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Many ultrafine particles comprised classically of low-toxicity, low-solubility materials such as carbon black and titanium dioxide have been found to have greater toxicity than larger, respirable particles made of the same material. The basis of the increased toxicity of the ultrafine form is not well understood and a programme of research has been carried out in Edinburgh on the toxicology of ultrafines aimed at understanding the mechanism. We used fine and ultrafine carbon black, TiO₂ and latex and showed that there was an approximately 10-fold increase in inflammation with the same mass of ultrafine compared with fine particles. Using latex particles in three sizes—64, 202 and 535 nm—revealed that the smallest particles (64 nm) were profoundly inflammogenic but that the 202 and 535 nm particles had much less activity, suggesting that the cut-off for ultrafine toxicity lies somewhere between 64 and 202 nm. Increased oxidative activity of the ultrafine particle surface was shown using the fluorescent molecule dichlorofluorescein confirming that oxidative stress is a likely process by which the ultrafines have their effects. However, studies with transition-metal chelators and soluble extracts showed that the oxidative stress of ultrafine carbon black is not necessarily due to transition metals. Changes in intracellular Ca²⁺ levels in macrophage-like cells after ultrafine particle exposure suggested one way by which ultrafines might have their pro-inflammogenic effects.

An increasing number of studies suggest that cell therapy approaches may be powerful tools for repair of injured or diseased lungs as well as for understanding mechanisms involved in both lung development and lung repair. This rapidly progressing field encompasses a number of disciplines and conceptual approaches including the study of endogenous stem and progenitor cells resident in the lung, and investigations utilizing exogenously administered cells for the repair of injured lung. Moreover, the field has undergone several conceptual shifts over recent years. For example, the initial focus on engraftment of exogenously administered cells as airway or alveolar epithelium has been shifted to the current emphases on immunomodulation of inflammatory and immune pathways in the lung by stem cells, and on bioengineering approaches to grow functional lung tissue ex vivo for subsequent use in in vivo implantation for destructive lung diseases, such as emphysema. Furthermore, it has become apparent that the variety of candidate stem and progenitor cell types can have different actions in the lung. Each of these areas is the focus of a comprehensive chapter in this book. The goal of this introductory chapter is to provide an overview of the field to date.

The major function of the lung in different organisms is to perform an efficient exchange of gas with the atmosphere. The thickness of the surface of gas diffusion of the mature lung is 1 micron in humans. However, this produces a surface area of 70 square meters, which is equivalent in size to a modern tennis court or the wing surface of a small aircraft. The lung has a complex organization within the chest as a honeycomb-like structure that comprises a network of extensively branched ducts that function to conduct air to and from the alveolar gas exchange surface. This occurs in a configuration that remarkably increases the surface that facilitates gas exchange between blood and air, while enabling maximally efficient packing of this surface within the chest cavity. This complex structure of the lung is developed sequentially by early branching of the epithelial tube and later on by the process of the septation of terminal air sacs. In addition, the development of pulmonary vasculature that occurs in conjunction with epithelial branching morphogenesis acts to facilitate the transport of respiratory gases to and from the developing alveolar surface. In conjunction with these developmental processes, the development of airway smooth muscle (ASM) takes place during early lung morphogenesis, and its contraction may function to regulate the growth of the lung. Any perturbation of these tightly regulated developmental processes can lead to the formation of abnormal lung structure, gas exchange deficiency and/or respiratory failure. Such disruption of normal lung growth and development is clinically exemplified in many cases, such as premature human delivery, bronchopulmonary dysplasia, or congenital lung defects or disorders. This chapter will describe different phases of lung development, genetic control of the formation pattern of early lung anlagen, distal airway branching morphogenesis, and the alveolar septum formation and its regulatory factors and molecular mechanisms as well as the development of various lung-specific cell types.

The lung contains both epithelial and mesenchymal cell types. Lung epithelial cells are characteristically localized at the interface between the organism and the environment and have many critical and vital functions such as the fluid balance, barrier protection, particulate clearance, production of both mucus and surfactants, and immune response initiation as well as tissue repair after injury. Lung cells are continuously exposed to mechanical stresses during their development and function. For example, lung epithelial cells are continuously exposed to varying levels of mechanical stresses due to lung’s complex structure and the cyclic deformation of the lung during the respiratory cycle. The normal functions of the lung are maintained under these tightly regulated conditions, and changes in mechanical stresses may profoundly affect different functions of lung cells and therefore the overall lung functions. A major goal of lung mechanobiology is to understand how the mechanical behavior of the lung emerges from its cellular and molecular constituents. The central role of mechanics in the lung function was revealed with the help of the rapid progress in seminal historical developments, including both the identification and characterization of the functions of lung surfactants. In this chapter, we will describe the effects of mechanical factors on lung development, and how the airway peristalsis affects lung development. In addition, we will describe the functional roles of parathyroid hormone-related protein (PTHrP) in lung development and stretch transduction, as well as the functions of extracellular calcium-sensing receptor (CaSR) in fetal lung development.

Preterm birth results in several respiratory complications, one of the major causes of infant morbidity and mortality. There is a high risk of development of chronic lung disease and respiratory distress syndrome among preterm infants. In addition, follow-up studies show that the functional impairment of airways is commonly seen in preterm children. Bronchopulmonary dysplasia (BPD) is one form of chronic lung disease affecting most premature newborns and infants, and results from lung damages. Studies on surviving children with BPD suggest persisting defects in the structure of both the airways and the parenchyma of the lung. Preterm birth survivors have several respiratory consequences such as immediate breathing challenges due to lungs that are still underdeveloped, which usually manifest as respiratory distress syndrome (RDS). The current therapies for neonatal lung diseases enable the survival of preterm infants who are born at week 22 of pregnancy or later, although they still suffer from some health consequences. Stem cells have therapeutic applications and potential for the treatment of infants with pulmonary complications associated with preterm birth, such as BPD.

Both the conducting airways (the bronchiolar and tracheobronchial airways) and the gas exchange airspaces (the alveolar regions) are the two major distinct compartments of the lung. Each of these regions contains distinct types of epithelial cells with characteristic compartments of stem and progenitor cells that include epithelial and alveolar stem/progenitor cells, stem and progenitor cells of the bronchi and trachea, and lung mesenchymal stem and progenitor cells such as airway smooth muscle (ASM) stem and progenitor cells and vascular stem and progenitor cells. In addition, the cellular plasticity of different lung-specific stem cells is currently an emerging field of research. Many recent studies have, therefore, used lineage tracing to determine distinct populations of epithelial stem and progenitor cells in the lung. Moreover, stem cells are likely involved in some major lung diseases. Yet, little is known about the functions of different stem cell types in the lung, despite common agreements that lung stem cells may have a major role in the repair and regeneration of the lung. In this chapter, we describe different types of stem and progenitor cells in the lung and mechanisms that regulate both their development, including their proliferation and differentiation, and plasticity during lung morphogenesis, as well as stem cell contribution to lung repair and regeneration. Furthermore, we describe stem cell-related diseases in the lung and stem cell contributions to both the immunomodulation of lung diseases and lung repair and regeneration, as well as the potential of stem cell-based therapies in different lung diseases.

The germ layer of the endoderm can contribute to the formation of both the gastrointestinal and respiratory tracts, and other associated organs. The endoderm is generally responsible for the formation of the internal epithelial tube that will eventually become the digestive tract. During embryogenesis, the endoderm represents the inner germ layer in both triploblastic and diploblastic embryos. The anterior–posterior (A–P) and proximal–distal (P–D) patterning are among the earliest developmental events during embryogenesis. They are tightly regulated with a highly coordinated network of several signaling molecules and pathways. Accumulated data in the last two decades from studies on animal model organisms have enhanced our understanding of the anterior endoderm development and patterning and P–D patterning of the lung. These data have also uncovered many of the molecular mechanisms and signaling molecules that regulate these processes. In this chapter, we will describe this progress with a focus on the anterior endodermal patterning and its regulatory molecular mechanisms and signaling pathways, as well as the P–D patterning of lung embryonic cells. Lastly, we discuss the role of stem and progenitor cells in the P–D patterning of the lung.

New data have recently accumulated on how stem cell behave, self-renew and differentiate. Many studies have also focused on defining stem cells, and determination of the properties, including the mode of cell division and polarity, and regulatory environment(s) of both embryonic and tissue-specific stem cells in the last decades. In the lung, recent data show evidences that lung epithelial stem and progenitor cells are polarized, highly mitotic, have characteristic perpendicular cell divisions, and show a mode of division that is similar to other systems. They further show that the asymmetric division is probably the common mode of division in the mitotically dividing distal epithelial stem and progenitor cells of the embryonic lung. Both symmetric and asymmetric mode of cell divisions are tightly regulated in different stem cell types during tissue development and morphogenesis. How to choose between a symmetric and asymmetric cell division is one of the major questions in the stem cell field. It largely affects tissue development, morphogenesis and disease in different organs since improper asymmetric divisions badly affect organ morphogenesis, whereas uncontrolled symmetric division can lead to tumor formation. Moreover, the proper balance between self-renewal and differentiation of lung epithelial stem and progenitor cells is absolutely required for maintaining normal lung morphogenesis and for lung repair and regeneration since a deficiency of this balance probably can lead to a premature or injured lung. Therefore, identification of lung-specific stem cell types, understanding their behavior, and how they balance their self-renewal and differentiation could lead to the identification of innovative solutions for restoring normal lung morphogenesis and/or regeneration and repair of the lung. Furthermore, understanding the molecular mechanisms that control the asymmetrical cell division and both cell polarity and fate of lung epithelial stem and progenitor cells can help identifying new targets for prevention and rescuing lethal lung diseases in infants and children, and for regeneration of injured lungs. In this chapter, we will discuss recently accumulated data on the lung cell polarity, and the mode of division of lung epithelial stem and progenitor cells. In addition, we will describe the functions of Numb in stem cell fate and mode of division, and compare cell polarity and mode of division in the lung stem cells with other systems, as well as discuss the regulatory mechanisms of lung stem cell polarity, fate, behavior and mode of division.