Rationale: The underlying mechanisms and effector molecules involved in mediating in utero smoke exposure-induced effects on the developing lung are only beginning to be understood. However, the effects of the newly discovered category of smoke, i.e., thirdhand smoke (THS), on the developing lung are completely unknown. We hypothesized that in addition to nicotine, other components of THS would also affect lung development adversely. Methods: Fetal rat lung explants were exposed to nicotine, 1-(N-methyl-N-nitrosamino)-1-(3-pyridinyl)-4-butanal (NNA), or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the two main tobacco-specific N-nitrosamine constituents of THS, for 24h. Following which key markers for alveolar paracrine signaling [epithelial differentiation markers, surfactant phospholipid and protein synthesis and mesenchymal differentiation markers, PPARγ, fibronectin, and calponin], the BCL-2/Bax ratio, a marker of apoptosis, and the involvement of nicotinic acetylcholine receptors (nAChR)-α3 and -α7 in mediating NNA's and NNK's effects on the developing lung were determined. Main Results: Similar to the effects of nicotine, exposure of the developing lung to either NNK or NNA resulted in disrupted homeostatic signaling, indicated by the down-regulation of PPARγ, up-regulation of fibronectin and calponin protein levels, decreased BCL-2/Bax ratio, and the accompanying compensatory stimulation of surfactant phospholipid and protein synthesis. Furthermore, nAChR-α3 and -α7 had differential complex roles in mediating these effects. Conclusions: NNK and NNA exposure resulted in breakdown of alveolar epithelial-mesenchymal cross-talk, reflecting lipofibroblast-to-myofibroblast transdifferentiation, suggesting THS constituents as possible novel contributors to in utero smoke exposure-induced pulmonary damage. These data are particularly relevant for designing specific therapeutic strategies, and for formulating public health policies to minimize THS exposure.
- Thirdhand smoke
- Lung development
- Copyright © 2010, American Journal of Physiology - Lung Cellular and Molecular Physiology