Abstract
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.