The management of inflammation in periodontal disease

Abstract

It has become clear in recent years that periodontitis is an inflammatory disease initiated by oral microbial biofilm. This distinction implies that it is the host response to the biofilm that destroys the periodontium in the pathogenesis of the disease. As our understanding of pathways of inflammation has matured, a better understanding of the molecular basis of resolution of inflammation has emerged. Resolution of inflammation is an active, agonist-mediated, well-orchestrated return of tissue homeostasis. There is an important distinction between anti-inflammation and resolution; anti-inflammation is pharmacologic intervention in inflammatory pathways, whereas resolution is biologic pathways restoring homeostasis. A growing body of research suggests that chronic inflammatory periodontal disease involves a failure of resolution pathways to restore homeostasis. This article reviews the resolution of inflammation in the context of periodontal disease and the potential for the modification of resolution pathways for the prevention and treatment of periodontal diseases. Proof-of-concept studies in the 1980s demonstrated that pharmacologic anti-inflammation prevented and slowed the progression of periodontal diseases in animals and man. However, the side-effect profile of such therapies precluded the use of non-steroidal anti-inflammatory drugs or other enzyme inhibitors or receptor antagonists in periodontal therapy. The isolation and characterization of resolving agonist molecules has opened a new area of research using endogenous lipid mediators of resolution as potential therapeutic agents for the management of inflammatory periodontitis. Work in animal models of periodontitis has revealed the potential of this therapeutic approach for its prevention and treatment and forced the reconsideration of our understanding of the pathogenesis of human periodontal diseases.

Figure 1

Phospholipase A₂ (PLA₂) catalyzes phosphatidylcholine into AA in response to agonist stimulation of a G-protein–coupled cell surface receptor. AA acts as a substrate for COX activity to produce prostanoids (e.g., prostaglandins and thromboxanes) and prostacyclin, whereas leukotrienes are generated by 5-LO. The LO-LO pathway produces lipoxins, whereas aspirin triggers the production of 15-epi-lipoxins from AA through acetylation of COX-2. Through this pathway, 15-epi-H(p)ETEs are produced, which are then converted to lipoxins by transcellular biosynthesis using 5-LO from neutrophils. Nonsteroidal anti-inflammatory drugs (NSAIDs) act through antagonism of COX-1 and -2 enzymes. Reprinted with permission from the International and American Associations for Dental Research.

Figure 2

Chemical mediators involved in the initiation of acute inflammation, such as prostaglandins (PGs) and LTs, induce “class switching” toward proresolving lipid mediators. The proresolving mediators include ω-6 PUFAs, AA-derived LXs, ATLs, ω-3 PUFA EPA-derived RvEs, docosahexaenoic acid (DHA)-derived RvDs, and protectins (PDs) (or neuroprotectins in neural tissues). Reprinted with permission from Macmillan Publishers, copyright 2008.

Figure 3

Although baseline periodontal disease at 6 weeks resulted in ∼30% bone loss, RvE1 treatment over the subsequent 6 weeks restored ∼95% of the lost bone. Groups treated with vehicle alone, LTB₄, and PGE₂ showed an additional ∼13%, 9%, and 18% bone loss, respectively. *P <0.05. Copyright 2007 The American Association of Immunologists.