Developmental Airway Cell Biology

There is increasing awareness in the research community that events in early childhood have a profound influence on the expression of respiratory disease in later life, but is there any value in studying airway cells from healthy children? Why not use the extensive body of information about airway cells derived from adult volunteers? Adults are easy to recruit, whereas ingenious and time-consuming ways of sampling the lower airways of children must be devised to overcome ethical problems. Even if there are developmental changes, could these be defined in animal models? There are several reasons why children must be studied. First, research published within the last 5 yr clearly shows that there are major changes in immunocompetent and inflammatory cells during normal human development. Second, there are significant species differences in the release of mediators by immunocompetent cells. Third, age-associated changes in human airway cells are a result of complex interactions between genetic and environmental factors. It is therefore impossible to model the combination of even a handful of potential variables, for example, frequency of colds, exposure to lipopolysaccharide, nutritional state, and age. The technique of bronchoalveolar lavage (BAL) before elective surgery, initially developed to overcome the ethical problems of sampling cells from normal children, is uniquely suited to studying large numbers of individuals (the mean number of children per study is currently more than 50). It is now possible to tease out the independent effects of environmental stimuli on airway cell function. Clues to the relevant factors have been provided by epidemiological research. For example, having older siblings reduces the risk of aeroallergen sensitization (1). This association, if true, must also be associated with an effect on immune function at the cellular level. The goal of pediatric airway cell research is therefore not just to generate normal values for comparison with established disease, but to focus on the critical functional mechanisms that protect the normal lung from developing disease. Although the lung of the young child may seem to be particularly vulnerable to a range of environmental insults (2), this does not necessarily reflect immaturity of airway cell function. Young children may have more respiratory infections not because of a defect in microbial killing by cells, but because their immunoglobulin repertoire is not fully developed. Similarly, early childhood may seem to be the vulnerable period for antigen sensitization, not because of a possible immaturity in the ability of alveolar macrophages (AMs) to suppress pulmonary immune cells (3), but because it is the period when the lung is first exposed to antigen. These considerations are important, because a true developmental immaturity of airway cell function may be amenable to accelerated maturation by exposure to an appropriate environmental factor (e.g., exposure to traditional farms) (4), or an anthroposophic lifestyle (5).