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Published on: January 10, 2015
Environmental tobacco smoke suppresses nuclear factor-kappaB signaling to increase apoptosis in infant monkey lungs
Cai-Yun Zhong1, Ya Mei Zhou, Jesse P Joad
1Center for Health and the Environment, University of California, Old Davis Road, Davis, CA 95616, USA.
Rationale:
Exposure to environmental tobacco smoke in early life has adverse effects on lung development. Apoptosis plays an essential role in development; however, the molecular mechanisms of pulmonary apoptosis induced by environmental tobacco smoke is unknown.
Objectives:
To investigate the mechanistic role of nuclear factor (NF)-kappaB, a critical cell survival pathway, in the developing lungs exposed to environmental tobacco smoke.
Methods:
Timed-pregnant rhesus monkeys and their offspring were exposed to filtered air or to aged and diluted sidestream cigarette smoke as a surrogate to environmental tobacco smoke (a total suspended particulate concentration of 0.99 mg/m(3) for 6 h/d, 5 d/wk) from 45-50 d gestational age to 72-77 d postnatal age (n = 4/group).
Measurements And Main Results:
NF-kappaB-DNA binding activity, regulated anti-apoptotic genes, and apoptosis were measured in lung tissues. Exposure to environmental tobacco smoke significantly suppressed NF-kappaB activation pathway and activity. Environmental tobacco smoke further down-regulated NF-kappaB-dependent anti-apoptotic genes and induced activation of caspases, cleavage of cellular death substrates (poly(ADP)-ribose polymerase and caspase-activated DNase) and an increase in the rate of apoptosis in the lung parenchyma. No significant alterations were observed for activator protein 1, p53 or Akt activity.
Conclusions:
Our results indicate that exposure to low levels of environmental tobacco smoke during a critical window of maturation in the neonatal nonhuman primate may compromise lung development with potential implications for future lung growth and function. These findings support our hypothesis that NF-kappaB plays a key role in the regulation of the apoptotic process.
Insights
Environmental tobacco smoke exposure in infant monkeys suppresses the NF-kappaB survival pathway, increasing lung cell apoptosis. This suggests a mechanism for impaired lung development and potential long-term respiratory issues.
Area of Science:
- Pulmonary Medicine
- Developmental Biology
- Toxicology
Background:
- Early-life exposure to environmental tobacco smoke (ETS) adversely impacts lung development.
- The precise molecular mechanisms driving pulmonary apoptosis due to ETS remain unclear.
Purpose of the Study:
- To elucidate the role of the nuclear factor kappa B (NF-kappaB) pathway in neonatal lung development under ETS exposure.
- Investigate NF-kappaB's function as a critical cell survival pathway in the context of ETS.
Main Methods:
- Timed-pregnant rhesus monkeys and offspring were exposed to filtered air or diluted cigarette smoke (ETS surrogate).
- Exposure occurred from gestational age 45-50 days to postnatal age 72-77 days.
- Lung tissue analysis included NF-kappaB DNA binding activity, apoptosis markers, and related gene expression.
Main Results:
- ETS exposure significantly inhibited the NF-kappaB activation pathway and its DNA binding activity.
- Down-regulation of NF-kappaB-dependent anti-apoptotic genes was observed.
- Increased caspase activation and apoptosis rates were detected in lung parenchyma, while AP-1, p53, and Akt activities remained unchanged.
Conclusions:
- Low-level ETS exposure during neonatal development in nonhuman primates can disrupt lung maturation.
- NF-kappaB plays a crucial role in regulating the apoptotic process in the developing lung.
- These findings highlight potential implications for compromised lung growth and function in later life.
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