In utero nicotine exposure alters fetal rat lung alveolar type II cell proliferation, differentiation, and metabolism

Abstract

We recently suggested that alveolar interstitial fibroblast-to-myofibroblast transdifferentiation may be a key mechanism underlying in utero nicotine-induced lung injury. However, the effects of in utero nicotine exposure on fetal alveolar type II (ATII) cells have not been fully determined. Placebo, nicotine (1 mg/kg), or nicotine (1 mg/kg) + the peroxisome proliferator-activated receptor (PPAR)-gamma agonist prostaglandin J(2) (PGJ(2), 0.3 mg/kg) was administered intraperitoneally once daily to time-mated pregnant Sprague-Dawley rats from embryonic day 6 until their death on embryonic day 20. Fetal ATII cells were isolated, and ATII cell proliferation, differentiation (surfactant synthesis), and metabolism (metabolic profiling with the stable isotope [1,2-(13)C(2)]-d-glucose) were determined after nicotine exposure in utero or in vitro. In utero nicotine exposure significantly stimulated ATII cell proliferation, differentiation, and metabolism. Although the effects on ATII cell proliferation and metabolism were almost completely prevented by concomitant treatment with PGJ(2), the effects on surfactant synthesis were not. On the basis of in utero and in vitro data, we conclude that surfactant synthesis is stimulated by nicotine's direct effect on ATII cells, whereas cell proliferation and metabolism are affected via a paracrine mechanism(s) secondary to its effects on the adepithelial fibroblasts. These data provide evidence for direct and indirect effects of in utero nicotine exposure on fetal ATII cells that could permanently alter the "developmental program" of the developing lung. More importantly, concomitant administration of PPAR-gamma agonists can effectively attenuate many of the effects of in utero exposure to nicotine on ATII cells.

Antenatally administered PPAR-γ agonist rosiglitazone prevents hyperoxia-induced neonatal rat lung injury

“…To elaborate on the mechanism of the effects of hyperoxia on lung injury and how it is mediated by RGZ, e20 fetal rat lung fibroblasts were cultured according to previously described methods (20). At 80% confluence, cells were pretreated for 1 h with either transforming growth factor (TGF)-␤1, -␤2, or -␤3 antibody (10 M, R&D System, Minneapolis, MN) or RGZ (10 M, St. Louis, MO).…”

“…The trafficking of neutral lipid from the circulation is mediated by the lipofibroblast phenotype (34), which is determined by the expression of peroxisome proliferator-activated receptor-␥ (PPAR-␥), which plays a critical role in normal lung development and injury/repair (30,35). Our laboratory has recently shown that administration of PPAR-␥ agonist rosiglitazone (RGZ) postnatally enhances lung maturation and can prevent hyperoxia-induced neonatal lung injury, suggesting the potential therapeutic usefulness of PPAR-␥ agonists in preventing and/or treating bronchopulmonary dysplasia (4,20,36). However, it is not known whether administration of PPAR-␥ agonists antenatally could prevent neonatal lung injury.…”

The Effect of Prenatal Exposure to Nicotine versus Thiocyanate on Pituitary-Testicular Axis of Juvenile Albino Rats: A Comparative Histological and Electron Microscopic Study

“…In adition, rapidly dividing cells are more vulnerable to the effects of foreign substances such as nicotine [30]. Now it is more interesting to show our finding on examining testicular sections.…”

Transgenerational Effects of Maternal Nicotine Exposure During Gestation and Lactation on the Respiratory System

“…This is important as nicotine is genotoxic [30] and induces the release of oxidants [31]. Since rapidly dividing cells are more vulnerable to the effects of foreign substances such as nicotine [32], it is conceivable that nicotine exposure during gestation and early postnatal life via maternal milk may interfere with growth and development. This can be achieved in two ways: by having a direct effect on cells and/or by reducing the nutrient supply to the fetus during gestation and lactation.…”

“…It has been shown that long-term nicotine exposure results in a predisposition for the induction of genetic instability [32,34,45]. Gene amplification is a hallmark of gene instability.…”