Abstract
We report here senescent changes in the structure and organization of the mucociliary pseudostratified epithelium of the mouse trachea and main stem bronchi. We confirm previous reports of the gradual appearance of age-related, gland-like structures (ARGLS) in the submucosa, especially in the intercartilage regions and carina. Immunohistochemistry shows these structures contain ciliated and secretory cells and Krt5+ basal cells, but not the myoepithelial cells or ciliated ducts typical of normal submucosal glands. Data suggest they arise de novo by budding from the surface epithelium rather than by delayed growth of rudimentary or cryptic submucosal glands. In old mice the surface epithelium contains fewer cells per unit length than in young mice and the proportion of Krt5+, p63+ basal cells is reduced in both males and females. However, there appears to be no significant difference in the ability of basal stem cells isolated from individual young and old mice to form clonal tracheospheres in culture or in the ability of the epithelium to repair after damage by inhaled sulfur dioxide. Gene expression analysis by Affymetrix microarray and quantitative PCR, as well as immunohistochemistry and flow sorting studies, are consistent with low-grade chronic inflammation in the tracheas of old versus young mice and an increase in the number of immune cells. The significance of these changes for ARGL formation are not clear since several treatments that induce acute inflammation in young mice did not result in budding of the surface epithelium.
Highlights
Recent studies in a variety of epithelial tissues have shown that aging is associated with a loss of homeostasis and alterations in stem cells and their niches
We found age-related glandlike structures (ARGLS) intermingled with normal submucosal glands (SMGs) in the proximal trachea (Fig 1F)
ARGLS were never seen to connect to the surface epithelium by ducts lined by multiciliated cells, a feature typical of SMGs (Fig. 1E); rather it appears that their contents could be released directly into the tracheal lumen (Fig. 1F)
Summary
Recent studies in a variety of epithelial tissues have shown that aging is associated with a loss of homeostasis and alterations in stem cells and their niches. The trachea and main stem bronchi of the mouse lung, and most of the intralobar airways of the human lung, are lined by a pseudostratified mucociliary epithelium [12] This contains mainly ciliated cells and different classes of secretory cells (serous, club/ Clara and goblet cells) that change in their proportion along the proximal-distal axis. The airways of the human lung contain numerous submucosal glands (SMGs) These are composed of acini with serous and mucus secretory cells and myoepithelial basal cells. In 1970 Nettesheim and Martin reported the presence in old mice of numerous epithelial cysts in the submucosal tissue underlying the lumen of the distal trachea and extralobar bronchi Small clusters of these age-related glandlike structures (ARGLS) were seen at 7 months and they increased in number up to 2 years [17]. Our findings indicate that senescence of the mouse lung is associated with numerous changes in the cellular composition, organization and local microenvironment of the epithelium lining the upper airways
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