Field Of Inflammation Research Articles

HMG-CoA reductase inhibitors (statins), inflammation, and endothelial progenitor cells-New mechanistic insights of atherosclerosis.

Statins have been shown to favorably affect the prognosis of patients with risk factors to atherosclerosis-both as a primary and a secondary prevention. The beneficial effects observed with statin therapy are not merely related to changes in lipid profile but also are due to a positive effect on vascular inflammation and on immune-modulation of T lymphocytes and endothelial progenitor stem cells (EPCs). This dual effect has been demonstrated mainly in clinical trials where a change in endothelial function was observed within hours, much earlier than the effects of statins on the lipid profile (weeks). Based on all the knowledge that we have today questions were raised as to the mechanistic pathways that may explain the process of atherosclerosis and through this pathway to find better solutions and therapies to prevent and fight atherosclerosis. Our review will focus on the new updates in the field of inflammation and stem cells in vascular biology-in relation with atherosclerosis.

Of mice, men, and inflammation

In PNAS, Seok et al. advocate against relying on mouse models to study human inflammatory diseases, because genomic responses in human and mouse leukocytes correlate poorly (1). We fully agree with the conclusion of the authors that it is incorrect to believe “that molecular results from current mouse models developed to mimic human diseases translate directly to human conditions” (1). Several mouse studies—although yielding solid and interesting results—have been the victim of overinterpretation; for example, by extrapolating successful pretreatment in mice to therapeutic treatment in men. However, this aspect does not render these results useless. In the field of inflammation, valuable human therapies have been derived from mouse studies (e.g., anti-TNF treatment for rheumatoid arthritis and inflammatory bowel disease). In the field of sepsis, failure of the phase III clinical trial inhibiting NO synthases, which had to be terminated because of excess mortality, was actually predicted in assorted murine shock models (2).

The Immune System in Stroke: Clinical Challenges and Their Translation to Experimental Research

Stroke represents an unresolved challenge for both developed and developing countries and has a huge socio-economic impact. Although considerable effort has been made to limit stroke incidence and improve outcome, strategies aimed at protecting injured neurons in the brain have all failed. This failure is likely to be due to both the incompleteness of modelling the disease and its causes in experimental research, and also the lack of understanding of how systemic mechanisms lead to an acute cerebrovascular event or contribute to outcome. Inflammation has been implicated in all forms of brain injury and it is now clear that immune mechanisms profoundly influence (and are responsible for the development of) risk and causation of stroke, and the outcome following the onset of cerebral ischemia. Until very recently, systemic inflammatory mechanisms, with respect to common comorbidities in stroke, have largely been ignored in experimental studies. The main aim is therefore to understand interactions between the immune system and brain injury in order to develop novel therapeutic approaches. Recent data from clinical and experimental research clearly show that systemic inflammatory diseases -such as atherosclerosis, obesity, diabetes or infection - similar to stress and advanced age, are associated with dysregulated immune responses which can profoundly contribute to cerebrovascular inflammation and injury in the central nervous system. In this review, we summarize recent advances in the field of inflammation and stroke, focusing on the challenges of translation between pre-clinical and clinical studies, and potential anti-inflammatory/immunomodulatory therapeutic approaches.

Mapping the crossroads of immune activation and cellular stress response pathways

The innate immune cell network detects specific microbes and damages to cell integrity in order to coordinate and polarize the immune response against invading pathogens. In recent years, a cross-talk between microbial-sensing pathways and endoplasmic reticulum (ER) homeostasis has been discovered and have attracted the attention of many researchers from the inflammation field. Abnormal accumulation of proteins in the ER can be seen as a sign of cellular malfunction and triggers a collection of conserved emergency rescue pathways. These signalling cascades, which increase ER homeostasis and favour cell survival, are collectively known as the unfolded protein response (UPR). The induction or activation by microbial stimuli of several molecules linked to the ER stress response pathway have led to the conclusion that microbe sensing by immunocytes is generally associated with an UPR, which serves as a signal amplification cascade favouring inflammatory cytokines production. Induction of the UPR alone was shown to promote inflammation in different cellular and pathological models. Here we discuss how the innate immune and ER-signalling pathways intersect. Moreover, we propose that the induction of UPR-related molecules by microbial products does not necessarily reflect ER stress, but instead is an integral part of a specific transcription programme controlled by innate immunity receptors.

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Modern toxicology has embraced in vitro methods, and major hopes are based on the omics technologies and systems biology approaches they bring along (Hartung and McBride, 2011; Hartung et al., 2012). A culture of stringent validation has been developed for such approaches (Leist et al., 2010, 2012a,b), while the quality and usefulness of animal experiments have been little scrutinized. A new study (Seok et al., 2013) now shows the low predictivity of animal responses in the field of inflammation. These findings corroborate earlier findings from comparisons in the fields of neurodegeneration, stroke and sepsis. The low predictivity of animal experiments in research areas allowing direct comparisons of mouse versus human data puts strong doubt on the usefulness of animal data as key technology to predict human safety.

Inflammation, wound repair, and fibrosis: reassessing the spectrum of tissue injury and resolution

Estimates from various disease-specific registries suggest that chronic inflammatory and fibrotic disorders affect a large proportion of the world's population, yet therapies for these conditions are largely ineffective. Recent advances in our collective understanding of mechanisms underlying both physiological and pathological repair of tissue injury are informing new clinical approaches to deal with various human inflammatory and fibrotic diseases. This 2013 Annual Review Issue of The Journal of Pathology offers an up-to-date glimpse of ongoing research in the fields of inflammation, wound healing, and tissue fibrosis, and highlights novel pathways and mechanisms that may be exploited to provide newer, more effective treatments to patients worldwide suffering from these conditions.

Viewing Transplantation Immunology Through Today's Lens: New Models, New Imaging, and New Insights

The last several decades have brought significant immunologic advances in the fields of inflammation, infection, and transplantation tolerance. Heretofore, our understanding of how complex immune interactions occur has been limited to static in situ tissue analysis and in vitro dynamic studies using isolated cells devoid of stromal elements typically present in vivo. Recent advances in molecular, flow cytometry, and intravital imaging have provided new insight into the dynamic interactions occurring among a variety of cells within the bone marrow (BM) and immune systems, ranging from undifferentiated hematopoietic progenitors to fully committed effector memory cells, which will likely have direct clinical and translational implications. In this review we highlight how the application of these cutting-edge technologies will sculpt the landscape of the next generation of immunologic advances.

Winds of change in East Asia

With the increasing growth and development of the economies of countries in East Asia, it was inevitable that this would have repercussions on science publishing. Over the last decade, manuscript submissions to Inflammation Research from this part of the world have been increasing steadily. Currently, nearly 50% of published papers in the journal originate from countries in the region. East Asia has long been represented on the Editorial Board of Inflammation Research by Prof Makoto Katori. Dr Katori’s association with the journal extends back to the days when the journal was called Agents and Actions and he has been an Associate Editor for over 25 years. He has accompanied and helped mould many of the changes we have experienced, as the journal metamorphosed to become one of the leading journals in the field of inflammation. (This year we achieved an impact factor of 2.04). Undoubtedly, Dr Katori’s scientific reputation has facilitated the increasing use of the journal by researchers in East Asia. Dr Katori has now decided to relinquish his role as editor and to pass on the task to a younger scientist. The Editorial Board and publisher are very grateful for his conscientious and unstinting support over the many years and wish him all the very best. We now welcome to the Editorial Board Dr Ikuo Morita, Professor and Vice-President, Tokyo Medical and Dental University. Dr Morita is also the official representative on the Editorial Board of the Japanese Society of Inflammation and Regeneration (JSIR). With this appointment the journal is, therefore, more tightly associated with the JSIR, a major member of the International Association of Inflammation Societies (IAIS), for which Inflammation Research is the official publication organ. Like Dr Katori before him, Dr Morita is a globally recognized researcher in the field of vascular biology and inflammation and will be the journal expert for this area, as well as representing Japan and East Asia on the Editorial Board. We are very pleased to be joined by Dr Morita and hope that this will be a further incentive to submission of high quality manuscripts from the East. Inflamm. Res. (2011) 60:1081 DOI 10.1007/s00011-011-0391-9 Inflammation Research

Augmented plasma microparticles during acute Plasmodium vivax infection

BackgroundIn the last few years, the study of microparticles (MPs) - submicron vesicles released from cells upon activation or apoptosis - has gained growing interest in the field of inflammation and in infectious diseases. Their role in the human malaria parasite Plasmodium vivax remains unexplored. Because acute vivax malaria has been related to pro-inflammatory responses, the main hypothesis investigated in this study was that Plasmodium vivax infection is associated with elevated levels of circulating MPs, which may play a role during acute disease in non-immune patients.MethodsPlasma MPs were analysed among thirty-seven uncomplicated P. vivax infections from an area of unstable malaria transmission in the Brazilian Amazon. The MP phenotype was analysed by flow cytometry using the classical MP marker, annexin, and fluorochrome-labeled monoclonal antibodies against specific cell surface markers. The frequencies of plasma MPs in P. vivax patients (n = 37) were further compared to malaria-unexposed controls (n = 15) and ovarian carcinoma patients (n = 12), a known MPs-inducing disease non-related to malaria.ResultsThe frequencies of plasma circulating MPs were markedly increased in P. vivax patients, as compared to healthy age-matched malaria-unexposed controls. Although platelets, erythrocytes and leukocytes were the main cellular sources of MPs during vivax malaria, platelet derived-MPs (PMPs) increased in a linear fashion with the presence of fever at the time of blood collection (β = 0.06, p < 0.0001) and length of acute symptoms (β = 0.36, p < 0.0001). Finally, the results suggest that plasma levels of PMPs diminish as patient experience more episodes of clinical malaria (β = 0.07, p < 0.003).ConclusionsAbundant circulating MPs are present during acute P. vivax infection, and platelet derived-MPs may play a role on the acute inflammatory symptoms of malaria vivax.

The 2009 Stock Conference Report: Inflammation, Obesity and Metabolic Disease

Obesity is linked with many deleterious health consequences and is associated with increased risk of chronic disease including type 2 diabetes, atherosclerosis and certain forms of cancer. Recent work has highlighted the impact of obesity to activate inflammatory gene networks and suggests a causal function of inflammation in the pathogenesis of the metabolic syndrome. Since 2005, when Dr Gokhan Hotamisligil chaired the fourth Stock Conference in Istanbul, Turkey, entitled 'Obesity and Inflammation', there has been an explosion of studies investigating the relationship between obesity, inflammation and substrate metabolism. The exuberance surrounding this field of research is exemplified by the body of work that has been published in these past 4 years, including over 1400 publications. During this time, several novel mechanisms relating to cellular inflammation have been uncovered including the role of the hematopoietic system, toll-like receptor activation, endoplasmic reticulum stress and very recently T-cell activation in obesity-induced insulin resistance. These discoveries have led us to rethink cellular nutrient sensing and its role in inflammation and metabolic disease. Despite burgeoning investigation in this field, there still remain a number of unanswered questions. This review that evolved from the 2009 Stock Conference summarizes current research and identifies the deficiencies in our understanding of this topic. The overall goal of this Stock Conference was to bring together leading investigators in the field of inflammation and obesity research in the hope of fostering new ideas, thus advancing the pursuit of novel therapeutic strategies to reduce disease risk and or better treat chronic disease including type 2 diabetes, cardiovascular disease and cancer.

Major advances in the development of histamine H4 receptor ligands

The search for new and potent histamine H4 receptor ligands is leading to a steadily increasing number of scientific publications and patent applications. Several interesting and structurally diverse compounds have been found, but fierce IP competition for a preferred 2-aminopyrimidine scaffold is becoming apparent. Recent investigations into the role of the histamine H(4)R in (patho)physiology and the use of H4R ligands in in vivo disease models reveal enormous potential in the field of inflammation and allergy, among others. The development of ligands that display activity at two or more histamine receptor (HR) subtypes is another clinical opportunity that is currently being explored. Taken together, the histamine H4R field is gearing up for clinical studies and has the potential to deliver another generation of blockbuster drugs.

Correlating the phenotype of in vitro-polarized Th17 cells with expression of IL-17A and IL-17F (47.6)

Abstract The T-helper 17 (Th17) lineage has surfaced as a topic of great interest in the fields of inflammation and autoimmunity. The secretion of interleukin (IL)-17A and IL-17F has implicated these cells in many autoimmune diseases including rheumatoid arthritis, Crohn's disease, asthma and multiple sclerosis. IL-17A and IL-17F have been shown to form both homodimers and heterodimeric complexes. Characterization of the expression of these Th17 effector molecules together with surface proteins such as CCR6, CD161 and RORγt will be useful for studying further the role of Th17 cells in human disease. In this study, in vitro-polarized Th17 cells were analyzed for surface expression, secretion or intracellular expression of Th17-related proteins. Using an ELISA with minimal cross-reactivity to IL-17A/A and IL-17F/F, IL-17A/F was found to be a major product of in vitro-polarized Th17 cells. Furthermore, IL-17A/A expression was less than or equal to IL-17A/F, while IL-17F/F expression was consistently lower than IL-17A/A or IL-17A/F.

Novel targets for immunotherapy in glomerulonephritis

Glomerulonephritis is a common cause of chronic kidney disease and end stage renal failure. Current therapy relies on variably effective, nonspecific and toxic immunosuppression. Recent insights into underlying biology and disease pathogenesis in human glomerulonephritis combined with advances in the fields of inflammation and autoimmunity promise a cadre of novel targeted interventions. This review highlights the therapeutic potential of two antigens, alpha3 (IV)NC1 collagen and podocyte neutral endopeptidase, and two cell signaling and effector molecules, IgG Fc receptors and complement, judged to be particularly amenable to therapeutic manipulation in man. It is anticipated that continued dissection of pathogenesis in the diverse disorders that comprise the glomerulonephritides will provide the basis for individualized disease-specific therapy.

Synthesis and Characterization of Novel Quinazoline Type Inhibitors for Mutant and Wild-Type EGFR and RICK Kinases

The development of selective protein kinase inhibitors has become an important area of drug discovery for the treatment of different diseases. We report the synthesis and characterization of a series of novel quinazoline derivatives against three therapeutically important and pharmacologically related kinases: 1) epidermal growth factor receptor (EGFR; wild type and mutant) in the field of cancer, 2) receptor-interacting caspase-like apoptosis-regulatory kinase (RICK) in the field of inflammation, and 3) pUL97 of human cytomegalovirus (HCMV). For reference purpose we have synthesized the four clinically relevant quinazolines, including the lead compounds, which we previously identified for RICK and pUL97. A total of 52 quinazoline derivatives were synthesized and tested on the basis of these leads to specifically target the hydrophobic pocket of the ATP-binding site. Selected compounds were tested on wild-type and mutant forms of EGFR, RICK, and pUL97 kinases; their logP and logS values for assessing suitability as drugs were calculated and hit or lead compounds identified.

Mechanisms of sepsis-induced organ dysfunction.

The past several years have seen remarkable advances in understanding the basic cellular and physiologic mechanisms underlying organ dysfunction and recovery relating to sepsis. Although several new therapeutic approaches have improved outcome in septic patients, the far-reaching potential of these new insights into sepsis-associated mechanisms is only beginning to be realized. The Brussels Round Table Conference in 2006 convened >30 experts in the field of inflammation and sepsis to review recent advances involving sepsis and to discuss directions that the field is likely to take in the near future. Current understanding of the pathophysiology underlying sepsis-induced multiple organ dysfunction highlights the multiple cell populations and cell-signaling pathways involved in this complex condition. There is an increasing appreciation of interactions existing between different cells and organs affected by the septic process. The intricate cross-talk provided by temporal changes in mediators, hormones, metabolites, neural signaling, alterations in oxygen delivery and utilization, and by modifications in cell phenotypes underlines the adaptive and even coordinated processes beyond the dysregulated chaos in which sepsis was once perceived. Many pathologic processes previously considered to be detrimental are now viewed as potentially protective. Applying systems approaches to these complex processes will permit better appreciation of the effectiveness or harm of treatments, both present and future, and also will allow development not only of better directed, but also of more appropriately timed, strategies to improve outcomes from this still highly lethal condition.

Leukocyte Trafficking: Molecular Mechanisms, Therapeutic Targets, and Methods

This book fulfills a unique and important niche for investigators in the fields of inflammation, leukocyte biology, and immunology. The editors have assembled 23 chapters, which are for the most part authoritative in a range of topics from basic cell biology of leukocyte trafficking, receptors, transmigration, and molecular events through inflammatory mechanisms of chemotaxis and inflammation, and finally, use of these mechanisms in therapeutic targets and in clinical studies. The major strengths of the volume are the outstanding illustrations, both black and white and color plates, as well as an accompanying CD which shows the biologic events. The chapter authors were selected from international leaders in these fields. A further strength of the volume is the use of contemporary nomenclature for the complex processes of chemokines, cytokines, and their signaling pathways. Since this is a multiauthor book, there is unevenness to the various chapters, which is inevitable in a volume of this type. Nevertheless, in aggregate, it is a unique and outstanding contribution. The volume is highly recommended for students of inflammation and leukocytes, as well as investigators of host-parasite interaction. It is provides a wealth of information in this rapidly evolving field.

Nitric Oxide and Inflammation

There are several pre-clinical studies on the involvement of NO in inflammation. From this large amount of information it is clear that virtually every cell and many immunological parameters are modulated by NO. Thus, the final outcome is that NO cannot be rigidly classified as an anti-inflammatory or pro-inflammatory molecule. This peculiar aspect of the pathophysiology of NO has hampered the development of new drugs based on the concepts developed. Recent therapeutic approach are targeted to increase endogenous NO by activating the gene and some promising early data are available. At the present stage one of the most promising approach in the inflammation field is represented by a new class of NO-releasing compounds namely NO-NSAIDs that have recently enrolled in phase 2 clinical studies.

Effect of Inhibitors of Nitric Oxide in Animal Models and Future Directions for Therapy in Inflammatory Disorders

The aim of the current article is to overview the recent developments in the field of inflammation, as it relates to the roles of nitric oxide (NO) and peroxynitrite in the pathogenesis of this condition. The first part of the review focuses on the roles of NO and peroxynitrite, a reactive oxidant produced from the reaction of NO and superoxide. The second part of the review deals with the novel findings related to the recently identified regulatory roles of the inducible isoform of nitric oxide synthase (iNOS) in the expression of pro-inflammatory mediators in inflammation. Reactive oxygen species can initiate a wide range of toxic oxidative reactions. These include initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3phosphate dehydrogenase, inhibition of membrane sodium / potassium ATP-ase activity, inactivation of membrane sodium channels, and other oxidative modifications of proteins. All these toxicities are likely to play a role in the pathophysiology of inflammation. Reactive oxygen species (e.g., superoxide, peroxynitrite, hydroxyl radical and hydrogen peroxide) are all potential reactants capable of initiating DNA single strand breakage, with subsequent activation of the nuclear enzyme poly (ADP ribose) synthetase (PARS), leading to eventual severe energy depletion of the cells, and necrotic-type cell death. Recently, it has been demonstrated that iNOS inhibitor prevents the activation of poly (ADP ribose) synthetase, and prevents the organ injury associated with inflammation. Although the severity and duration of inflammation may dictate the timing and extent of NOS expression, it is now evident that the upregulation of NOS can take place during sustained inflammation. Pharmacological inhibition of iNOS or genetic inactivation of NOS (iNOS knockout mice) attenuates the activation of the transcription factors nuclear factor kappa B (NFKB) and Signal Transducer and Activator of Transcription 3 (STAT3), and ameliorates the increases in G-CSF messenger RNA levels in the tissue. Thus, induced nitric oxide, in addition to being a “final common mediator” of inflammation, is essential for the upregulation of the inflammatory response. Furthermore, a picture of a pathway is evolving that contributes to tissue damage both directly via the formation of peroxynitrite, with its associated toxicities, and indirectly through the amplification of the inflammatory response. Keywords: toxicities, G-CSF messenger RNA, ADP ribose, iNOS inhibitor

Chemokines and their receptors in asthma and chronic obstructive pulmonary disease.

Recruitment of inflammatory cells into the airways is a critical event that triggers and sustains the clinical manifestations of asthma and chronic obstructive pulmonary disease. Since the identification of the family of chemotactic cytokines, known as chemokines, as critical regulators of cell trafficking in the immune system, these molecules have come to the center stage in the field of inflammation and immunity. The goal of this article will be to summarize the recent developments in our understanding of the complex role that chemokines play in the pathogenesis of asthma and COPD.

The regulation of sulphurated amino acid junctions: fact or fiction in the field of inflammation?

The diet of industrialised countries is usually rich in amino acids, which are in part used as a source of calories. However, metabolic alterations are observed in diseased patients and a preferential retention of Sulphurated Amino Acids (SAA) occurs during the inflammatory response. Moreover, it has been demonstrated in a model of an acute sepsis phase of rats that the metabolism of Cysteine is modified. The liver converts Cysteine at a different ratio of Sulphate to Taurine (Tau) i.e. the sulphate production decreases while the Tau conversion increases. The Glutathione (GSH) concentration is greater in the liver, kidneys and other organs and the Cysteine incorporation into proteins is higher in the spleen, lungs and plasma (Acute Phase Proteins) while the Albumin level decreases. The pro-inflammatory cytokines such as Interleukin-1, Interleukin-6 and TNF- alpha are the main initiators that alter protein and amino acid metabolism. Another important phenomenon is the impairment of Methionine conversion to Cysteine during stress. For example, premature infants or AIDS patients are capable of synthesizing Cysteine from Methionine at a much lower rate. Thus, the metabolic flow through the trans-sulphuration path may be inadequate to meet the Cysteine demand under critical conditions. In this complex picture, an SAA supply may contribute to an immune system regulation.