Clara cell heterogeneity in differentiation: correlation with proliferation, ultrastructural composition, and cell position in the rat bronchiole.

Postnatal differentiation of nonciliated bronchiolar epithelial (Clara) cells occurs in a wave-like pattern beginning in the upper airways and ending in the terminal bronchiole. The heterogeneity of Clara cell differentiation observed during postnatal development in rats may be due to both cell turnover rate and cell position in the airways. To test the importance of these two factors in Clara cell differentiation, terminal bronchioles were examined in rats from gestational day 21 through postnatal day 100. The volume fraction of smooth endoplasmic reticulum (SER), a marker of differentiation, was seen to increase with age, while the epithelial cell labeling index of terminal bronchioles decreased over the same period. This represented a significant inverse correlation between SER volume density and cell proliferation rates (r2 = 0.80, P < 0.02). To evaluate the importance of cell position as a factor in cellular differentiation, the abundance of SER and secretory granules and the expression of cytochrome P450 isozyme 2B in Clara cells were examined along the entire length of the terminal bronchiole in animals 1, 21, and 100 days of age. For all three characteristics, Clara cells showed a similar degree of maturation from the proximal bronchiolar bifurcation to the bronchiole-alveolar duct junction (BADJ) (a span of approximately 35 cells). We conclude that during prenatal and postnatal bronchiolar development in rats: (1) the Clara cell is the most actively dividing cell type for the lower airways; (2) the stage of Clara cell differentiation is inversely related to Clara cell mitotic activity; and (3) the heterogeneity of Clara cell maturation and mitotic activity is not influenced by position within the terminal bronchiole.