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Developmental Biology of Lung Stem Cells

Acknowledgments This work was supported by the Canadian Institutes of Health Research (CIHR), the German Research Foundation (Deutsche Forschungsgemeinschaft), the Ontario Institute for Regenerative Medicine (OIRM), the Stem Cell Network, the Heart and Stroke Foundation Canada, the Ontario Graduate Scholarship, and the Canadian Lung Association—Breathing as One Studentship. Abbreviations Abbreviation Meaning αSMA α-Smooth muscle actin ABCA3 ATP binding cassette subfamily A member 3 AcLDL Acetylated low-density…

Regulation of Pulmonary Circulation

Introduction Throughout fetal life, the pulmonary circulation forms and establishes a hierarchical system that is essential for postnatal gas exchange. In humans, a continuity of the circulation between the heart and the capillary plexus of the lung appears at approximately 34 days of gestation. , There is no appreciable reactivity of pulmonary vessels at midterm gestation, but reactivity increases with advancing gestation thereafter, with increased pulmonary…

Antenatal Factors That Influence Postnatal Lung Development and Injury

Spectrum of Lung Disease in Preterm Infants The normal fetal lung at 26 weeks gestation is in a late canalicular or early saccular stage of development and surfactant deficient. Surfactant treatment and the use of more gentle modes of assisted ventilation have resulted in populations of very preterm infants with a wide range of lung diseases not easily classifiable into the traditional categories of respiratory distress…

Impaired Lung Growth After Injury in Preterm Lung

Acknowledgments Portions of this work were supported by NIH grants HL110002 (KHA), HL62875 (KHA), HL56401 (KHA; PL Ballard, P.I.), and AHA Grant-in-Aid 96014370 (KHA). Introduction Infants born as early as 22 weeks estimated gestational age may survive if supported by neonatal intensive care, which includes the routine use of antenatal steroids, postnatal surfactant-replacement therapy, and respiratory support. These and other therapies are required because the gas-exchange…

Mechanisms of Neonatal Lung Injury

Introduction At birth, the term newborn lung is at the alveolar phase of lung development, with a smaller number of alveoli normalized to body weight than an adult has. The lung must make the rapid transition from a fluid-filled structure with low stretch frequency and low strain, to an air-filled structure subjected to high strain at variable frequency to support gas exchange. Spontaneous breathing efforts just…

Evaluation of Pulmonary Function in the Neonate

Introduction The ability to measure lung function is essential for understanding lung growth and developmental physiology, diagnosing pathologic conditions, and assessing therapeutic interventions and management. Neonatal pulmonary function evaluation in the 21st century has achieved a remarkable level of sophistication, making use of new and emerging technologic innovations; these advances stand in stark contrast to very early lung function evaluation efforts that occurred in the 19th…

Basic Mechanisms of Oxygen Sensing and Adaptation to Hypoxia

Introduction A large body of experimental work has been performed on oxygen sensing and on the cellular events that result from oxygen deprivation in a variety of cell types and organisms. Such comparative studies have contributed to our understanding of O 2 sensing and adaptation to hypoxia. As a result, a number of new concepts and mechanisms regarding O 2 sensing and hypoxia adaptation have emerged.…

Control of Breathing in Fetal Life and Onset and Control of Breathing in the Neonate

Acknowledgment The late Dr. Henrique Rigatto was the original author of this chapter, which still contains parts of those original contributions. Introduction There are at least three important considerations regarding the study of the control of breathing during the fetal and neonatal periods. First, the fetus sleeps all the time and the neonate most of the time. This means that their control of breathing must be…

Oxygen Transport and Delivery

Acknowledgment This chapter is based on a previous contribution by Maria Delivoria-Papadopoulos and Jane E. McGowan. Introduction Because aerobic metabolism is critically dependent on a consistent and adequate supply of oxygen, oxygen is an essential fuel source for normal cellular metabolic function. Hence, control of oxygen uptake, transport, and release are essential functions. Although molecular oxygen participates in numerous oxidative reactions necessary for cellular metabolism (e.g.,…

Pulmonary Gas Exchange in the Developing Lung

Introduction Integral to the system of pulmonary gas exchange are mechanisms to maintain matching of pulmonary perfusion and alveolar ventilation, known as ventilation / perfusion matching . The goal is that alveolar oxygen and pulmonary capillary blood have intimate contact to optimize diffusion of O 2 and CO 2 . Requisite features of the efficient gas-exchange apparatus include sustained effective ventilation to replenish the oxygen stores…

Mechanics of Breathing

Introduction The human infant has at least two important advantages over the adult in the evaluation of respiratory mechanical function. First, the infant, like newborn mammals of many species, is often asleep and does not immediately react to gently performed maneuvers. Hence, a maneuver consisting of a very brief occlusion of the airways during spontaneous breathing is often used in the evaluation of the mechanical properties…

Functional Development of Respiratory Muscles

Introduction This chapter provides a snapshot of fetal and neonatal development of the diaphragm muscle (DIAm), the major inspiratory muscle in mammals, and partition between the thoracic and abdominal cavities. The DIAm appears rather late in evolution, being present only in mammals, while other vertebrates use different means of ventilation. The embryologic origin of the DIAm has been elucidated by studies using molecular markers of muscle…

Regulation of Lower Airway Function

Acknowledgment This chapter was prepared through the financial support of grant HL 56470 (R.J. Martin and Y.S. Prakash), HL138402 (P.M. MacFarlane), and HL 133459 (T.M. Raffay) from the National Institutes of Health. Introduction Significant progress has been made in elucidating the fetal and neonatal development of lower airway structures and regulation of their function. During early development, airway smooth muscle differentiates from the mesenchyme of the…

Upper Airway Structure: Function, Regulation, and Development

Introduction Although the conducting airways are formed well in advance of fetal viability, they undergo significant maturational changes in late gestation. Conducting airways are susceptible to damage until they acquire the characteristics of more mature airways. Controversy exists concerning the pathogenesis of bronchopulmonary dysplasia (BPD) in the neonate ; in any case, prolonged mechanical ventilation and oxygen toxicity appear to be major contributing factors. Serial evaluations…

Regulation of Liquid Secretion and Absorption by the Fetal and Neonatal Lung

Acknowledgment The editors wish to thank David P. Carlton for his excellent work on this chapter in the fifth edition. It has been republished here essentially unchanged. Introduction Before birth, the lung is filled with liquid secreted by the epithelia lining the potential air spaces of the fetal lung. The amount of liquid retained in the fetal lung is similar to the functional residual capacity of…

Molecular Mechanisms of Lung Development and Lung Branching Morphogenesis

The need to extract and utilize sufficient amounts of oxygen from the environment to sustain life has had an incredible impact on the evolution of the respiratory systems. In particular, breathing amphibians and mammals with their high metabolic rates have been forced to evolve a sophisticated organ to meet their oxygen requirements and get rid of carbon dioxide, the cellular waste of aerobic metabolism. We explore…

Physiologic Mechanisms of Normal and Altered Lung Growth Before and After Birth

Introduction Growth and development of the lung occurs both before and after birth and is a major determinant of respiratory health throughout postnatal life. Adequate lung growth before birth is necessary for the successful transition from fetal to postnatal life. Normal lung growth after birth is necessary to enable the lung to meet increasing metabolic demands during infancy and childhood and into adulthood. During its development,…

Regulation of Alveolarization

Introduction Lung development is a continuous process, starting very early in embryonic life with the differentiation of the tracheal bud from the ventral side of the primitive gut and ending in postnatal life with the multiplication of alveoli and the maturation of the pulmonary microvasculature. Alveoli represent the functional unit of the lung, the site at which oxygen and carbon dioxide are exchanged between inspired air…

Normal and Abnormal Structural Development of the Lung

Acknowledgments The author thanks Dr. Susan E. Wert for her writing of this chapter for the fifth edition, which is the foundation for this updated chapter. The author would also like to thank Dr. Jamie Verheyden for assistance with this manuscript. Introduction The respiratory system functions to provide oxygen from the external environment to the organism, while removing excess carbon dioxide from the blood. The respiratory…