The proliferative effects of retinoic acid on primary cultures of adult rat type II pneumocytes depend upon cell density

Abstract

Retinoic acid (RA) is important for maintaining integrity of alveolar epithelial cells, but the mechanism has not been defined. We cultured type II pneumocytes at confluent, high cell density (10(4) cells/mm(2)) and found that RA (10(-6) M) inhibited thymidine incorporation to 60% of control, despite a dose-dependent increase in epidermal growth factor receptor (EGFR) levels. However, at lower, subconfluent density (10(2) cells/mm(2)), RA stimulated thymidine incorporation to 280% of control. EGF increased thymidine incorporation at concentrations as low as 0.1 ng/mL, but no further increase was observed at higher concentrations up to 100 ng/mL. In subconfluent cells co-treated with EGF (100 ng/mL) and increasing concentrations of RA (10(-8) M-10(-5) M RA), thymidine incorporation was significantly greater at all concentrations than RA alone, with greatest increases observed at 10(-7) (422% of control) and 10(-6) (470% of control) M RA. In summary, the effects of RA on thymidine incorporation are sensitive to changes in cell density. RA inhibits thymidine incorporation at high cell density and stimulates thymidine incorporation at low density. RA increases EGFRs in cultured type II pneumocytes, and EGF stimulates thymidine incorporation independent of the cultured cell density. These data may help to explain how RA mediates lung repair in vivo.

Deficient retinoid-driven angiogenesis may contribute to failure of adult human lung regeneration in emphysema

“…Together, this suggests that RA signalling does not directly regulate alveolar epithelial repair. This was surprising and contrasts with previous reports of a proliferative role of RA in rat neonatal alveolar epithelial cells,38 suggesting the role of RA signalling in juvenile and adult alveolar epithelium may be distinct. Therefore, although alveolar epithelial growth necessarily occurs during RA-induced adult lung regeneration, this may be indirect, mediated by effects of RA on other lung cell types.…”

Integrated Transcriptomic and Epigenomic Analysis of Primary Human Lung Epithelial Cell Differentiation

“…Retinoid X receptors can homodimerize or heterodimerize with a large variety of proteins, including retinoic acid receptors (RARs), thyroid hormone receptor (THR), the vitamin D receptor (VDR), farnesoid X receptor (NR1H4) and other nuclear receptors (NRs), as well as the family of peroxisome proliferator-activated receptors (PPARs) [40]. While retinoic acid and its receptor has been implicated in lung development and injury [41]–[48] the precise role of RXR remains to be clarified. Because of their many potential binding partners, the function of RXRs can be complex; certain NR heterodimers (e.g.…”

Effect of keratinocyte growth factor on growth and transdifferentiationof primary alveolar epithelial type II cells

“…Our observations are consistent with these results, suggesting that higher SP-C levels induced by KGF treatment may be an intrinsic protective mechanism in pulmonary injury. Earlier studies showed that AECIIs are the progenitors of alveolar epithelial cells (16). After lung injury and AECI damage, AECIIs can proliferate and repair the epithelium.…”