Hypoxia induced by inflammation may impact the critical functions of polymorphonuclear phagocytes (PMN), including superoxide anion (O2-) generation. Iron is essential for regulation of O2- generation and iron metabolism is regulated by ceruloplasmin (CP), which is one of the target genes for hypoxia inducible factor-1a (HIF-1a). While hypoxia has been suggested to play a role in several PMN function, the mechanism of regulation is unclear. PMN are locally hyperactivated, or primed, in periodontitis and LAP provides a convenient human model for constitutively primed PMN. Therefore, primed PMN could respond to increased hypoxia (e.g. periodontal pockets) with excessive superoxide production, which in turn could be detrimental to the host tissues. In this application, we provide preliminary data that hypoxia enhances agonist-induced O2- generation in PMN and this is significantly increased in primed PMN. Hypoxia-mediated PMN activity seems to be mediated by HIF-1a and CP expression all of which are elevated in LAP. Thus, the hypothesis of this study is that local inflammation induces hypoxia, which in turn stimulates periodontal tissue destruction through the actions of PMN. Based on our previous in vitro and in vivo findings on periodontal inflammation, we also hypothesized that Resolvin E1 (RvE1) can reverse the hypoxia-mediated changes in both normal and primed PMN. There are 2 specific aims: 1) To determine the mechanism of hypoxia-mediated superoxide generation by PMN. 2) To identify the potency of Rve1 and its selective activity on hypoxia-mediated PMN function. The potential impact of these studies is high, since if our hypothesis is confirmed, a new pathway for pharmacologic intervention in the pathogenesis of periodontitis (and at large in inflammatory diseases) will be identified. RvE1 has the potential to prevent and restore the hypoxia-mediated PMN-initiated tissue injury providing a new tool to combat the destructive inflammatory processes in periodontal tissues.

Public Health Relevance

This proposal will determine the mechanism of PMN superoxide release in response to hypoxia-mediated inflammation and the potential treatment by RvE1.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-MOSS-B (02))
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Burgoon, Penny W
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Forsyth Institute
United States
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