Estudio del efecto de la exposición repetitiva a dosis agudas de nicotina sobre el epitelio bronquial humano

Resumen

Estudio del efecto de la exposición repetitiva a dosis agudas de nicotina sobre el epitelio bronquial humano. Effects of recurrent exposure to nicotine on human bronchial epitelial cells. Cigarette smoking is the major preventable cause of lung cancer in developed countries. Nicotine (3-(1- methyl-2-2pyrrolidingyl)-pyridine) is one of the major alkaloids present in tobacco. Besides its addictive properties, its effects have been described in panoply of cell types. In fact, recent studies have shown that nicotine behaves as a tumor promoter in transformed epithelial cells. This research focuses on the effects of acute repetitive nicotine exposure on normal human bronchial epithelial cells (NHBE cells) and the comparison with the effects on small cell lung cancer cells (SCLC). Here we show that treatment of NHBE cells and SCLC with recurrent doses of nicotine up to 500 µm triggered cell differentiation towards a neuronal markers such as neuronal n and Pax-3. We also demonstrate that nicotine treatment induced NF-KB translocation to the nucleus, phosphorylation of the epidermal growth factor receptor (EGFR), and accumulation of heparin binding ¿ EGF in the extracellular medium (data not seen in SCLC). Moreover, addiction of AG1478, an inhibitor of EGFR tyrosine phosphorylation, or cetuximab, a monoclonal antibody that precludes ligand binding to the same receptor, prevent cell differentiation by nicotine in primary and tumoral cells. Lastly, we show that differentiated cells increased their adhesion to the extracellular matrix and their protease activity . Besides, nicotine increased the colony formation in soft agar, migration and adhesion and transmigration through lymphatic endothelial cells, showing and increase in malignant capacity after nicotine exposure in SCLC. Given that lung carcinoma is strongly related to tobacco consumption, these results may help to better understand the damaging consequences of nicotine exposure.