Lethal synergistic effect of cigarette smoke and saliva in an in vitro model: does saliva have a role in the development of oral cancer?

Exposure of oral mucosal cells to cigarette smoke induces oral cancer, presumably via the injurious effect of free radicals. To explore the effects of cigarette smoke on cells in the presence of saliva, we used peripheral blood lymphocytes (PBL) and exposed them to cigarette smoke, alone or in the presence of saliva. After 80 min exposure to cigarette smoke alone, a time-dependent cellular loss and survival rate of 52% was observed. By contrast, following the exposure of the lymphocytes to cigarette smoke in the presence of saliva, less than 20% of the cells survived. Saliva secreted from the submandibular/sublingual (Sm/Sl) glands was highly cytotoxic, while saliva secreted from the parotid glands was only moderately cytotoxic. Redox active iron ions in saliva and aldehydes in cigarette smoke were shown to play the major injurious roles in this synergistic phenomenon. The salivary-borne redox active iron ions participate in Fenton and Haber-Weiss reactions to transform low-reactive free radicals, which originate from cigarette smoke into highly-reactive .OH(-)-free radicals. In light of these results, a comprehensive mechanism for the induction of oral cancer by cigarette smoke is suggested where saliva may be a pivotal player.