Regulation of MAPK/AP-1 and NF-kappaB signal pathways in tobacco smoke-induced pulmonary cell proliferation and apoptosis

Tobacco smoke (TS) is the most clear etiological factor in various lung diseases such as lung cancer and chronic obstructive pulmonary disease. Exposure to environmental tobacco smoke (ETS) in early life has substantial adverse effects on the developing lungs, including developmental defects. These diseases are associated with impaired cell growth and apoptosis. The molecular mechanisms for these TS-related diseases remain unclear. It is speculated modulation of critical cell signal pathways such as MAKP/AP-1 and NF-kappaB that sense external insults and control cell proliferation, differentiation and apoptotic processes are implicated in the pathogenesis of TS-related diseases. However, information on the regulation of these signal pathways in response to TS is lacking. The aims of this study were to: (1) examine the effects of TS on pulmonary cell proliferation and differentiation and the signal pathways that trigger these detrimental events, (2) investigate the effects of TS on the induction of apoptosis and the signal pathways involved in this process, and (3) explore the apoptotic effect of ETS and its underlying mechanisms in developing lungs. From the present study it has been demonstrated that exposure of rats to TS dramatically induced cell proliferation and squamous metaplasia in the lungs in a dose-dependent manner. TS activated AP-1 through all four distinct MAPK pathways including ERK1/2, JNK, p38 and ERK5. AP-1-dependent cell cycle proteins were upregulated, while its targeted cell differentiation markers were altered correspondingly. We have also demonstrated TS-induced apoptosis in the lungs of rats, effect that paralleled with inhibition of NF-kappaB activity, downregulation of NF-kappaB-dependent anti-apoptotic proteins and activation of caspases. The involvement of the JNK/p38 MAPK/c-Jun/FasL pathway was also observed in TS-induced apoptosis. Moreover, exposure to ETS during perinatal development suppressed NF-kappaB activity and NF-kappaB-dependent anti-apoptotic gene expression. Our study provides the first report to demonstrate the regulation of the MAPK/AP-1 pathway in TS-induced aberrant cell proliferation and squamous metaplasia, as well as the role of NF-kappaB activity in TS-induced apoptosis. These findings provide new insights into the molecular mechanisms of TS-associated pathogenesis.