Apoptosis has a central role in the process of oral mucositis and can be sustained by proinflammatory cytokines. Some studies have demonstrated increased levels of tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6) in saliva after radiotherapy and chemotherapy, which has been associated to severe oral mucositis. However, little is known about the role of these cytokines in the pro and anti-apoptosis process of oral cells exposed to antineoplastic agents. The aim of this study was to verify whether there was an association of salivary cytokines with oral cells exhibiting apoptosis or anti-apoptotic Bcl-2 expression in patients who experienced oral mucositis during hematopoietic cell transplantation (HCT).
We collected saliva and oral mucosa cells from 77 HCT patients before the conditioning (T0), during the neutropenia period (T1), and after the marrow recovery (T2). We quantified the oral exfoliated cells exhibiting TUNEL positivity and immunocytochemical expression of Bcl-2. We also determined the salivary levels of TNF-α, IL-1β, and IL-6 in the three periods.
The number of cells exhibiting positivity to TUNEL (p = 0.021) and Bcl-2 (p = 0.020) increased from T0 to T2. The levels of TNF-α increased significantly from T0 to T1 (p < 0.001). There were no significant alterations of IL-1β and IL-6 comparing the three periods. There was a significant positive correlation between TNF-α and TUNEL in T0 (rho=0.277, p = 0.033) and T1 (rho=0.451, p = 0.020). Bcl-2 expression in T1 (rho=--0.335, p = 0.048) was negatively correlated with time duration of oral mucositis.
Oral cells exhibited apoptosis even after the marrow recovery. Oral cells apoptosis was associated with salivary TNF-α during the neutropenia period. Oral cells also exhibited high expression of antiapoptotic protein Bcl-2, which was inversely proportional to the duration of oral mucositis, suggesting the activation of a surveillance mechanism in the oral cells. Alterations on salivary TNF-α during the HCT may have a putative role in the apoptosis presented in oral mucositis.
Clinical trial identification
Legal entity responsible for the study
Hospital Israelita Albert Einstein.
São Paulo Research Foundation (2016/03650-4) and AmigoOH - Brazil.
All authors have declared no conflicts of interest.