Respiratory Pharmacology and Pharmacotherapy – serie

Infection of the lower respiratory tract is a major determinant of the course of cystic fibrosis. Although numerous efforts have been made to elucidate the specific mechanisms predisposing the respiratory mucosa of cystic fibrosis patients to infection, so far no clinically relevant procedures for completely effective prevention or control of infection have resulted. Hence, in dealing with infections in cystic fibrosis, we continue to rely mainly on antimicrobials. Antiinfective measures are inseparably correlated with microbiology, and the quality of antiinfec­ tive therapy directly reflects the quality of microbial monitoring. Vali­ dated guidelines for microbiologic testing and antiinfective use need to be developed and made available to all health providers and their cystic fibrosis patients. Several years ago, the editors cochaired a symposium at the Interna­ tional Congress of Chemotherapy on the Global Perspectives of Micro­ biological and Clinical Infectious Diseases in Patients with Cystic Fibrosis. During this half-day symposium, the editors heard reports from several countries around the world with an alarming range of survival for patients with cystic fibrosis. This sent a dramatic message to us that the understanding of this disease, its diagnosis, management and prevention was different in various countries and that patients may be inconsistently served. That is how our journey began.

Most studies on autonomic innervation of smooth muscle have focused on the short-term mechanisms involved in neurotransmission in physiological and pathophysiological conditions. However recent obser­ vations of the long-term plasticity of this system, i. e. its capacity for regeneration and for compensatory change in pattern of innervation and expression of cotransmitters and receptors in ageing, following surgery, trauma or in disease, have indicated that an understanding of the mechanisms involved could influence the design of therapeutic regimes. There is increasing evidence for long-term communication between nerves and smooth muscle cells during development and throughout adult life. To date, the trophic interactions between nerves and airway musculature have attracted little interest, consequently, much of the information presented here is drawn from studies using other smooth muscles. However, the questions posed about trophic interactions dur­ ing development apply as much to airways smooth muscle neuroeffector systems as to other autonomic neuroeffector systems. These are: i) How do developing nerve fibres know where to go and how do they reach their target sites? ii) What determines the density and pattern of inner­ vation at reaching the effector? iii) How do the nerves survive and maintain their position once established? iv) What factors influence neurochemical differentiation such that genetically multipotential neu­ rones are triggered to synthesize one or combinations of neurotransmit­ ters? v) What influence do nerves have on the structure, function and receptor expression of their effector cells? vi) How do diseases interrupt these processes? - see [1].

Many factors may influence the release of neurotransmitters from airway nerves [1]. This is likely to be important in physiological control of airway functions and may be particularly relevant in airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Neural elements in airways interact in a complex manner and the activation of certain neural pathways may profoundly influence the release of transmitters from other neural pathways. Similarly inflamma­ tory mediators released from inflammatory cells in the airways may also modulate neurotransmitter release. There are marked differences be­ tween species in airway innervation and in neuromodulatory effects and, wherever possible, studies in human airways have been emphasised, although information on neuromodulation in human airways is some­ what limited at present. Release of neurotransmitters from nerve terminals occurs via a Ca2+­ dependent secretion evoked by a nerve action potential, but may also be evoked experimentally by a high extracellular K + concentration which directly depolarises the nerve terminal membrane. Modulation refers to the alteration of neurotransmitter release, which may either be increased (facilitation) or reduced (inhibition) by the action of a particular agent, thus changing the magnitude of the neurally-mediated response. Such agents would normally act on receptors on the nerve terminal which are referred to as pre-junctional (or presynaptic) receptors, in contrast to post-junctional (or post-synaptic) receptors located on the target cells which are influenced by that particular transmitter.

Nitric oxide is an endogenously produced gas with a wide range of biological effects and has been implicated in many physiological and pathophysiological processes. It is released by many cell types in various organs but is particularly important in the maintenance of normal lung function. Nitric oxide in exhaled breath has been identified as a marker for lung disease in some patients. Thus, it is appropriate to consider the lung separately for the role and functioning of nitric oxide. The authors identify key areas in the history, biochemistry, physiology, pathophysiology, immunology and clinical applications of nitric oxide in the lung. The contents of this book will be of particular importance to scientists and clinicians with an interest in lung disease. Moreover, the authors encompass state of the art opinions of and rational for the therapeutic potential of nitric oxide and its inhibitors.

1. 1. Invasive versus Non-Invasive Clinical Measurements in Medicine Clinical measurement has become an essential complement to traditional physical diagnosis. An ideal clinical measurement should be quantitative, have a high level of reliability and accuracy, be safe, acceptable to the patient, easy to perform and non-invasive. The latter demands that the technique should not break the skin or the lining epithelium and should be devoid of effects on the tissues of the body by the dissipation of energy or the introduction of infection [1]. It is therefore logical that for a given measurement, a non-invasive test will be preferred if it provides the same information with the same accuracy and precision. In the following sections, we will discuss the role of various non-invasive or relatively non-invasive methods to assess airway inflammation in asthma and concentrate on the only direct method of induced sputum examination. 1. 2. Why Is Assessment of Airway Inflammation Important in Asthma? Inflammation is a localized protective response elicited by injury or destruc­ tion of tissues which serves to destroy, dilute or wall off both the injurious agent and the injured tissue [2]. The role of inflammation in asthma was rec­ ognized long ago. In his textbook The Principles and Practice of Medicine, in 1892, Sir William Osler described "bronchial asthma . . . in many cases is a spe­ cial form of inflammation of the smaller bronchioles . . .

The biology of the family of endogenous autocrine peptides known as the endothelins (ETs) has been a source of intense study for researchers since 1988, following the identification of ET-l as the previously described endothelium-derived contractile factor. Initial interest focussed on the actions of the ETs in the cardiovascular system, and this remains the pri­ mary source of published work involving these peptides. Importantly, evi­ dence is mounting for a significant mediator role for ET-l in cardiovascu­ lar diseases including systemic hypertension and congestive heart failure. However, it was also recognized early on that the ETs exert an array of powerful actions in the respiratory tract, many of which prompted specula­ tion concerning mediator roles for ET-l in several lung diseases including asthma and pulmonary hypertension. In recent years the evidence for the involvement of ET-l in lung diseases has become more compelling. There is now real hope and anticipation that novel ET receptor antagonists may eventually be used therapeutically against asthma and other major lung pathologies. It is this atmosphere of excitement created by new discoveries and the increasing scientific ratio­ nale for a significant impact ofthe ETs in pulmonary diseases that prompt­ ed the creation of this book, the first on this topic. Most of the information presented relates to ET-l, which is the most widely studied member of the ET family.

Conceptually unsavoury, airway mucus is vital to homeostasis in the respiratory tract. In contrast, when abnormal, mucus contributes significantly to the pathophysiology of a number of severe bronchial diseases, including asthma, chronic bronchitis and cystic fibrosis. This volume provides wide ranging and in-depth coverage of the scientific and clinical aspects of airway mucus. It commences with introductory chapters which address the biochemical and molecular biological basis of airway mucus and continues with comprehensive coverage of the various physiological and rheological aspects of respiratory secretions. The clinical aspects of the topic are then considered, with chapters discussing the involvement of mucus secretions in bacterial infection and in hypersecretory diseases of the airway. The volume concludes with a discussion of the therapeutic aspects of the topic, both in terms of the possible approaches to the treatment of mucus hypersecretion and the interaction of these drugs with airway mucus. Written by leading experts in the field, each contribution provides a comprehensive review of its particular subject. Reflecting the latest advances in this important area of respiratory research, this volume will be of great interest to scientists and clinicians working in the field of airway secretions and related areas.

Lung cancer is a disease with pandemic public health implications as it is now the leading cause of cancer mortality throughout the world. This book results from two recent International Association for the Study of Lung Cancer (IASLC) Workshops on lung cancer prevention. It strikes a balance between considering public health approaches to tobacco control and population-based screening, advances in clinical evaluation of chemoprevention approaches, and the biology of lung carcinogenesis. Indeed, while the science of smoking cessation is evolving as new pharmacological tools are moving into clinical evaluation, the current impact of molecular diagnostics is profound. The rapidly-evolving diagnostic technologies are revolutionizing basic scientific investigation of cancer, and this trend is expected to soon spill over into the clinical practice of medicine. The evolution of economical diagnostic platforms to allow for direct bronchial epithelial evaluation in high-risk populations promises to improve the diagnostic lead-time for this disease. The hope is that enough progress will occur to permit lung cancer detection in advance of clinical cancer so that the disease can be addressed early on, while it is still confined to the site of origin. Chemoprevention, which is designed to intervene in the early phase of carcinogenesis prior to any subjective clinical manifestation of a cancer, is also generating greater research interest. Moreover, the benefit of aerosolized administration of chemoprevention agents over conventional oral administration has strong appeal and may result in the reduction of the incidence of cancer when combined with new diagnostic technologies.

The lung and its contiguous structures are commonly involved in several of the rheumatic diseases (Table 1), either by direct manifestation of disease or as a secondary effect from infection or complications of therapy. In this chapter, we detail the various pulmonary manifestations of the major rheu- matological conditions. The common symptoms of pulmonary diseases and how frequently they are implicated in rheumatic disorders are review- ed. In addition, radiology and physiology of the lung, diagnostic proce- dures and therapeutic options are discussed. Table l.Respiratory associations of the rheumatic disorders Disease Airways Parenchyma Vessels WalVmuscles Lung Pleura Pulmonary Chest pleurisy hypertension Rheumatoid bronchiectasis, pneumonia, arthritis obliterative fibrosing effusion bronchiolitis alveolitis, empyema nodules Systemic pneumonia pleurisy hypertension lupus fibrosing effusion shrinking lungs erythematosus alveolitis, with high atelectasis diaphragm Systemic bronchiectasis fibrosing hypertension "encased chest" sclerosis alveolitis, aspiration pneumonia Sjogren's bronchitis fibrosing alveolitis syndrome lymphoma Dermatomyositis aspiration myopathy polymyositis pneumonia, fibrosing alveolitis Ankylosing upper lobe cos- spondylitis fibrosis vertebral fixation joint Behget's haemorrhage aneurysm syndrome Relapsing upper airway polychondritis narrowing Pulmonary vasculitides nodules The Respiratory System in Rheumatic Diseases 25 1. 2. Respiratory Symptoms The most common respiratory symptoms in patients with rheumatic disease and pulmonary involvement are non-specific and include cough, breathlessness and chest pain and can be the result of involvement of air- ways, lung parenchyma, pleura, chest wall or pulmonary vessels. 1.3. Tissue Involvement 1. 3. 1.

Focussed specifically on children and pediatric respiratory diseases, "The Pediatric Lung+" reviews the current status of pharmacological therapy for asthma, viral pneumonia, cystic fibrosis, bronchopulmonary dysplasia and acute respiratory failure. A review of aerosol delivery systems in children and an up-to-date treatise on mucolytic agents is also included. The chapters are written by leading specialists in the field and summarize the latest developments in pediatric pulmonology, as well as covering a comprehensive range of respiratory diseases in children. Pediatric pulmonologists, allergologists, intensivists, neonatologists and general pediatricians will find "The Pediatric Lung" an invaluable source of reference. Clinicians will be particularly interested in the new information concerning aerosol delivery systems, gene therapy for cystic fibrosis, new modalities of therapy for asthma, the emerging role of nitric oxide and a treatise on modern mycolytic agents.

Building on the existing titles in the "Airways Smooth Muscle" sub-series, the sixth volume explores physiological and pharmacological processes in the lung in vivo. The various animal models available for studying the bronchospasm and inflammation associated with human asthma are thoroughly reviewed by internationally recognised scientists. Specific chapters focus on the problems of administering drugs to animal airways, the mechanics of assessing lung function in the models, and describe in detail the species used, from rodents to primates. The use of genetically altered animals, an area of particular interest to molecular biologists, is also considered in depth. This up-to-date and extensively referenced work will prove invaluable to pharmacologists, physiologists and other biological scientists at all levels in academia and in the pharmaceutical industry.

Continuing the Respiratory Pharmacology and Pharmacotherapy series, this volume explores the pathophysiology and therapy of rhinitis. The volume is introduced by a chapter describing the normal anatomy and physiology of the nose and sinuses. Against this background the contributing authors describe and discuss the immunological and pathological changes which occur in rhinitis. The various causes and the types of rhinitis - such as allergic, vasomotor, and infectious - are discussed as are the treatments available (pharmacotherapy, immunotherapy, surgery). The book concludes with a description of the animal models of rhinitis which are now available. This book will be of interest to bench scientists and clinicians alike.

Continuing the Respiratory Pharmacology and Pharmacotherapy series, this volume explores the pathophysiology and therapy of rhinitis. The volume is introduced by a chapter describing the normal anatomy and physiology of the nose and sinuses. Against this background the contributing authors describe and discuss the immunological and pathological changes which occur in rhinitis. The various causes and the types of rhinitis - such as allergic, vasomotor, and infectious - are discussed as are the treatments available (pharmacotherapy, immunotherapy, surgery). The book concludes with a description of the animal models of rhinitis which are now available. This book will be of interest to bench scientists and clinicians alike.

Although conceptually unsavoury, airway mucus is nevertheless vital to homeostasis in the respiratory tract. When abnormal, however, mucus contributes to the pathophysiology of severe bronchial diseases, such as chronic bronchitis, cystic fibrosis, and asthma. This text covers both the scientific and clinical aspects of airway mucus. The introductory chapters cover the biochemical and molecular biological basis of airway mucus, and the text then examines the rheology and physiology of respiratory secretions. It then discusses the clinical aspects of the topic, with chapters discussing the involvement of mucus secretions in bacterial infections and hypersecretory diseases of the airway. The text concludes with a discussion of the therapeutic aspects of the topic, both in terms of the possible approaches to the treatment of mucus hypersecretion and the interaction of these drugs with airway mucus.

Focussed specifically on children and pediatric respiratory diseases, "The Pediatric Lung+" reviews the current status of pharmacological therapy for asthma, viral pneumonia, cystic fibrosis, bronchopulmonary dysplasia and acute respiratory failure. A review of aerosol delivery systems in children and an up-to-date treatise on mucolytic agents is also included. The chapters are written by leading specialists in the field and summarize the latest developments in pediatric pulmonology, as well as covering a comprehensive range of respiratory diseases in children. Pediatric pulmonologists, allergologists, intensivists, neonatologists and general pediatricians will find "The Pediatric Lung" an invaluable source of reference. Clinicians will be particularly interested in the new information concerning aerosol delivery systems, gene therapy for cystic fibrosis, new modalities of therapy for asthma, the emerging role of nitric oxide and a treatise on modern mycolytic agents.

In this text the authors have identified key areas in the history, biochemistry, physiology, pathophysiology, immunology and clinical applications of nitric oxide in the lung.

This text seeks to strike a balance between considering public health approaches to tobacco control and population-based screening, advances in clinical evaluation of chemoprevention approaches, and the biology of lung carcinogenesis.

This volume provides an update on the use of molecular biology of the lung and their diseases. The text applies to the basic mechanisms of cell biology, receptors and cell activation, as well as providing an insight as to how the technology influences the concepts of pathogenesis and vice-versa.

This text features an analysis of the epidemiology of asthma in children and adults, the role of steroids in asthma management and new and novel asthma therapies. The book addresses clinicians and basic scientists with an interest in asthma epidemiology, steroids and future therapies.