Emerging Concepts in the Resolution of Periodontal Inflammation: A Role for Resolvin E1

Abstract

Inflammatory response is a protective biological process intended to eliminate the harmful effect of the insulting influx. Resolution of inflammation constitutes an active sequence of overlapping events mediated by specialized proresolving mediators, such as lipoxins, resolvins, protectins, and maresins, which originate from the enzymatic conversion of polyunsaturated fatty acids (PUFAs). An unresolved acute inflammatory response results in chronic inflammation, which is a leading cause of several common pathological conditions. Periodontitis is a biofilm-induced chronic inflammatory disease, which results in loss of periodontal connective tissue and alveolar bone support around the teeth, leading to tooth exfoliation. An inadequate proresolving host response may constitute a mechanism explaining the pathogenesis of periodontal disease. An emerging body of clinical and experimental evidence has focused on the underlying molecular mechanisms of resolvins and particularly Resolvin E1 (RvE1) in periodontitis. Recently, RvE1 has been directly correlated with the resolution of inflammation in periodontal disease. Herein, we provide a comprehensive overview of the literature regarding the role and possible mechanisms of action of RvE1 on different cell populations recruited in periodontal inflammation as well as its potential therapeutic implications. Along with recent data on the benefits of PUFAs supplementation in periodontal clinical parameters, we touch upon suggested future directions for research.

Keywords: Resolvin E1; inflammation; periodontitis; proresolving mediators; resolution.

Figure 1

Transcellular biosynthesis of Resolvin E1 (RvE1). Edema formation delivers eicosapentaenoic acid (EPA) to the inflamed tissue. Aspirin acetylates cyclooxygenase 2 (COX2), which is present in vascular endothelial cells. The ASA-acetylated form of COX2 is still active and converts EPA to 18R-HEPE, which is then released from the endothelium. Activated polymorphonuclear neutrophils rapidly convert 18R-HEPE to Resolvin E1 (RvE1) via the action of 5-lipoxygenase (5-LO). Cytochrome P450, present in different microbes, can alternatively mediate the generation of 18R-HEPE, which will be converted to RvE1 by the host’s leukocytes.

Figure 2

Cellular components and mediators of inflammation resolution. An increase in vascular permeability, in combination with the expression of cellular adhesion molecules (i.e., selectins and integrins), enables diapedesis of polymorphonuclear neutrophils (PMNs) to the inflamed periodontal tissue. Under the influence of chemotactic factors, PMNs transmigrate into tissues. The early stages of the inflammatory reaction are characterized by the synthesis of eicosanoids (leukotrienes and prostaglandins), which initiate and amplify PMN chemotaxis. Exposure of PMNs to agents such as PGE2 and PGD2 in the exudate initiate a shift (“lipid mediator class switching”) from proinflammatory eicosanoids toward proresolving lipid mediators, such as Resolvin E1 (RvE1). Acting either as an agonist or antagonist at certain receptors, RvE1 inhibits PMN infiltration and reactive oxygen species production, enhances PMN apoptosis and clearance by “resolving” macrophages and promotes the reduction of PMN influx, a critical prerequisite for the resolution of inflammation.