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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
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