Introduction: Perinatal infection in combination with exposure to nicotine confers a high risk for fetal death, growth restriction and poor lung development in infants. Alarmingly, up to 25% of Australian women continue to smoke throughout pregnancy, while 30% have a subclinical infection during their pregnancy. To date it is not known why the combination of smoking and infection during pregnancy is so dangerous to the infant. In a recent study in mice, we found that nicotine and lipopolysaccharide (LPS) treatment in pregnancy causes high mortality in mouse pups. In seeking an explanation for this finding we focused on whether the insults could exert their effect through the epithelial sodium channel (ENaC) which is essential for lung liquid reabsorption in late labour and the newborn period. We hypothesize that the pups that received the combination of prenatal insults have an increase in lung inflammation and reduced ENaC activity.
Methods: At day 14 of pregnancy, C57BL/6 dams were implanted with osmotic mini-pumps that delivered nicotine (NIC, 6mg/kg/day) or a control vehicle (VEH) for 14 days. At E16, the implanted mice were either additionally injected with LPS (150µg/kg; ip) or left untreated. At E18, lungs were harvested for cytokine analysis, histological examination of lung architecture, abundance of pulmonary IL1-β and α-ENaC expression.
Results: An increase in IL1-β, IL-4, IL-5, IL-16, and IL-17 was observed in NIC and NIC+LPS lung tissue compared to controls. Immunohistochemistry confirmed a profound up-regulation of IL1-β in lungs treated with NIC alone, or in combination with LPS. At a molecular level at E18, the lungs from NIC+LPS pups exhibited a decrease in α-ENaC expression on alveolar luminal surface compared to the VEH pup
Conclusion: Our findings suggest the lethality of antenatal nicotine and inflammation results from impaired gas exchange across a wet and inflamed pulmonary epithelium.