Background In utero nicotine exposure is known to disrupt fetal lung alveolar development significantly. However, the mechanism underlying this disruption is not known. Our recent work has implicated alveolar interstitial lipofibroblast-to-myofibroblast transdifferentiation as a key contributing mechanism. However, the effect of nicotine on alveolar type II (ATII) proliferation, differentiation, and metabolism have not been fully explored.
Objective To determine the effect of in utero nicotine exposure on ATII cell proliferation, differentiation, and metabolism.
Methods Time-mated pregnant Sprague Dawley rats were divided into controls (placebo), nicotine, and nicotine + Peroxisome Proliferator Activated Receptor (PPAR)γ agonist groups. Pregnant dams received placebo (diluent), nicotine (1 or 2 mg/kg) alone, or nicotine (2 mg/kg) with a PPARγ agonist, prostaglandin J2 (PGJ2) i. p. in 100 μl volumes once daily from embryonic day (e) 6 of gestation until their sacrifice on e20, when ATII cells were isolated following the standard techniques. Cells were grown in 6- and 96-well plates, 100-mm dishes, and T-75 cm2 flasks, as needed. Cell proliferation was studied by tetrazolium dye assay, differentiation by Surfactant Protein-B expression and choline incorporation into saturated phosphatidylcholine, and metabolism by metabolic profiling using stable isotope [1,2-13C2]-D-glucose as a single tracer to measure lactate, RNA ribose, glutamate and fatty acid production rates.
Results In utero nicotine affected cell proliferation and differentiation in a dose-dependent manner and this affect was completely prevented by the concomitant PGJ2 administration. Further, metabolic profiling of cultured ATII cells indicated profound changes, also in a dose-dependent manner. One mg of nicotine significantly increased RNA synthesis through the non-oxidative transketolase pathway along with a significant increase in de novo fatty acid synthesis of the long-chain saturated species. Two mg/kg nicotine had an adverse effect on fatty acid synthesis from glucose by inducing a significant decrease in de novo palmitate, stearate and oleate synthesis. All of these metabolic changes were also completely prevented by PGJ2 administration to the mother.
Conclusions Our data, for the first time, explain the changes in ATII proliferation and differentiation in response to in utero nicotine exposure on the basis of significant cell metabolic alterations, which can be completely prevented by targeting PPARγ and other specific metabolic targets.
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