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PREFACE
Welcome to the new edition of Kendig, to which the distinguished name of Robert Wilmott has been added. This is his valedictory volume, having been involved in four previous editions, two as Editor in Chief. Bob has set us all high standards, which he himself has always achieved, not merely in Kendig, but in so many positions in academic and clinical pediatrics. Bob, you will be sorely missed when you hang up your red pen, always meticulous and always good-humored even with those recalcitrant authors who consistently deliver excuses more readily than their chapters (you know who you are!). There has never been a more exciting time to be in Pediatric Respiratory Medicine. Novel improved prevention strategies such as better immunizations have dramatically reduced infectious diseases and have been key in COVID. Yet global inequity in access to existing effective preventive and treatment options still remains a major hurdle. Fundamental basic science discoveries are giving us transformative novel treatments. Highly effective modulator therapies have transformed the lives in 90% of patients with cystic fibrosis, but sadly only in high income settings, although this still leaves unmet need for specific genotypes. Gene therapy and oral correctors of the Survival Motor Neuron-2 (SMN-2) gene splicing issue have respectively led to many babies with severe spinal muscular atrophy starting to develop normally and improved muscle power in less severe forms of the disease. Biologics targeted at type 2 inflammation mean that the days of chronic oral corticosteroid treatment for severe asthma are passing, and there are many more examples just around the corner. A challenge is the enormous cost of these treatments, and it is a scandal that they are denied to millions of children in low- and middle-income settings because the price has been set unaffordably high. When will we follow the example of antiretroviral treatment, where costs were brought down so that they were freely available at all points of need? There are now ever more powerful techniques to manage the extraordinary big data that are routinely being collected in every setting, from the molecular laboratory to the field of epidemiology. We have also had to grapple with new diseases and their consequences, most notably the COVID pandemic and its aftermath. The authors and editors have extensively refreshed this new volume, the 10th edition. All the chapters have been rewritten. Many authors have retired, and we thank them for earlier contributions. We have nearly 90 new authors and 11 new chapters. As well as standard old favorites, we have a chapter on big data and -omics in respiratory disease, a topic that has exploded since the last edition. COVID has an important place in the chapter on novel respiratory diseases. The evils of vaping and nicotine addiction have a chapter, which is important as the tobacco industry markets aggressively and successfully to children and young people. Increased molecular knowledge has led to hereditary hemorrhagic telangiectasia and pulmonary lymphatic disorders being separated from congenital lung disease and being allocated their own chapters. Obesity and its consequences figure in many chapters as prevalence increases, not least due to worsening child poverty. There is also a huge new library of on-line video resources, especially including bronchoscopic videos thanks to Bob Wood. This greatly augments what was available in the previous edition. Overall, we have attempted to put together a truly international book covering the whole spectrum of our specialty across the globe with a big repository of online resources. It’s an ambitious goal, and we would value feedback for the next edition. Which of your pet topics have we omitted? We will not know unless you tell us, and we aspire to make this the best possible book in ours or (being modest) in any other field. Finally, thanks are due to all who contributed, to Lisa Barnes and Sarah Barth from Elsevier for incredible support, which sometimes even kept us on the straight and narrow, and above all, for the forbearance of our partners. Kendig’s Disorders has yet to be cited in a divorce, and we hope that will continue. Thanks all, and we so hope you enjoy using the volume as much as we did putting it together.
Molecular and Cellular Determinants of Lung Morphogenesis
Daniel T. Swarr, MD and Jeffrey A. Whitsett, MD
INTRODUCTION
The adult human lung consists of a gas exchange area of approximately 100 m2 that provides oxygen delivery and carbon dioxide removal required for cellular metabolism. In evolutionary terms, the lung represents a relatively late phylogenetic solution for the efficient gas exchange needed for terrestrial survival of organisms of increasing size, an observation that may account for the similarity of lung structure in vertebrates.1 The respiratory system consists of mechanical bellows and conducting tubules that bring inhaled gases to a large gas exchange surface that is highly vascularized. Alveolar epithelial cells (AECs) come into close apposition to pulmonary capillaries, providing efficient transport of gases from the alveolar space to the pulmonary circulation. The delivery of external gases to pulmonary tissue necessitates a complex organ system that (1) keeps the airway free of pathogens and debris, (2) maintains humidification of alveolar gases and precise hydration of the epithelial cell surface, (3) reduces collapsing forces inherent at air-liquid interfaces within the air spaces of the lung, and (4) supplies and regulates pulmonary blood flow to exchange oxygen and carbon dioxide efficiently. This chapter provides a framework for understanding the molecular mechanisms that lead to the formation of the mammalian lung, focusing attention to processes contributing to cell proliferation and differentiation involved in organogenesis and postnatal respiratory adaptation. Where possible, the pathogenesis of congenital or postnatal lung disease is considered in the context of the molecular determinants of pulmonary morphogenesis and function.
ORGANOGENESIS OF THE LUNG
Formation of the Basic Body Plan
Events critical to organogenesis of the lung begin with formation of anterior-posterior (A-P), dorsal-ventral, and left-right axes in the early embryo, which, in turn, specifies the basic body plan of each organism. The formation of these axes is determined by genes that control cellular proliferation and differentiation, and depends on complex interactions among many cell types. The fundamental principles determining embryonic organization have been elucidated in simpler model organisms (e.g., amphibians, fruit flies, sea urchins, snails, worms, and zebra fish) and applied to increasingly complex organisms (e.g., mouse and human) as the genes determining axial segmentation, organ formation, cellular proliferation, and differentiation have been identified. Segmentation and organ formation in the embryo are profoundly influenced by sets of master control genes that include various classes of transcription factors. Critical to formation of the axial body plan are the homeotic, or HOX, genes.2 HOX genes are arrayed in clearly defined spatial patterns within clusters on several chromosomes. HOX gene expression in the developing embryo is determined in part by the position of the individual genes within these gene clusters, which are aligned along the chromosome in the same order as they are expressed along the A-P axis. Complex organisms have more individual HOX genes within each locus and have more HOX gene loci than simpler organisms. In addition, HOX genes encode nuclear proteins that bind to DNA via a highly conserved homeodomain motif that modulates the transcription of specific sets of target genes. The temporal and spatial expressions of these nuclear transcription factors, in turn, control the expression of other HOX genes and their transcriptional targets during morphogenesis and cytodifferentiation.3,4 Expression of HOX genes influences many downstream genes, such as transcription factors, growth factors, signaling peptides, and cell adhesion molecules,4 which are critical to the formation of the primitive endoderm from which the respiratory epithelium is derived
Specification of the Foregut Endoderm
The primitive endoderm develops very early in the process of embryogenesis, that is, during gastrulation and prior to formation of the intraembryonic mesoderm, ectoderm, and the notochord, which occurs in humans at 3 weeks postconception (WPC).6 Specification of the definitive endoderm and the primitive foregut requires the activity of a number of nuclear transcription factors that regulate gene expression in the embryo, including forkhead box A2 (FOXA2) (also known as hepatocyte nuclear factor 3-beta [HNF-3b]), GATA-binding protein 6 (GATA6), sex-determining region Y (SRY)-related high mobility group (HMG)-box (SOX) 17 (SOX17), SOX2, b-catenin, retinoic acid receptors (RAR), and members of the T-box family of transcription factors.7e15 Genetic ablation of these transcription factors disrupts formation of the primitive foregut endoderm and its developmental derivatives, including the trachea and the lung.11,12,16e20 Some of these transcription factors are also expressed in the respiratory epithelium later in development, when they play important roles in the regulation of cell differentiation and organ function.8,2
