Perinatal infection in combination with exposure to nicotine confers a high risk for fetal death, growth restriction and poor lung development in human 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. Here we present an unexpected finding that nicotine and lipopolysaccharide treatment of pregnant mice cause high mortality in mouse pups: in seeking an explanation for this finding we focused on whether the insults could exert their effect through an action on the developing lungs.
At day 14 of pregnancy, C57BL/6 dams were implanted with osmotic minipumps that delivered nicotine (NIC, 6mg/kg/day) or a control vehicle (VEH) for 14 days. At day 16 of pregnancy, the implanted mice were either additionally injected with LPS (150µg/kg;ip) or left untreated. After birth, the lungs of surviving pups were harvested for cytokine analysis. In separate pups we compared wet/dry lung ratios between NIC+LPS vs VEH treated groups.
On day 1, the mortality of untreated pups was zero, but showed a tendency to rise to 50% in NIC pups (p=0.055) and rose to 90% in those treated with NIC+LPS (p<0.01). A significant increase in MIP-2 concentration was observed in NIC and NIC+LPS groups compared to controls (VEH vs. NIC:128.2±20.42 vs.246.7±27.60 pg/ml; VEH+LPS vs.NIC+LPS:75.68±8.9 vs.312.7±19.27 pg/ml, p<0.0001). NIC+LPS pups also had a higher wet/dry lung ratio compared to the VEH pups (6.572±0.18 vs 5.386±0.21 p<0.0002).
Our findings suggest the lethality of antenatal nicotine and inflammation results from impaired gas exchange across a wet and inflamed pulmonary epithelium.