| Background: The biological oxidative state reflects the net balance between reactive oxygen species (ROS) and antioxidants (AO). An increase in ROS levels will result in oxidative stress, which has been linked to aging as well as pathologic conditions, including inflammatory, degenerative, and multi-organ diseases.;Periodontal disease is an inflammatory disease regulated in part by oxidative states in periodontal tissues. In its most common form, chronic periodontitis (CP) is an inflammatory disease initiated by subgingival biofilms, which induce a local immune response, host-mediated tissue destruction and unresolved inflammation. The well-documented heterogeneity of such immune responses among patients with CP is, in part, attributed to neutrophil functional alterations including generation of oxidative stress.;Goals: To investigate the factors affecting oxidative stress in oral neutrophils and their role in periodontal tissue destruction. I hypothesize that oral neutrophils in chronic periodontitis (CP) have a pro-oxidative phenotype. This phenotype presents as hyperactive oral neutrophils, which contribute to oxidative stress and tissue destruction during CP.;Results: Increase in cytoprotective proteins, including AO, was demonstrated in an experimental gingivitis model, suggesting that the regulation of physiologic oxidative state has a role in preventing clinical attachment loss (CAL). Increased oral neutrophil ROS production was associated with severe iii periodontal tissue damage (CAL) in CP patients whose disease was resistant to treatment (refractory disease). Gene expression microarray completed in both oral and peripheral blood neutrophils revealed that oral neutrophils in CP patients present with a deficient oxidative stress response, which is mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. The role of the Nrf2 pathway in neutrophil function and periodontal tissue destruction was then further investigated in a murine periodontal disease model. Nrf2 null mice have a hyperactive neutrophil phenotype when activated. Furthermore, Nrf2 null mice have more severe bone loss and increased ROS-mediated damage compared to control mice in response to ligature-induced periodontitis.;Conclusions: Nrf2 down-regulation in oral neutrophils is associated with more severe periodontal tissue destruction. Reduced production of AO by neutrophils in the context of increased recruitment in the periodontium aggravates tissue destruction. It can therefore be concluded that reduced AO production by oral neutrophils in un-resolved periodontal inflammation may contribute to increased severity of CP through local oxidative stress. |
