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Possible role of the α7 nicotinic receptors in mediating nicotine's effect on developing lung - implications in unexplained human perinatal death.
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Prenatal nicotine absorption, in particular, is associated with alterations in lung development and functions at birth and with respiratory disorders in infancy.In addition, we observed a significantly higher incidence of strong α7 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.This work stresses the importance of implementing preventable measures to decrease the noxious potential of nicotine in pregnancy.
Affiliation: Department of Biomedical, Surgical and Dental Sciences, "Lino Rossi" Research Center for the study and prevention of unexpected perinatal death and SIDS, University of Milan, Via della Commenda 19, 20122 Milan, Italy. anna.lavezzi@unimi.it.
ABSTRACT
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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 α7 nAChR 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 the α7 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 α7 nAChR subunit identification. 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 63% of SIUDS/SIDS cases and 8% of controls. In addition, we observed a significantly higher incidence of strong α7 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 Kölliker-Fuse, the arcuate and the pre-Bötzinger nuclei was at the same time 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 lung and nervous system defective development, respectively. This work stresses the importance of implementing preventable measures to decrease the noxious potential of nicotine in pregnancy. Related in: MedlinePlus |
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Figure 5: Identification of pulmonary perivascular fibroblasts and collagen. A) identification of fibroblastic cells around a lung vessel by FSP-1 immunohistochemistry (brown reaction product). B) Perivascular blue collagen fibers highlighted by histochemistry – SIDS case, 2 month-old. A) FSP-1 immunostain; magnification: 20x - B) AZAN stain; magnification 20×. Mentions: Examination of the immunostained preparations revealed a strong immunoreactivity for the nAChR α7 subunit (“Class 3” of nAChR-I) in densely packed cells of compact lung parenchyma areas (Figure 2) and in epithelium surrounding both alveoli and bronchioles (Figure 3) in 22 SIUDS and 8 SIDS victims. In these cases an intense α7 immunoreactivity was also frequently expressed in fibroblasts of the airway and vessel walls (Figure 4). The vascular walls, in particular, appeared thick due to the increase of connective tissue, as demonstrated by the intense histochemical positivity for the collagen and the positive immunostaining for fibroblasts (Figure 5). |
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Affiliation: Department of Biomedical, Surgical and Dental Sciences, "Lino Rossi" Research Center for the study and prevention of unexpected perinatal death and SIDS, University of Milan, Via della Commenda 19, 20122 Milan, Italy. anna.lavezzi@unimi.it.
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 α7 nAChR 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 the α7 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 α7 nAChR subunit identification. 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 63% of SIUDS/SIDS cases and 8% of controls. In addition, we observed a significantly higher incidence of strong α7 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 Kölliker-Fuse, the arcuate and the pre-Bötzinger nuclei was at the same time 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 lung and nervous system defective development, respectively. This work stresses the importance of implementing preventable measures to decrease the noxious potential of nicotine in pregnancy.
