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Environmental Tobacco Smoke Suppresses Nuclear Factor-B Signaling to Increase Apoptosis in Infant Monkey Lungs

Center for Health and the Environment, and Department of Pediatrics, University of California, Davis, California

Correspondence and requests for reprints should be addressed to Dr. Kent E. Pinkerton, Center for Health and the Environment, University of California, Old Davis Road, Davis, CA 95616. E-mail: kepinkerton{at}ucdavis.edu

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)-B, 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/m³ 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-B–DNA binding activity, regulated anti-apoptotic genes, and apoptosis were measured in lung tissues. Exposure to environmental tobacco smoke significantly suppressed NF-B activation pathway and activity. Environmental tobacco smoke further down-regulated NF-B–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-B plays a key role in the regulation of the apoptotic process.

Key Words: apoptosis • environmental tobacco smoke • infant monkeys • lung development • NF-B

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