The role of TGFb in alveolar epithelial homeostatic turnover in mice

The lung epithelium consists of alveolar Type I (ATI) and Type II (ATII) cells, with ATI cells covering the majority of the alveolar surface due to their thin, elongated shape. During homeostasis, there is slow cell turnover. ATI and ATII cells occasionally die, and the thicker, cuboidal ATII cells act as progenitor cells by proliferating and differentiating into new ATI cells. The rate of ATII cell proliferation during homeostasis is slow since ATII cells only proliferate if ATI or ATII cells perish, but exactly how slow is unknown. Moreover, the mechanisms that suppress ATII cell proliferation during homeostasis are unknown. We used unbiased stereological analysis to more accurately calculate the rate of ATII cell turnover in uninjured mice during homeostasis. Stereology refers to the three-dimensional analysis of tissue using measurements performed on two-dimensional sections, which provides more accurate measures of cell counts. We also investigated whether the transforming growth factor beta (TGFb) protein suppresses ATII cell proliferation during homeostasis. We studied the effect of the TGFb protein on ATII cell proliferation by using stereological analysis to compare ATII cell proliferation over a 3-month period between wild-type mice and mice with the TGFb receptor knocked out in ATII cells. The rate of ATII cell turnover during homeostasis varied among different litters of mice but had a range between 0.49-1.41% per day. TGFb receptor knock-out mice had a nonsignificant trend towards higher total ATII cell counts after 3 months compared to wild-type mice. However, since this difference was statistically insignificant, no conclusions can currently be made about TGFb's role as a repressor of ATII cell proliferation during homeostasis. Strengthened understanding of these molecular mechanisms may ultimately lead to development of new clinical treatments that accelerate lung repair in individuals with excessive lung damage, such as patients with lung fibrosis and emphysema.