American Journal of Respiratory and Critical Care Medicine

The airway epithelium is the first point of contact for the lung with many constituents of the environment, such as bacteria and viruses, allergens, particulate or gaseous pollutants, and cigarette smoke. While providing a physical hurdle to these potential insults, the airway epithelium has evolved additional defense mechanisms, including specific adaptive responses. Epithelial cells are metabolically active and are capable of contributing to inflammation by generating inflammatory cytokines and chemokines, of repairing themselves and proliferating after injury, and of communicating and interacting with adjacent mucosal cells, such as dendritic cells and fibroblasts. Although this fundamental response of the airway epithelium is important in determining protective immunity, it could also dictate the pathophysiology of many lung diseases, including asthma, which is the most common chronic airway disease, affecting up to 10% of the population, and associated with significant morbidity and mortality.

Studies of mucosal biopsies and primary cultures of airway epithelial cells from patients with asthma have indeed established that the airway epithelium is abnormal (1). There are increased mucous goblet cells in the asthmatic epithelium. The epithelium could also be a site for amplification of asthmatic inflammation since there is an increase in the baseline expression of the proinflammatory cytokines interleukin (IL)-8 and granulocyte-macrophage colony–stimulating factor (GM-CSF) (2, 3), and in the inducibility of the chemokines IL-8, GM-CSF, RANTES (regulated upon activation, normal T-cell expressed and secreted), and macrophage inflammatory protein-3α (MIP-3α [CCL20]) by T-helper (Th) type 2 cytokines, including IL-4 and IL-13, and by environmental particulates (47). Overexpression of receptors such as protease-activated receptor-2 (PAR-2) and epithelial growth factor receptor (EGFR) (8, 9), which mediate the processes of repair and proliferation, is an indication that the asthmatic epithelial cell may possess such propensities in response to injury. Paradoxically, the airway epithelium in bronchial biopsies from patients with asthma has been reported to express less of the proliferation marker proliferating cell nuclear antigen (PCNA), which has been attributed to an increased expression of p21waf, a cyclin-dependent kinase inhibitor that negatively regulates cell growth (10, 11).

In this issue of the Journal (pp. 1110–1118), Kicic and colleagues (12) report that airway epithelial cells obtained from children with asthma demonstrate biochemical and functional differences that could be nearer to an inherent asthmatic diathesis. Previous studies that demonstrated alterations of the airway epithelium in adults with asthma could have been secondary to the effects of the concomitant airway inflammation or to the effects of treatment used by the patient. Several points about the experimental approach used in this study are worth comment. First, Kicic and colleagues safely and ethically obtained viable epithelial cells from patients as young as 2 yr of age with very mild untreated atopic asthma. However, what is missing in the study are cells obtained from adult patients with established asthma of varying severity. Second, they also included an atopic nonasthmatic control group, an important comparison that is rarely included in such studies; indeed, some of the differences found in the epithelium could be attributed to the atopic state rather than to the asthma diathesis. Third, these investigators have optimized the use of relatively small numbers of epithelial cells obtained by bronchial brushings for cellular characterization. Proteomic and genomic approaches could be applied to delineate extensively the epithelial abnormality in asthma.

Kicic and colleagues report some findings that contrast with previously reported data, such as no increase in spontaneous release of IL-1β, IL-8, and soluble intercellular adhesion molecule-1, compared with nonasthmatic epithelial cells, but prostaglandin E2 and IL-6 were increased, indicating that epithelial cells were not of a proinflammatory phenotype. Stimulated release of mediators from these epithelial cells would need to be studied. On the other hand, the asthmatic epithelial cells were in a greater proliferative state, with highly elevated expression of PCNA mRNA, an observation that corroborated well with the increase in EGF release, although the expression of EGFR was not reported. The release of transforming growth factor β1 was markedly reduced, which could relate to the lower expression of cytokeratin-19 in the asthmatic cells. However, since these abnormalities were also observed in atopic nonasthmatic cells, they could be secondary to the atopic status. Nevertheless, if these features are those of early asthma, they emphasize the remodeling potential of the airway epithelium in asthma.

Are the findings reported by Kicic and colleagues linked to the cause of asthma? Certainly, the increased proliferation and the expression of EGF could be related to the remodeling potential of the abnormal epithelium in asthma and could be an early feature of asthma that antedates the onset of inflammation. This observation is supported by studies in children with asthma in whom subepithelial fibrosis (measured as thickened reticular basement membrane) has been reported even before the onset of asthma symptoms (13, 14). Although Kicic and colleagues did not obtain evidence of inflammation or remodeling in the children they studied, their findings would fall within the concept of the epithelial–mesenchymal trophic unit, which is important for normal developmental branching morphogenesis in the fetus, remaining abnormally active or being reactivated after birth to induce airway wall remodeling through the expression of remodeling mediators and growth factors (15). In addition, the epithelial abnormality could represent a gene–environment interaction, with the genetic background (for asthma or atopy) leading a stable reprogramming of the epithelial cell response at a very early stage to potential external insults, particularly allergens, viruses, or even pollutants (16). Because the functional and cellular abnormalities reported in the atopic nonasthmatic and atopic asthmatic epithelial cells were preserved with successive passages in culture, the reported abnormalities may be intrinsic to the asthmatic diathesis and unlikely to be secondary to any “inflammatory” factors. A study of the molecular basis of the abnormal epithelial cells obtained from atopic nonasthmatic and atopic asthmatic children and of their interactions with environmental factors and cells such as dendritic cells and fibroblasts may lead us nearer to the origins of asthma. In addition, these studies could firmly establish the airway epithelium as a major orchestrator of asthma.

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