Pathogenesis of Mucous Cell Metaplasia in a Murine Asthma Model

Abstract

Increased mucus production in asthma is an important cause of airflow obstruction during severe exacerbations. To better understand the changes in airway epithelium that lead to increased mucus production, ovalbumin-sensitized and -challenged mice were used. The phenotype of the epithelium was dramatically altered, resulting in increased numbers of mucous cells, predominantly in the proximal airways. However, the total numbers of epithelial cells per unit area of basement membrane did not change. A 75% decrease in Clara cells and a 25% decrease in ciliated cells were completely compensated for by an increase in mucous cells. Consequently, by day 22, 70% of the total epithelial cell population in the proximal airways was mucous cells. Electron microscopy illustrated that Clara cells were undergoing metaplasia to mucous cells. Conversely, epithelial proliferation, detected with 5-chloro-2-deoxyuridine immunohistochemistry, was most marked in the distal airways. Using ethidium homodimer cell labeling to evaluate necrosis and terminal dUTP nick-end labeling immunohistochemistry to evaluate apoptosis, this proliferation was accompanied by negligible cell death. In conclusion, epithelial cell death did not appear to be the stimulus driving epithelial proliferation and the increase in mucous cell numbers was primarily a result of Clara cell metaplasia. (Am J

Differential expression of chitinases identify subsets of murine airway epithelial cells in allergic inflammation

“…1B, arrow), whereas there is no mucus in the most distal airways (Fig. 1C, first column) as has previously been reported (16,40). AMCase expression is a mirror image of mucus expression in which central airways are negative (Fig.…”

“…Qualitative differences in response to quantitatively differing doses of IL-13 have also been described (1). Previous work on mucus induction in proximal airway cells was unable to address the issue of differences in the local production of mediators being responsible for the effects seen (16,40). Although we could not directly measure concentrations of IL-13 along the airway, our in situ hybridization result indicates that differences in local amounts of IL-13 cannot account for production of mucus in proximal airways.…”

“…However, the inflammatory infiltrate in the distal airways is comparable to that seen in the proximal airways. Previous work has shown that this pattern holds despite multiple administrations of antigen (16,40). Finally, this explanation would only apply to the transgenic mice if there were a limiting amount of IL-13 in the distal airway of these animals as well.…”

“…However, it is noteworthy that basal cells only exist in the proximal airway and thus can only contribute to proximal airway epithelial repair, whereas local stem cells for distal airway cells include so-called variant Clara cells, cells that express CCSP but not CYP-2F2 (22,23,41). Finally, it is known that the proximal but not distal secretory cells undergo mucus metaplasia in response to allergic inflammation, whereas distal cells undergo relatively more proliferation under the same stimulus (16,40). Thus much previous data suggest both qualitative and quantitative differences between proximal and distal CCSP-expressing secretory cells.…”

“…In murine asthma models, this increase in mucus production is limited to the surface epithelium, since no submucosal glands exist in the mouse lung proper, although submucosal glands do exist in the proximal trachea near the thyroid. Mucus production in mice is due to acquisition of a mucus phenotype in secretory cells expressing the Clara cell marker Clara cell secretory protein (CCSP) rather than to proliferation of existing mucus-producing cells (16,40). Strikingly, in mice, only the Clara cells of the proximal airway undergo this change, whereas those of the distal airway do not.…”