Regulation Of Inflammation In Chronic Disease

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This book provides readers with the most up-to-date information on cutting-edge research concerning chronic inflammation. We now know that when inflammation becomes chronic, it acts as a strong disease-promoting factor in a variety of disorders including arteriosclerosis, obesity, cancer, and Alzheimer disease. Chronic inflammation is hence called as the “silent killer”; it upsets the body’s homeostatic mechanism insidiously. In spite of these developments, we know very little about the mechanism underlying chronic inflammation. Particularly, we do not know precisely what induces chronic inflammation or what promotes its prolongation in a spatiotemporal framework. Neither do we have clear knowledge about how chronic inflammation destroys various tissues or how it predisposes individuals to many different diseases. To make the situation worse, we have no effective treatment against chronic inflammation. Since 2010, two major research programs (CREST and PRESTO) aimed at clarifying the mechanisms underlying chronic inflammation were launched in Japan, and investigators of different research areas with a brilliant track record were selected by their research proposals. Subsequently they have made their best efforts to answer the conundrum concerning chronic inflammation. This book is a compendium of such research efforts. In each chapter, the CREST- or PRESTO-funded researchers summarize their original work concerning mechanisms of induction, progression, or resolution underlying chronic inflammation. The most emphasized characteristic is the molecular aspect of chronic inflammation. The book thus presents the most recent progress made in the molecular understanding of chronic inflammation.

Oxidative stress and inflammation are among the most important factors of disease. Chronic infections, obesity, alcohol and tobacco usage, radiation, environmental pollutants, and high-calorie diets have been recognized as major risk factors for a variety of chronic diseases from cancer to metabolic diseases. All these risk factors are linked to ch

Inflammation is a fundamental protective mechanism and at the same time the driving force of a variety of major diseases in humans. Indeed, acute self-resolving inflammation usually plays a positive role for the host, as exemplified by infectious diseases where its positive role is well established and testified by its perception as innate immunity. On the other hand, non-resolving inflammation and consequent chronicization is a key determinant of immunopathology and clinical manifestations of most major diseases in humans. As a consequence, it is increasing appreciated that the problem with inflammation is not how often it starts, but how often it fails to resolve. Appropriate resolution of inflammatory responses, which also drives activation of tissue damage repair mechanisms and return of local tissues to homeostasis, is a necessary process for ongoing health. Interestingly, cells sustaining these processes are also key to the proinflammatory responses, and the underlying “pro-resolving” molecular pathways are triggered as part of the pro-inflammatory response. This clearly indicates resolution of inflammation as an active process requiring functional repolarization of inflammatory cells that calls our attention on the underlying molecular mechanisms. The increasing number of anti-inflammatory drugs best-sellers in the pharma market is a clear indication of the relevance of having inflammation under check; nonetheless, there is still a great need for better acting pharmacological tools for the control of inflammation. Indeed, the remarkable success of biological drugs targeting proinflammatory cytokines has indicates that tools able to block proinflammatory mediators have promising applications, but at the same time has made clear that there are intrinsic limitations to this approach which frequently vanish undermine the activity of single targeting drugs, including the well-known redundancy of inflammatory mediators. Under self-limiting conditions inflammation spontaneously resolves in an active process. Some cellular and molecular mechanisms involved in inflammation resolution have been uncovered in the recent past, and include generation of specific cytokines, apoptosis of inflammatory leukocytes, lipid mediators, macrophage repolarization and others are likely to be revealed in the next future, since loss-of-function mutations of an increasing number of genes results in the development of spontaneous inflammation in experimental animals. We argue that “pushing for“ inflammation resolution by exploiting active naturally-occurring pro-resolving processes may have significant advantages over the attempt to simply “push back” inflammation by passive blockade of proinflammatory mediators. At present the research in the field of inflammation aims at identifying and validates new molecules involved in the resolution of inflammation as a basis for the development of innovative therapeutic strategies in chronic inflammatory and autoimmune diseases. This involves the discovery of new natural or synthetic “pro-resolving” molecules from plant and animals and the investigation of endogenous inflammation “pro-resolving” mechanisms, including atypical chemokine receptors, decoy receptors, and microRNA. An extensive effort is focused on the regulation by “pro-resolving” agents on two molecular systems of key relevance in inflammation: the chemokine system, which regulates recruitment, permanence and egress of leukocyte in tissues; and the Toll Like Receptor (TLR)/IL-1R system, which is central for the activation of infiltrating leukocytes.

Chronic inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, inflammatory bowel diseases, and others typically stimulate a systemic response of the entire body. This response has a uniform character in many diseases because common pathways are switched on. The uniform response regulates systemic energy and water provision. However, long-term application of this program leads to typical disease sequelae such as fatigue / depressive symptoms, sleep disturbances, anorexia, malnutrition, muscle wasting – cachexia, cachectic obesity, insulin resistance, dyslipidemia, alterations of steroid hormone axes, disturbances of the hypothalamic-pituitary-gonadal axis, elevated sympathetic tone, hypertension, volume expansion, decreased parasympathetic tone, inflammation–related anemia, bone loss, hypercoagulability, circadian rhythms of symptoms, and disease exacerbation by stress . The Origin of Chronic Inflammatory Systemic Diseases and Their Sequelae demonstrates concepts of neuroendocrine immunology, energy and water regulation, and evolutionary medicine in order to show that the uniform response that regulates systemic energy and water provision, has been positively selected for acute physiological responses and short-lived disease states, but is a misguided program in chronic inflammatory diseases and aging. Offers a broad conceptual framework with a strong clinical link, written in an easy to grasp style and demonstrating the link to aging research Describes the important principles derived from basic immunology that are used to explain pathogenesis of chronic inflammatory systemic diseases with a focus on autoimmunity Defines the bioenergetics and energy regulation of the body explaining common response pathways typical for systemic inflammation Makes use of evolutionary medicine theory to demonstrate the uniformity of the systemic response Explains the appearance of typical disease sequelae on the basis of the three pillars: neuroendocrine immunology, energy regulation, and evolutionary medicine theory Contains color figures and tables that explain the field to newcomers

Scientific interest in regulatory T cells has revived during the last decade. Initially described in the early seventies as suppressor T cells, the concept of suppressor/regulatory T cells went through turbulent times during the eighties when molecular analysis failed to identify putative suppressor genes. The constructive and elegant cellular experiments on regulatory T cells during the nineties, initiated by Shimon Sakaguchi and co-workers, however have brought these cells back into the limelight. Nowadays, regulatory T cells are regarded as essential components of the immune system, and several different subsets of regulatory T cells have been described. Considerable regulatory function has been attributed to the CD4+CD25+ T cell subset. These cells act by suppressing adaptive and possibly also innate immune responses thereby maintaining or restoring the balance between immunity and tolerance. The suppressive effects of CD4+CD25+ regulatory T cells are cell-contact dependent but a role for soluble factors, particularly in vivo, has been suggested as well. The aim of this book is to bring together recent developments and viewpoints in the field of CD4+CD25+ regulatory T cells and to discuss the potential use of regulatory T cells in immunotherapy of inflammatory diseases. By linking data on regulatory T cells from experimental models with recent findings from the clinic, this topical book will be of interest to immunologists and other biomedical researchers as well as clinicians that are interested in regulation and manipulation of the immune response during (chronic) inflammatory disease.

Although acute inflammation is a healthy physiological response indicative of wound healing, chronic inflammation has been directly implicated in a wide range of degenerative human health disorders encompassing almost all present day non-communicable diseases including autoimmune diseases, obesity, diabetes and atherosclerosis. Chronic Inflammation: Molecular Pathophysiology, Nutritional and Therapeutic Interventions provides an exposition of the process of chronic inflammation in three parts: Systems Biology of Inflammation and Regulatory Mechanisms describes the process of chronic inflammation including initiation, progression, and resolution. Pathologies Associated with Inflammation gives a rigorous and critical treatment of specific human health disorders where chronic inflammation plays a major role. Nutrition & Therapeutics for Inflammatory Diseases details the protective abilities of structurally diverse antioxidants, phytochemicals, anti-inflammatory diets, omega-3 fatty acids, NSAIDs, disease modifying anti-rheumatic drugs, and novel regimens. Designed for scientists as well as clinicians, Chronic Inflammation provides critical understanding of the key checkpoints that regulate chronic inflammation. Going beyond the epidemiology of chronic inflammation, the text covers regulatory mechanisms controlling inflammation initiation, progression, and resolution. The authors address pathologies associated with inflammation and provide various nutritional and therapeutic interventions for inflammatory diseases.

This book provides recent advances in the understanding of the central processes in the resolution of inflammation. It also describes the active, specialized pathways that bring the resolution of inflammation. Further, the book examines the key molecular and cellular events that are involved in the resolution of inflammation processes involved in tissue repair and regain of physiological function. Importantly, it sheds light on the cellular and molecular processes through which conventional inflammatory cytokines control mammalian tissue repair and regeneration. It also explores the perturbation of processes that are involved in the resolution of inflammation with aging and reviews clinical trials of anti-inflammatory and immunomodulatory therapies. Towards the end, the book discusses the role of inflammation in the development and progression of cancer. This book is an invaluable resource for scientists, academicians, and research scholars interested in the latest cutting-edge knowledge in the field of immunology, inflammation, inflammation resolution, and inflammatory diseases. ​