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The microcirculation is highly responsive to, and a vital participant in, the inflammatory response. All segments of the microvasculature (arterioles, capillaries, and venules) exhibit characteristic phenotypic changes during inflammation that appear to be directed toward enhancing the delivery of inflammatory cells to the injured/infected tissue, isolating the region from healthy tissue and the systemic circulation, and setting the stage for tissue repair and regeneration. The best characterized responses of the microcirculation to inflammation include impaired vasomotor function, reduced capillary perfusion, adhesion of leukocytes and platelets, activation of the coagulation cascade, and enhanced thrombosis, increased vascular permeability, and an increase in the rate of proliferation of blood and lymphatic vessels. A variety of cells that normally circulate in blood (leukocytes, platelets) or reside within the vessel wall (endothelial cells, pericytes) or in the perivascular space (mast cells, macrophages) are activated in response to inflammation. The activation products and chemical mediators released from these cells act through different well-characterized signaling pathways to induce the phenotypic changes in microvessel function that accompany inflammation. Drugs that target a specific microvascular response to inflammation, such as leukocyte-endothelial cell adhesion or angiogenesis, have shown promise in both the preclinical and clinical studies of inflammatory disease. Future research efforts in this area will likely identify new avenues for therapeutic intervention in inflammation. Table of Contents: Introduction / Historical Perspectives / Anatomical Considerations / Impaired Vasomotor Responses / Capillary Perfusion / Angiogenesis / Leukocyte-Endothelial Cell Adhesion / Platelet-Vessel Wall Interactions / Coagulation and Thrombosis / Endothelial Barrier Dysfunction / Epilogue / References
Recent research into the anatomy and pathophysiology of the blood-brain and blood-spinal cord barriers suggests that a breakdown in these barriers can result in several diseases affecting the central nervous system (CNS). This book presents new findings in the area of blood-brain barrier research that suggest barriers play important roles in health and disease conditions. It also discusses the development of new drugs that can modulate the barrier function in the CNS and may provide new approaches to treating neurological diseases such as Alzheimer's disease and other motor neuron diseases, as well as spinal cord trauma. Key Features * Presents the recent progress made in the research on the blood-brain and spinal cord barrier * Contains numerous illustrations of light and electron micrographs * Includes Foreword written by two eminent researchers in the field, Milton Brightman and Jorge Cervos-Navarro
Inflammation is considered as a hallmark of host defense against infections and injuries. On the flipside, prolonged and non-resolving chronic inflammation is also associated with various pathological conditions. In the immune and inflammatory responses, it is the leukocyte integrins and their physiologic ligands that provide the essential molecular basis for cell adhesion and recognition. As important as these molecules are in maintaining healthy immune system, aberrant activities have been implicated in dysregulated inflammation, making integrins and their ligands a major therapeutic target. In this dissertation, I have developed and applied protein engineering techniques for modulating structure and function of integrins and their ligands, and thereby rendering opportunities for therapeutic development. Integrins have at least two distinct conformations, denoted as inactive or active. We have engineered the major ligand binding domains, or the inserted (I) domains, of leukocyte integrins into an activated state, competent for ligand binding. Possessing the ability to harness the I domains expressed in their inactive (wild-type) and active (high affinity mutants) states allowed us to discover neoepitope specific antibodies that preferentially bind to the active conformation of integrins. This was a streamlined process performed with the novel protein engineering platform, yeast surface two-hybrid, that we developed, which greatly facilitated the process of antigen engineering and novel antibody discovery. The discovered antibody potently inhibited leukocyte migration on ligand coated surfaces. Such antibodies specific against active conformation of integrins may be safer and administered at lower dosages, and result in better clinical outcomes. We also used the engineered I domains to create drug and gene delivery nanoparticles that mimic how leukocytes would bind and migrate selectively to inflammatory sites. More specifically, we used the I domain derived from the integrin lymphocyte function associated antigen-1 (LFA-1) for inflammation-specific accumulation of anti-inflammatory drugs, which otherwise would create systemic cytotoxicity. Delivery by the I domain was inflammation-specific because the physiological ligand of LFA-1, intercellular adhesion molecule-1 (ICAM-1) has a highly inducible expression on numerous cell types, including endothelial cells and immune cells. Specificity toward inflammation was dependent on the avidity of the I domain on delivery vehicles, and such optimally adjusted multimeric binding to ICAM-1 elicited rapid endocytosis. In this dissertation, I demonstrate that the use of the interaction between ICAM-1 and the engineered I domain provide a great opportunity to pierce through the barriers of gene delivery systems, with the addition of one more component for endosomal escape. Indeed, by using a cationic polymer previously known to elicit efficient endosomal escape, we were able to formulate nanoparticles that deliver genes like viruses, with improved gene transfer efficiency and for systemic applications. We anticipate that our virus-like particles may greatly contribute to a successful translation of such therapeutics into the clinics.
Antioxidants are an increasingly important ingredient in food processing. Their traditional role is, as their name suggests, in inhibiting the development of oxidative rancidity in fat-based foods, particularly meat and dairy products and fried foods. However, more recent research has suggested a new role in inhibiting cardiovascular disease and cancer. Antioxidants in Food: Practical Applications provides a review of the functional role of antioxidants and discusses how they can be effectively exploited by the food industry. The first part of the book looks at antioxidants and food stability with chapters on the development of oxidative rancidity in foods, methods for inhibiting oxidation, and ways of measuring antioxidant activity. Part 2 looks at antioxidants and health, including chapters on antioxidants and cardiovascular disease, their antitumour properties, and bioavailability. A major trend in the food industry, driven by consumer concerns, has been the shift from the use of synthetic to natural ingredients in food products. Part 3 looks at the range of natural antioxidants available to the food manufacturer. The final section of the book looks at how these natural antioxidants can be effectively exploited, covering such issues as regulation, preparation, antixoxidant processing functionality and their use in a range of food products from meat and dairy products, frying oils and fried products, to fruit and vegetables and cereal products.
Comparative Biology of the Normal Lung, Second Edition, offers a rigorous and comprehensive reference for all those involved in pulmonary research. This fully updated work is divided into sections on anatomy and morphology, physiology, biochemistry, and immunological response. It continues to provide a unique comparative perspective on the mammalian lung. This edition includes several new chapters and expanded content, including aging and development of the normal lung, mechanical properties of the lung, genetic polymorphisms, the comparative effect of stress of pulmonary immune function, oxygen signaling in the mammalian lung and much more. By addressing scientific advances and critical issues in lung research, this 2nd edition is a timely and valuable work on comparative data for the interpretation of studies of animal models as compared to the human lung. Edited and authored by experts in the field to provide an excellent and timely review of cross-species comparisons that will help you interpret and compare data from animal studies to human findings Incorporates lung anatomy and physiology, cell specific interactions and immunological responses to provide you with a single and unique multidisciplinary source on the comparative biology of the normal lung Includes new and expanded content on neonatal and aged lungs, developmental processes, cell signaling, antioxidants, airway cells, safety pharmacology and much more Section IV on Physical and Immunological Defenses has been significantly updated with 9 new chapters and an increased focus on the pulmonary immunological system
Vascular Disease in Women highlights the epidemiology, natural history and treatment of vascular disease, specifically as it pertains to women. The book provides a thorough overview of what is known and waht is now known about vascular disease in women and highlights opportunities for further education and research on this topic. The book will serve as an essential reference for both clinicians and researchers, discussing the disease prevalence, treatment options, and treatment outcomes for vascular disease in women and explores the need for future research in vascular disease specifically as it pertains to women. Provides a comprehensive overview of vascular disease as it affects women Includes contributions from world-renowned vascular surgeons of both genders, who have a vested interest in women’s vascular health Covers what is known and not known about vascular disease in women, prompting further research in the area for what is still unknown
The fourth edition of The Cytokine Handbook provides an encyclopedic coverage of the molecules that induce and regulate immune responses. Expanded to two volumes, the scope of the book has been broadened to include a major emphasis on the clinical applications of cytokines. The early chapters discuss individual cytokines, chemokines and receptors. Additional chapters discuss the clinical implications and applications of cytokines, including cytokine gene transfer, antisense therapy and assay systems.
Methods in Enzymology volumes provide an indispensable tool for the researcher. Each volume is carefully written and edited by experts to contain state-of-the-art reviews and step-by-step protocols. In this volume, we have brought together a number of core protocols concentrating on Cell, Lipid and Carbohydrate, complementing the traditional content that is found in past, present and future Methods in Enzymology volumes. Indispensable tool for the researcher Carefully written and edited by experts to contain step-by-step protocols In this volume we have brought together a number of core protocols concentrating on Cell, Lipid and Carbohydrate
Pression of DC-SIGN by the erythroleukemic cell line (B) Adhesion of immature DC to ICAM-3 in the presence of blocking K562 as well as the promonocytic cell line THP-1 re- mAb (20 mg/ml) against b2 integrins (b2 chain, AZN-L19), b1 integrins sulted in strong binding of ICAM-3 (data not shown).(b1 chain, AIIB2), and ICAM-3 (CBR-IC3/1, CBR-IC3/2) and in the Since both DC-SIGN and LFA-1 bind ICAM-3,. [...] Specific adhesion of DC-SIGN and the b2 integrins is calculated from the inhibition of adhesion in the presence of the blocking mAb AZN-D1 or AZN-L19, respectively. [...] Also, LFA-1- and LFA-tempt to evaluate the role of DC-SIGN in this process, we analyzed the capacity of DC to cluster with ICAM-3 3-mediated DC-T cell clustering is transient and fol- lowed the kinetics of the DC-SIGN-mediated adhesion,transfectants (K562-ICAM-3). [...] The observation that resting T cells express high lev- The finding that C-type lectins are involved in the uptake els of ICAM-3 and low levels of ICAM-1, compared to and presentation of antigens via DC (Jiang et al., 1995), activated T cells that express equal amounts of ICAM-3 and the fact that mannosylation of antigen leads to a and ICAM-1 (de Fougerolles and Springer, 1992; Hauss selective targ. [...] TCR signaling alters the avidity gen-presenting cells (DC) to T cells requires the forma- of LFA-1 and CD2, thereby strengthening the interaction tion of a specialized junction between these cells that between DC and T cell via multiple adhesive contacts is generated by carefully orchestrated recruitment of through LFA-1 and LFA-3 that will provide further posi- specific receptors into the contact.