Targeted Therapy, lcsh:Science, Multidisciplinary, biology, Antibodies, Monoclonal, purl.org/becyt/ford/3.1 [https], 3. Good health, Medicina Básica, Host-Pathogen Interactions, purl.org/becyt/ford/3 [https], medicine.symptom, CIENCIAS MÉDICAS Y DE LA SALUD, Phagocytosis, Science, Intercellular Adhesion Molecule-1, CD40 Ligand, Inmunología, Macrophage-1 Antigen, Inflammation, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, In vivo, Sepsis, Animals, Humans, Innate immune system, Binding Sites, business.industry, General Chemistry, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Mac-1, Macrophage-1 antigen, biology.protein, Cancer research, lcsh:Q, business, Cytokine storm
Abstract

Integrin-based therapeutics have garnered considerable interest in the medical treatment of inflammation. Integrins mediate the fast recruitment of monocytes and neutrophils to the site of inflammation, but are also required for host defense, limiting their therapeutic use. Here, we report a novel monoclonal antibody, anti-M7, that specifically blocks the interaction of the integrin Mac-1 with its pro-inflammatory ligand CD40L, while not interfering with alternative ligands. Anti-M7 selectively reduces leukocyte recruitment in vitro and in vivo. In contrast, conventional anti-Mac-1 therapy is not specific and blocks a broad repertoire of integrin functionality, inhibits phagocytosis, promotes apoptosis, and fuels a cytokine storm in vivo. Whereas conventional anti-integrin therapy potentiates bacterial sepsis, bacteremia, and mortality, a ligand-specific intervention with anti-M7 is protective. These findings deepen our understanding of ligand-specific integrin functions and open a path for a new field of ligand-targeted anti-integrin therapy to prevent inflammatory conditions., Integrin-based therapeutics could block inflammatory processes but they also impair host defence, limiting their usefulness. Here the authors report an anti-Mac1 antibody that blocks its interaction with pro-inflammatory ligand CD40L but not other ligands, and show that it can protect against sepsis in mice.

Published
2018

12. Platelet Serotonin Aggravates Myocardial Ischemia/Reperfusion Injury via Neutrophil Degranulation

Author

Christoph Koentges, Tim Lämmermann, Korbinian Kienle, Claudia Schoenichen, Daniel Duerschmied, Ludwig Dorner, Benoît Ho-Tin-Noé, Carmen Härdtner, Daniela Stallmann, Claus Normann, Ingo Ahrens, Véronique Ollivier, Paul Walther, Klaus Ley, Maximilian Mauler, Heiko Bugger, Maximilian Schell, Christopher Wippel, Ingo Hilgendorf, Christoph Bode, Dennis Wolf, Thilo Witsch, Timoteo Marchini, and Nadine Herr

Subjects
Inflammation, 030204 cardiovascular system & hematology, Pharmacology, Article, 03 medical and health sciences, 0302 clinical medicine, INFLAMMATION, Physiology (medical), purl.org/becyt/ford/3.2 [https], medicine, Platelet, REACTIVE OXYGEN SPECIES, REPERFUSION INJURY, Thrombus, NEUTROPHILS, 030304 developmental biology, 0303 health sciences, business.industry, SEROTONIN, Degranulation, medicine.disease, INTEGRINS, Hemostasis, Neutrophil degranulation, purl.org/becyt/ford/3 [https], Serotonin, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Reperfusion injury, BLOOD PLATELETS
Abstract

Background: Platelets store large amounts of serotonin that they release during thrombus formation or acute inflammation. This facilitates hemostasis and modulates the inflammatory response. Methods: Infarct size, heart function, and inflammatory cell composition were analyzed in mouse models of myocardial reperfusion injury with genetic and pharmacological depletion of platelet serotonin. These studies were complemented by in vitro serotonin stimulation assays of platelets and leukocytes in mice and men, and by measuring plasma serotonin levels and leukocyte activation in patients with acute coronary syndrome. Results: Platelet-derived serotonin induced neutrophil degranulation with release of myeloperoxidase and hydrogen peroxide (H2O2) and increased expression of membrane-bound leukocyte adhesion molecule CD11b, leading to enhanced inflammation in the infarct area and reduced myocardial salvage. In patients hospitalized with acute coronary syndrome, plasmatic serotonin levels correlated with CD11b expression on neutrophils and myeloperoxidase plasma levels. Long-term serotonin reuptake inhibition - reported to protect patients with depression from cardiovascular events - resulted in the depletion of platelet serotonin stores in mice. These mice displayed a reduction in neutrophil degranulation and preserved cardiac function. In line, patients with depression using serotonin reuptake inhibition, presented with suppressed levels of CD11b surface expression on neutrophils and lower myeloperoxidase levels in blood. Conclusions: Taken together, we identify serotonin as a potent therapeutic target in neutrophil-dependent thromboinflammation during myocardial reperfusion injury. Fil: Mauler, Maximilian. No especifíca; Fil: Herr, Nadine. No especifíca; Fil: Schoenichen, Claudia. No especifíca; Fil: Witsch, Thilo. No especifíca; Fil: Marchini, Timoteo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Härdtner, Carmen. No especifíca; Fil: Koentges, Christoph. No especifíca; Fil: Kienle, Korbinian. Max Planck Institute Of Immunobiology And Epigenetics; Alemania Fil: Ollivier, Véronique. Inserm; Francia Fil: Schell, Maximilian. No especifíca; Fil: Dorner, Ludwig. No especifíca; Fil: Wippel, Christopher. No especifíca; Fil: Stallmann, Daniela. No especifíca; Fil: Normann, Claus. No especifíca; Fil: Bugger, Heiko. No especifíca; Fil: Walther, Paul. Universitat Ulm; Alemania Fil: Wolf, Dennis. La Jolla Institute for Allergy and Immunology; Estados Unidos Fil: Ahrens, Ingo. No especifíca; Fil: Lämmermann, Tim. Max Planck Institute Of Immunobiology And Epigenetics; Alemania Fil: Ho-Tin-Noé, Benoît. Inserm; Francia Fil: Ley, Klaus. La Jolla Institute for Allergy and Immunology; Estados Unidos Fil: Bode, Christoph. No especifíca; Fil: Hilgendorf, Ingo. No especifíca; Fil: Duerschmied, Daniel. No especifíca

Published
2019

13. Mecanismos de protección miocárdica a distancia

Author

María A. Goyeneche, Martín Donato, Diamela T. Páez, Mariana Garcés, Timoteo Marchini, Virginia Pérez, Martín Grinspun, Julieta del Mauro, Christian Höcht, Pablo Evelson, and Ricardo J. Gelpi

Subjects
lcsh:Internal medicine, lcsh:Diseases of the circulatory (Cardiovascular) system, lcsh:Specialties of internal medicine, Precondicionamiento isquémico, lcsh:RC581-951, lcsh:RC666-701, Infarto del miocardio, lcsh:R, Protección miocárdica, lcsh:Medicine, lcsh:RC31-1245
Published
2016

14. Inflammatory pathways regulated by tumor necrosis receptor-associated factor 1 protect from metabolic consequences in diet-induced obesity

Author

Dennis Wolf, Natalie Hoppe, Florian Willecke, Timoteo Marchini, Roland Schüle, Akula Bala Pramod, Timo Heidt, Peter Stachon, Ingo Hilgendorf, Christoph Bode, Andreas Zirlik, Christian Colberg, Konrad Buscher, Erik Ehinger, Ulrich Kintscher, Katharina Pfeiffer, Dietmar Pfeifer, Nathaly Anto Michel, Sebastian Brachs, Klaus Ley, Bianca Dufner, Constantin von zur Mühlen, Dominik von Elverfeldt, and Björn Sommer

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Chemokine, CIENCIAS MÉDICAS Y DE LA SALUD, Physiology, Inmunología, Adipose tissue, Adipokine, Inflammation, Diet, High-Fat, Article, Proinflammatory cytokine, Mice, 03 medical and health sciences, chemistry.chemical_compound, Adipocyte, Internal medicine, Adipocytes, medicine, Animals, Obesity, Cells, Cultured, Uncoupling Protein 1, METABOLIC SYNDROME, biology, business.industry, Interleukin, Thermogenesis, Lipid Metabolism, TNF Receptor-Associated Factor 1, ADIPOCYTES, Mice, Inbred C57BL, MICE, Medicina Básica, 030104 developmental biology, Endocrinology, chemistry, OBESITY, biology.protein, Tumor necrosis factor alpha, Insulin Resistance, medicine.symptom, Cardiology and Cardiovascular Medicine, business, LIPOLYSIS
Abstract

Rationale: The coincidence of inflammation and metabolic derangements in obese adipose tissue has sparked the concept of met-inflammation. Previous observations, however, suggest that inflammatory pathways may not ultimately cause dysmetabolism. Objective: We have revisited the relationship between inflammation and metabolism by testing the role of TRAF (tumor necrosis receptor-associated factor)-1, an inhibitory adapter of inflammatory signaling of TNF (tumor necrosis factor)-a, IL (interleukin)-1ß, and TLRs (toll-like receptors). Methods and Results: Mice defcient for TRAF-1, which is expressed in obese adipocytes and adipose tissue lymphocytes, caused an expected hyperinflammatory phenotype in adipose tissue with enhanced adipokine and chemokine expression, increased leukocyte accumulation, and potentiated proinflammatory signaling in macrophages and adipocytes in a mouse model of diet-induced obesity. Unexpectedly, TRAF-1-/-mice were protected from metabolic derangements and adipocyte growth, failed to gain weight, and showed improved insulin resistance-an effect caused by increased lipid breakdown in adipocytes and UCP (uncoupling protein)-1-enabled thermogenesis. TRAF-1-dependent catabolic and proinflammatory cues were synergistically driven by ß3-adrenergic and inflammatory signaling and required the presence of both TRAF-1-defcient adipocytes and macrophages. In human obesity, TRAF-1-dependent genes were upregulated. Conclusions: Enhancing TRAF-1-dependent inflammatory pathways in a gain-of-function approach protected from metabolic derangements in diet-induced obesity. These fndings identify TRAF-1 as a regulator of dysmetabolism in mice and humans and question the pathogenic role of chronic inflammation in metabolism. Fil: Michel, Nathaly Anto. University of Freiburg. University Medical Center; Alemania Fil: Colberg, Christian. University of Freiburg. University Medical Center; Alemania Fil: Buscher, Konrad. La Jolla Institute for Allergy and Immunology; Estados Unidos Fil: Sommer, Björn. Universitat Erlangen-Nuremberg; Alemania Fil: Pramod, Akula Bala. La Jolla Institute for Allergy and Immunology; Estados Unidos Fil: Ehinger, Erik. La Jolla Institute for Allergy and Immunology; Estados Unidos Fil: Dufner, Bianca. University of Freiburg. University Medical Center; Alemania Fil: Hoppe, Natalie. University of Freiburg. University Medical Center; Alemania Fil: Pfeiffer, Katharina. University of Freiburg. University Medical Center; Alemania Fil: Marchini, Timoteo Oscar. University of Freiburg. University Medical Center; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Willecke, Florian. University of Freiburg. University Medical Center; Alemania Fil: Stachon, Peter. University of Freiburg. University Medical Center; Alemania Fil: Hilgendorf, Ingo. University of Freiburg. University Medical Center; Alemania Fil: Heidt, Timo. University of Freiburg. University Medical Center; Alemania Fil: Von Zur Muhlen, Constantin. University of Freiburg. University Medical Center; Alemania Fil: Von Elverfeldt, Dominik. University of Freiburg. University Medical Center; Alemania Fil: Pfeifer, Dietmar. University of Freiburg; Alemania Fil: Schüle, Roland. University of Freiburg; Alemania Fil: Kintscher, Ulrich. University of Freiburg; Alemania Fil: Brachs, Sebastian. Center For Cardiovascular Research; Alemania Fil: Ley, Klaus. La Jolla Institute for Allergy and Immunology; Estados Unidos Fil: Bode, Christoph. University of Freiburg. University Medical Center; Alemania Fil: Zirlik, Andreas. University of Freiburg. University Medical Center; Alemania Fil: Wolf, Dennis. La Jolla Institute for Allergy and Immunology; Estados Unidos

Published
2018
Full Text
View/download PDF

15. Induction of ABCG2/BCRP restricts the distribution of zidovudine to the fetal brain in rats

Author

Fernanda De Fino, Juan Mauricio Minoia, Guillermo Javier Copello, Maria Fernanda Filia, Timoteo Marchini, Modesto C. Rubio, Pablo Evelson, Roxana Noemi Peroni, and Martin Ignacio Roma

Subjects
0301 basic medicine, Farmacología y Farmacia, CIENCIAS MÉDICAS Y DE LA SALUD, Abcg2, Bioavailability, Anti-HIV Agents, Placenta, Biological Availability, Biology, Pharmacology, Toxicology, Fetal Brain, Rats, Sprague-Dawley, 03 medical and health sciences, Zidovudine, Fetus, Pregnancy, medicine, ATP Binding Cassette Transporter, Subfamily G, Member 2, Animals, heterocyclic compounds, virus diseases, Brain, Hiv, Gefitinib, purl.org/becyt/ford/3.1 [https], medicine.disease, Mitochondria, Rats, Mitochondrial toxicity, Medicina Básica, 030104 developmental biology, medicine.anatomical_structure, In utero, embryonic structures, Toxicity, biology.protein, Quinazolines, Gestation, Reverse Transcriptase Inhibitors, purl.org/becyt/ford/3 [https], Female, Lipid Peroxidation, medicine.drug
Abstract

Safety concerns for fetus development of zidovudine (AZT) administration as prophylaxis of vertical transmission of HIV persist. We evaluated the participation of the ATP-binding cassette efflux transporter ABCG2 in the penetration of AZT into the fetal brain and the relevance for drug safety. Oral daily doses of AZT (60 mg/kg body weight) or its vehicle were administered between post gestational days 11 (E11) and 20 (E20) to Sprague-Dawley pregnant rats. At E21, animals received an intravenous bolus of 60 mg AZT/kg body weight in the presence or absence of the ABCG2 inhibitor gefitinib (20 mg/kg body weight, ip) and AZT in maternal plasma and fetal brain were measured by HPLC-UV. ABCG2 protein expression in placenta and fetal brain, as well as mitochondrial function and ultrastructure in fetal brain were also analyzed. In utero chronic exposure to AZT markedly induced ABCG2 expression in placenta and fetal brain whereas did not significantly alter mitochondrial functionality in the fetal brain. The area-under-the-concentration-time-curve of AZT significantly decreased in fetal brains isolated from AZT-exposed fetuses compared to control group, but this effect was abolished by ABCG2 inhibition. Our results suggest that the absence of mitochondrial toxicity in the fetal brain after chronic in utero administration of AZT could be attributed to its low accumulation in the tissue caused, at least in part, by ABCG2 overexpression. We propose that any interference with ABCG2 activity due to genetic, pathological or iatrogenic factors would increase the amount of AZT reaching the fetal brain, which could increase the risk of toxicity of this drug on the tissue. Fil: Filia, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina Fil: Marchini, Timoteo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Minoia, Juan Mauricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina Fil: Roma, Martin Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina Fil: de Fino, Fernanda Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina Fil: Rubio, Modesto Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina Fil: Copello, Guillermo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; Argentina Fil: Evelson, Pablo Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Peroni, Roxana Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina

Published
2017

16. The role of mitochondria in inflammatory syndromes

Author

Tamara Vico, Virginia Vanasco, Silvia Alvarez, Pablo Evelson, Timoteo Marchini, Natalia Magnani, Mariana Garcés, Alejandro Guaglianone, and Lourdes Cáceres

Subjects
Otras Ciencias Biológicas, General Medicine, BIOENERGETICS, Mitochondrion, Biology, Cell biology, MITOCHONDRIAL FUNCTION, Ciencias Biológicas, purl.org/becyt/ford/1 [https], AMBIENT AIR PARTICLE, HEART, ENDOTOXEMIA, purl.org/becyt/ford/1.6 [https], CIENCIAS NATURALES Y EXACTAS
Abstract

Several authors have addressed the importance of mitochondrial function in inflammatory syndromes,as it may play a role in the genesis of tissue injury. Sepsis and exposition to environmental particles are examples of inflammatory conditions. Sepsis occurs with an exacerbated inflammatory response that damagestissue mitochondria and impairs bioenergetic processes. One of the current hypotheses for the molecular mechanisms underlying the complex condition of sepsis is that enhanced NO production and oxidative stress lead to mitochondrial dysfunction, bioenergetic derangement and organ failure. The mechanism of particulate matter-health effects are believed to involve inflammation and oxidative stress. Components in particles that elicit inflammation have been poorly investigated, although recent research points out to the contribution of compositional elements and particle size. Oxygen metabolism and mitochondrial function appear to be important areas of study in inflammatory conditions for clarifying molecular mechanisms involved. Fil: Vanasco, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Marchini, Timoteo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Magnani, Natalia Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Vico, Tamara Antonela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Garces, Mariana Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Cáseres, Lourdes. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Guaglianone, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Evelson, Pablo Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Alvarez, Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina

Published
2016

17. Selective TNF-α targeting with infliximab attenuates impaired oxygen metabolism and contractile function induced by an acute exposure to air particulate matter

Author

Mariela L. Paz, Mariana Garcés, Virginia Perez, Deborah R. Tasat, Pablo Evelson, Natalia Magnani, Lourdes Cáceres, Ricardo J. Gelpi, Verónica D'Annunzio, Daniel Horacio Gonzalez Maglio, Virginia Vanasco, Silvia Alvarez, and Timoteo Marchini

Subjects
Cardiac function curve, medicine.medical_specialty, Lusitropy, Physiology, Heart Ventricles, medicine.medical_treatment, Intraperitoneal injection, Inflammation, Systemic inflammation, Coal Ash, Mitochondria, Heart, Mice, purl.org/becyt/ford/3.3 [https], Oxygen Consumption, Physiology (medical), Internal medicine, Air Pollution, medicine, Animals, Saline, Tumor Necrosis Factor-alpha, business.industry, Myocardium, Isoproterenol, Isolated Heart Preparation, Heart, Adrenergic beta-Agonists, Myocardial Contraction, Infliximab, Endocrinology, medicine.anatomical_structure, Ventricle, Antirheumatic Agents, Female, Particulate Matter, Tumor necrosis factor alpha, purl.org/becyt/ford/3 [https], medicine.symptom, Cardiology and Cardiovascular Medicine, business, Residual Oil Fly Ash
Abstract

Inflammation plays a central role in the onset and progression of cardiovascular diseases associated with the exposure to air pollution particulate matter (PM). The aim of this work was to analyze the cardioprotective effect of selective TNF-α targeting with a blocking anti-TNF- α antibody (infliximab) in an in vivo mice model of acute exposure to residual oil fly ash (ROFA). Female Swiss mice received an intraperitoneal injection of infliximab (10 mg/kg body wt) or saline solution, and were intranasally instilled with a ROFA suspension (1 mg/kg body wt). Control animals were instilled with saline solution and handled in parallel. After 3 h, heart O2 consumption was assessed by high-resolution respirometry in left ventricle tissue cubes and isolated mitochondria, and ventricular contractile reserve and lusitropic reserve were evaluated according to the Langendorff technique. ROFA instillation induced a significant decrease in tissue O2 consumption and active mitochondrial respiration by 32 and 31%, respectively, compared with the control group. While ventricular contractile state and isovolumic relaxation were not altered in ROFA-exposed mice, impaired contractile reserve and lusitropic reserve were observed in this group. Infliximab pretreatment significantly attenuated the decrease in heart O2 consumption and prevented the decrease in ventricular contractile and lusitropic reserve in ROFA-exposed mice. Moreover, infliximab-pretreated ROFA-exposed mice showed conserved left ventricular developed pressure and cardiac O2 consumption in response to a β-adrenergic stimulus with isoproterenol. These results provides direct evidence linking systemic inflammation and altered cardiac function following an acute exposure to PM and contribute to the understanding of PM-associated cardiovascular morbidity and mortality. Fil: Marchini, Timoteo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: D'Anunzio, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Paz, Mariela Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; Argentina Fil: Caceres, Lourdes Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Garces, Mariana Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Perez, María Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Tasat, Deborah Ruth. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Vanasco, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Magnani, Natalia Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Gonzalez Maglio, Daniel Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; Argentina Fil: Gelpi, Ricardo Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Alvarez, Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Evelson, Pablo Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina

Published
2015
Full Text
View/download PDF

18. Time course of systemic oxidative stress and inflammatory response induced by an acute exposure to Residual Oil Fly Ash

Author

Natalia Magnani, Virginia Vanasco, D. H. González Maglio, Pablo Evelson, Mariela L. Paz, Deborah R. Tasat, Silvia Alvarez, and Timoteo Marchini

Subjects
medicine.medical_specialty, Antioxidant, CIENCIAS MÉDICAS Y DE LA SALUD, Neutrophils, medicine.medical_treatment, Ciencias de la Salud, Inflammation, Ascorbic Acid, Toxicology, Protein oxidation, medicine.disease_cause, Coal Ash, Thiobarbituric Acid Reactive Substances, Antioxidants, Protein Carbonylation, Superoxide dismutase, Mice, chemistry.chemical_compound, INFLAMMATION, PARTICULATE MATTER, Internal medicine, Administration, Inhalation, medicine, TBARS, Animals, OXIDATIVE STRESS, Lung, Pharmacology, biology, Interleukin-6, Superoxide Dismutase, Tumor Necrosis Factor-alpha, Chemistry, Heart, Glutathione, Ascorbic acid, Otras Ciencias de la Salud, Oxidative Stress, Endocrinology, AIR POLLUTION, Immunology, biology.protein, Female, ROFA, medicine.symptom, Oxidative stress
Abstract

It is suggested that systemic oxidative stress and inflammation play a central role in the onset and progression of cardiovascular diseases associated with the exposure to particulate matter (PM). The aim of this work was to evaluate the time changes of systemic markers of oxidative stress and inflammation, after an acute exposure to Residual Oil Fly Ash (ROFA). Female Swiss mice were intranasally instilled with a ROFA suspension (1.0 mg/kg body weight) or saline solution, and plasma levels of oxidative damage markers [thiobarbituric acid reactive substances (TBARS) and protein carbonyls], antioxidant status [reduced (GSH) and oxidized (GSSG) glutathione, ascorbic acid levels, and superoxide dismutase (SOD) activity], cytokines levels, and intravascular leukocyte activation were evaluated after 1, 3 or 5 h of exposure. Oxidative damage to lipids and decreased GSH/GSSG ratio was observed in ROFA-exposed mice as early as 1 h. Afterwards, increased protein oxidation, decreased ascorbic acid content and SOD activity was found in this group at 3 h. The onset of an adaptive response was observed at 5 h after the ROFA exposure, as indicated by decreased TBARS plasma content and increased SOD activity. The observed increase in oxidative damage to plasma macromolecules, together with systemic antioxidants depletion, may be a consequence of a systemic inflammatory response triggered by the ROFA exposure, since increased TNF-α and IL-6 plasma levels and polymorphonuclear leukocytes activation was found at every evaluated time point. These findings contribute to the understanding of the increase in cardiovascular morbidity and mortality, in association with environmental PM inhalation. Fil: Marchini, Timoteo Oscar. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Magnani, Natalia Daniela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Paz, Mariela Laura. Universidad de Buenos Aires. Facultad de Farmacia y Bioquimica. Departamento de Microbiologia,inmunologia y Biotecnolog.. Catedra de Inmunologia; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "Profesor R. A. Margni"; Argentina Fil: Vanasco, Virginia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Tasat, D.. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina Fil: Gonzalez Maglio, Daniel Horacio. Universidad de Buenos Aires. Facultad de Farmacia y Bioquimica. Departamento de Microbiologia,inmunologia y Biotecnolog.. Catedra de Inmunologia; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "Profesor R. A. Margni"; Argentina Fil: Alvarez, Silvia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Evelson, Pablo Andres. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; Argentina

Published
2014

19. Impaired cardiac mitochondrial function and contractile reserve following an acute exposure to environmental particulate matter

Author

Pablo Evelson, Verónica D'Annunzio, Ricardo J. Gelpi, Silvia Alvarez, Timoteo Marchini, Natalia Magnani, and Deborah R. Tasat

Subjects
medicine.medical_specialty, Cardiotonic Agents, CIENCIAS MÉDICAS Y DE LA SALUD, Residual oil fly ash (ROFA), Biophysics, Respiratory chain, Air pollution, Ciencias de la Salud, Salud Pública y Medioambiental, Mitochondrion, Biochemistry, Coal Ash, Mitochondria, Heart, Ciencias de la Tierra y relacionadas con el Medio Ambiente, Contractility, Electron Transport, Mice, Adenosine Triphosphate, Organ Culture Techniques, Oxygen Consumption, Internal medicine, Respiration, medicine, Animals, Molecular Biology, Administration, Intranasal, Membrane Potential, Mitochondrial, Air Pollutants, Inhalation, Chemistry, Isoproterenol, Depolarization, Heart, Metabolism, Myocardial Contraction, Endocrinology, Cardiovascular Alteration, Ciencias Medioambientales, Female, Particulate matter, CIENCIAS NATURALES Y EXACTAS
Abstract

BACKGROUND: It has been suggested that mitochondrial function plays a central role in cardiovascular diseases associated with particulate matter inhalation. The aim of this study was to evaluate this hypothesis, with focus on cardiac O2 and energetic metabolism, and its impact over cardiac contractility. METHODS: Swiss mice were intranasally instilled with either residual oil fly ash (ROFA) (1.0 mg/kg body weight) or saline solution. After 1, 3 or 5 h of exposure, O2 consumption was evaluated in heart tissue samples. Mitochondrial respiration, respiratory chain complexes activity, membrane potential and ATP content and production rate were assessed in isolated mitochondria. Cardiac contractile reserve was evaluated according to the Langendorff technique. RESULTS: Three hours after ROFA exposure, tissue O2 consumption was significantly decreased by 35% (from 1180 +/- 70 to 760 +/- 60 ng-at O/min g tissue), as well as mitochondrial rest (state 4) and active (state 3) respiration, by 30 and 24%, respectively (control state 4: 88 +/- 5 ng-at O/min mg protein; state 3: 240 +/- 20 ng-at O/min mg protein). These findings were associated with decreased complex II activity, mitochondrial depolarization and deficient ATP production. Even though basal contractility was not modified (control: 75 +/- 5 mm Hg), isolated perfused hearts failed to properly respond to isoproterenol in ROFA-exposed mice. Tissue O2 consumption rates positively correlated with cardiac contractile state in controls (r2 = 0.8271), but not in treated mice (r2 = 0.1396). GENERAL SIGNIFICANCE: The present results show an impaired mitochondrial function associated with deficient cardiac contractility, which could represent an early cardiovascular alteration after the exposure to environmental particulate matter. Fil: Marchini, Timoteo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Programa de Radicales Libres; Argentina Fil: Magnani, Natalia Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Programa de Radicales Libres; Argentina Fil: D'Annunzio, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina Fil: Tasat, Deborah Ruth. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina Fil: Gelpi, Ricardo Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina Fil: Alvarez, Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Programa de Radicales Libres; Argentina Fil: Evelson, Pablo Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Programa de Radicales Libres; Argentina

Published
2013

20. Modulating Autoimmunity against LDL: Development of a Vaccine against Atherosclerosis

Author

Timoteo Marchini, Tijani Abogunloko, and Dennis Wolf

Subjects
Vaccines, autoimmunity, T cells, Autoimmunität, Hematology, Review Article, vaccination, Atherosclerosis, Plaque, Atherosclerotic, Atherosklerose, Lipoproteins, LDL, Mice, Antikörper, antibodies, Impfung, Animals, T Zelle
Abstract

Atherosclerosis is a chronic inflammatory disease of the arterial wall that leads to the build-up of occluding atherosclerotic plaques. Its clinical sequelae, myocardial infarction and stroke, represent the most frequent causes of death worldwide. Atherosclerosis is a multifactorial pathology that involves traditional risk factors and chronic low-grade inflammation in the atherosclerotic plaque and systemically. This process is accompanied by a strong autoimmune response that involves autoreactive T cells in lymph nodes and atherosclerotic plaques, as well as autoantibodies that recognize low-density lipoprotein (LDL) and its main protein component apolipoprotein B (ApoB). In the past 60 years, numerous preclinical observations have suggested that immunomodulatory vaccination with LDL, ApoB, or its peptides has the potential to specifically dampen autoimmunity, enhance tolerance to atherosclerosis-specific antigens, and protect from experimental atherosclerosis in mouse models. Here, we summarize and discuss mechanisms, challenges, and therapeutic opportunities of immunomodulatory vaccination and other strategies to enhance protective immunity in atherosclerosis.Die Atherosklerose stellt eine chronisch entzündliche Erkrankung der Arterienwand dar, die zur Bildung von Gefäß-verengenden atherosklerotischen Plaques führt. Ihre klinischen Folgen, Herzinfarkt und Schlaganfall, repräsentieren die weltweit häufigsten Todesursachen. Der Erkrankung liegt ein multifaktorieller Krankheitsprozess zu Grunde, der traditionelle Risikofaktoren und eine chronische lokale und systemische Entzündungsreaktion umfasst. Die Entstehung der Atherosklerose wird von einer starken Autoimmunreaktion begleitet, an der autoreaktive T-Zellen in Lymphknoten und atherosklerotischen Plaques sowie Autoantikörper beteiligt sind, die gegen

Full Text
View/download PDF

21. Genetic Deficiency of TRAF5 Promotes Adipose Tissue Inflammation and Aggravates Diet-Induced Obesity in Mice

Author

Gunnar Mellgren, Dennis Wolf, Timoteo Marchini, Nathaly Anto-Michel, Katharina Pfeiffer, Lisa Spiga, Christian Smolka, Christoph Koentges, Carmen Härdtner, Timothy Mwinyella, Jan Pennig, Steffen U. Eisenhardt, Andreas Zirlik, Dominik von Elverfeldt, Xiaowei Li, Sven Piepenburg, Peter Stachon, Simon N. Dankel, Constantin von zur Mühlen, Natalie Hoppe, Florian Willecke, Jan-Inge Bjune, Ingo Hilgendorf, Christoph Bode, Timo Heidt, Philipp Scherrer, Tijani Abogunloko, Heiko Bugger, Mark Colin Gissler, Lucia Sol Mitre, Bianca Dufner, and Gabriel Seifert

Subjects
Adult, Male, medicine.medical_specialty, Chemokine, Panniculitis, Adipose tissue, Inflammation, Diet, High-Fat, Proinflammatory cytokine, Internal medicine, Adipocytes, medicine, Animals, Humans, Lymphocytes, Obesity, Macrophage inflammatory protein, Adiposity, Aged, Mice, Knockout, TNF Receptor-Associated Factor 5, biology, business.industry, Macrophages, Middle Aged, Stromal vascular fraction, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, Adipose Tissue, biology.protein, Cytokines, Female, Tumor necrosis factor alpha, Inflammation Mediators, medicine.symptom, Metabolic syndrome, Cardiology and Cardiovascular Medicine, business, Signal Transduction
Abstract

Objective: The accumulation of inflammatory leukocytes is a prerequisite of adipose tissue inflammation during cardiometabolic disease. We previously reported that a genetic deficiency of the intracellular signaling adaptor TRAF5 (TNF [tumor necrosis factor] receptor–associated factor 5) accelerates atherosclerosis in mice by increasing inflammatory cell recruitment. Here, we tested the hypothesis that an impairment of TRAF5 signaling modulates adipose tissue inflammation and its metabolic complications in a model of diet-induced obesity in mice. Approach and Results: To induce diet-induced obesity and adipose tissue inflammation, wild-type or Traf5 −/− mice consumed a high-fat diet for 18 weeks. Traf5 −/− mice showed an increased weight gain, impaired insulin tolerance, and increased fasting blood glucose. Weight of livers and peripheral fat pads was increased in Traf5 −/− mice, whereas lean tissue weight and growth were not affected. Flow cytometry of the stromal vascular fraction of visceral adipose tissue from Traf5 −/− mice revealed an increase in cytotoxic T cells, CD11c + macrophages, and increased gene expression of proinflammatory cytokines and chemokines. At the level of cell types, expression of TNFα, MIP (macrophage inflammatory protein)-1α, MCP (monocyte chemoattractant protein)-1, and RANTES (regulated on activation, normal T-cell expressed and secreted) was significantly upregulated in Traf5 -deficient adipocytes but not in Traf5 -deficient leukocytes from visceral adipose tissue. Finally, Traf5 expression was lower in adipocytes from obese patients and mice and recovered in adipose tissue of obese patients one year after bariatric surgery. Conclusions: We show that a genetic deficiency of TRAF5 in mice aggravates diet-induced obesity and its metabolic derangements by a proinflammatory response in adipocytes. Our data indicate that TRAF5 may promote anti-inflammatory and obesity-preventing signaling events in adipose tissue.

Full Text
View/download PDF

22. Inflammatory Cell Recruitment in Cardiovascular Disease

Author

Timoteo Marchini, Lucía Sol Mitre, and Dennis Wolf

Subjects
0301 basic medicine, Chemokine, integrin, medicine.medical_treatment, Mini Review, Inflammation, Disease, 030204 cardiovascular system & hematology, 03 medical and health sciences, Cell and Developmental Biology, 0302 clinical medicine, medicine, cytokine, Myocardial infarction, Receptor, selectin, lcsh:QH301-705.5, biology, business.industry, chemokine, Cell Biology, medicine.disease, 3. Good health, 030104 developmental biology, Cytokine, myocardial infarction, recruitment, lcsh:Biology (General), Immunology, biology.protein, medicine.symptom, atherosclerosis, business, leukocyte, Selectin, Developmental Biology, Homing (hematopoietic)
Abstract

Atherosclerosis, the main underlying pathology for myocardial infarction and stroke, is a chronic inflammatory disease of middle-sized to large arteries that is initiated and maintained by leukocytes infiltrating into the subendothelial space. It is now clear that the accumulation of pro-inflammatory leukocytes drives progression of atherosclerosis, its clinical complications, and directly modulates tissue-healing in the infarcted heart after myocardial infarction. This inflammatory response is orchestrated by multiple soluble mediators that enhance inflammation systemically and locally, as well as by a multitude of partially tissue-specific molecules that regulate homing, adhesion, and transmigration of leukocytes. While numerous experimental studies in the mouse have refined our understanding of leukocyte accumulation from a conceptual perspective, only a few anti-leukocyte therapies have been directly validated in humans. Lack of tissue-tropism of targeted factors required for leukocyte accumulation and unspecific inhibition strategies remain the major challenges to ultimately translate therapies that modulate leukocytes accumulation into clinical practice. Here, we carefully describe receptor and ligand pairs that guide leukocyte accumulation into the atherosclerotic plaque and the infarcted myocardium, and comment on potential future medical therapies.

Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results