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Lung cancer stem cells arise from mutations in lung epithelial stem and progenitor cells that reside in the conducting airways and alveolar bed. This chapter summarizes how the inappropriate reactivation of developmental programs, and the dynamic bidirectional communication between lung cancer stem cells and their cancerized niche, determines the course of lung cancer initiation, progression and metastasis, and the development of inter- and intra-tumor heterogeneity.

In vivo inhalation methods for respiratory toxicity and disease in laboratory animals are time-consuming, technically demanding and of doubtful relevance for predicting effects in humans. They can also cause great suffering to the animals used. Fortunately, there has been increasing interest in developing in vitro alternatives. They can greatly simplify exposure and dosimetry, while using human cell lines and primary cells representative of all the cell types of the conducting airways. Maintained on membranes, fed basally and exposed apically at the air‒liquid interface, the cells retain their in vivo-like properties long enough for even chronic exposure and response studies to be undertaken. The predictive performance of several models is showing encouraging signs of improvement, especially when undertaken in conjunction with the latest airway particle deposition and gaseous exchange algorithms. Additional improvements in test substance delivery, automation and miniaturisation continue to be made. However, there needs to be more guidance and harmonisation applied to: (a) exposure modelling; (b) the need for exogenous metabolic activation; and (c) the use of positive and negative controls. With levels of inhalation testing and pulmonary diseases increasing, the need to expedite validation is now urgent. There are signs that the necessary dialogue and cooperation between the principal stakeholders is starting to occur, but regulatory authorities need to take the initiative to ensure that ‘actions speak louder than words’.

This chapter focuses on the epithelium of the distal conducting airways, or bronchioles, with emphasis on the area of transition between conducting airways and the gas-exchange area. The bronchiolar region has a substantial variation from one species of mammal to the next. This variability includes the microenvironment in which epithelial cells are found, particularly the zone of transition between bronchiolar, non-gas exchange regions and the alveolar gas-exchange regions. There is also considerable interspecies variability in the general composition of the bronchiolar epithelium. The principal alterations involve the distribution, number, and percentage of the population that is nonciliated cells. In addition, there is substantial variability in the composition and differentiated expression of the nonciliated epithelial population in this region.

The lung predominantly functions as a gas exchange unit between air and blood. Air and blood reach the gas exchange region via parallel conduction pathways. The tissues that form these units must also themselves be supplied with nutrients and oxygen. There has to be regulation of both blood flow and airflow into the exchange region in order to respond to changes in demand, which is accomplished via neural and locally acting reflexes. Finally, given the environmental exposure of the lung via the airways, there has to be a protective mechanism against harmful agents, including particulates, oxidants, and microorganisms. In order to accomplish this, the lung's major anatomical components are the airway, including the conducting airways and the alveoli; the vasculature, including both pulmonary and systemic circulations; the interstitium, including all supporting tissues, smooth muscles, and nerves; and finally the hematopoietic elements that provide host defense.

A summary of airway structural components with diagrams of the lung and conducting airways (trachea, bronchial divisions). The cellular structure of the conducting airways is presented in a table. The action of pharmacologic agents (drugs) on the physiology of airway function is discussed.

Like other organs, the lung is influenced by its nutritional environment during development. As lung tissue has a limited capacity to remodel itself following altered development, nutritionally induced alterations in lung structure can persist throughout life. Epidemiological evidence indicates that sub-optional nutrition during early life, leading to fetal growth restriction or retarded postnatal growth, can lead to impaired lung function in later life. Restricted nutrient intake during development can impact upon alveolarization and the small conducting airways; tethering of small airways is diminished. Although multiple tissue components of the lung can be affected by nutritional impairment during development, those most likely to have persistent effects on lung function are structural proteins such as elastin and basement membrane proteins. The long-term persistence of alterations in lung function and structure may be a reflection of the effective cessation of alveolarization in early life and epigenetic changes induced by early life exposures.

The anatomical character of both the conducting airways and of the functional gas exchange region exerts an important influence on rates of deposition of inhaled aerosol. In the present studies an attempt is made to use the rate of deposition of aerosol particles in the respiratory tract during breath-holding as an index of the effective lumen diameters of the respiratory branches. During breath-holding for periods up to about 30 sec, the ratio of exhaled to inhaled aerosol decreases exponentially with time; this was observed for all subjects at particle sizes from about 0×15 to 1×0 micron. Calculations of lumen diameter based on these observations yielded estimates which are consistent with those obtained by microscopic measurements on human lungs.