Possible role of the alpha7 nicotinic receptors in mediating nicotine's effect on developing lung - implications in unexplained human perinatal death

Background It is well known that maternal smoking during pregnancy is very harmful to the fetus. Prenatal nicotine absorption, in particular, is associated with alterations in lung development and functions at birth and with respiratory disorders in infancy. Many of the pulmonary disorders are mediated by the interaction of nicotine with the nicotinic receptors (nAChRs), above all with the alpha7 nAChRs subunits that are widely expressed in the developing lung. To determine whether the lung hypoplasia frequently observed in victims of sudden fetal and neonatal death with a smoker mother may result from nicotine interacting with lung nicotinic receptors, we investigated by immunohistochemistry the possible presence of this specific nAChR subunit overexpression in these pathologies. Methods In lung histological sections from 45 subjects who died of sudden intrauterine unexplained death syndrome (SIUDS) and 15 subjects who died of sudden infant death syndrome (SIDS), we applied the radial alveolar count (RAC) to evaluate the degree of lung maturation, and the immunohistochemical technique for nAChRs, in particular for the alpha7 nAChR subunit. In the same cases, an in-depth study of the autonomic nervous system was performed to highlight possible developmental alterations of the main vital centers located in the brainstem. Results We diagnosed a "lung hypoplasia", on the basis of RAC values lower than the normal reference values, in the 63% of SIUDS/SIDS group and in 8% of controls. In addition, we observed a significantly higher incidence of strong alpha7 nAChR immunostaining in lung epithelial cells and lung vessel walls in sudden fetal and infant death cases with a smoker mother than in age-matched controls. Hypoplasia of the raphe, the parafacial, the Kolliker-Fuse, the arcuate and the pre-Botzinger nuclei was simultaneously present in the brainstem of these victims. Conclusions These findings demonstrate that when crossing the placenta, nicotine can interact with nicotinic receptors of both neuronal and non-neuronal cells, leading to both lung and nervous system defective development. This work stresses the importance of implementing preventable measures to decrease the noxious potential of nicotine in pregnancy.