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Resolution of Inflammation: A New Paradigm for the Pathogenesis of Periodontal Diseases
T. E. Van Dyke1,* and
C.N. Serhan2
1 Department of Periodontology and Oral Biology, Boston University, Goldman School of Dental Medicine, 100 East Newton Street, Boston, MA 02118; and
2 Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115;
Correspondence: *corresponding author, tvandyke{at}bu.edu
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ABSTRACT
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The periodontal diseases are infectious diseases caused by predominantly Gram-negative bacteria. However, as our understanding of the pathogenesis of the periodontal diseases grows, it is becoming clear that most of the tissue damage that characterizes periodontal disease is caused by the host response to infection, not by the infectious agent directly. Investigation into the mechanism of action of host-mediated tissue injury has revealed that the neutrophil plays an important role in destruction of host tissues. In this paper, we review the biochemical pathways and molecular mediators that are responsible for regulation of the inflammatory response in diseases such as periodontitis, with a focus on lipid mediators of inflammation. Pro-inflammatory mediators, such as prostaglandins and leukotrienes, are balanced by counter-regulatory signals provided by a class of molecules called lipoxins. The role of lipoxins in the control and resolution of inflammation is discussed, as is the possibility of the development of new therapeutic strategies for the control and prevention of neutrophil-mediated tissue injury in inflammatory diseases like periodontitis.
Key Words: lipid mediators of inflammation • lipoxins • neutrophils • periodontal disease
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INTRODUCTION
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The periodontal diseases are comprised of a group of inflammatory conditions that result in the destruction of the supporting structures of the dentition. Periodontal diseases are infectious diseases. The etiology is specific Gram-negative micro-organisms, such as Porphyromonas gingivalis and Bacteroides forsythus in the case of chronic periodontitis, and Actinobacillus actinomycetemcomitans in the case of Localized Aggressive Periodontitis (LAP, formerly localized juvenile periodontitis, or LJP). These micro-organisms possess an array of virulence factors that enhance their infectivity and provide the ability for the organisms to multiply and persist in the periodontium.
While the etiology of periodontitis is bacterial, it is becoming clear that the pathogenesis of disease is mediated by the host response. A long-standing model for this concept comes from the study of Localized Aggressive Periodontitis (LAP, LJP). Until recently, defects associated with neutrophil functions were believed to predispose to infection. However, there is a growing body of evidence suggesting that the neutrophil abnormalities in LAP are the result of a chronic hyperactivated or "primed" state of the LAP neutrophil. Under this new paradigm, the neutrophil is not hypofunctional or deficient, but hyperfunctional, and it is the excess activity and release of toxic products from the cell that are responsible, in part, for the tissue destruction in chronic periodontal inflammation. Thus, the role of alterations in neutrophil function in LAP may serve as a model system for understanding periodontal pathology as an example of local neutrophil-mediated tissue injury.
A diverse range of endogenous chemical mediators orchestrates the host response (Gallin et al., 1999) and controls the inflammatory response. These chemical signals regulate the traffic of leukocytes and control the leukocyte response. The classic eicosanoids, such as prostaglandins and leukotrienes, exert a wide range of actions and play a key role in inflammation (Samuelsson et al., 1987). The scope and range of chemical mediators identified have, in recent years, expanded considerably (Gallin et al., 1999) to include novel lipid mediators, new cytokines and chemokines, gases such as nitric oxide and carbon monoxide, and reactive oxygen species, as well as new roles for nucleotides, such as adenosine and inosine (Cronstein et al., 1999a,b), as mediators. When generated in elevated levels as in human disease, many of these chemical signals are thought to be pro-inflammatory and/or promote amplification of inflammation. The interactions between these classes of mediators in vivo remain largely unexplored. However, investigations of interactions of these pathways are likely to reveal many new pathways of control and new signals.
Conversely, results from our group (Serhan, 1994, 1996) and other investigators indicate that endogenous lipid-derived mediators are generated by the host to dampen the host response and orchestrate resolution of inflammation (de Waal, 1999; Diamond et al., 1999; Gallin et al., 1999). The lipoxins (LX), in this regard, were the first to be identified and recognized as endogenous anti-inflammatory lipid mediators of resolution that function as "braking signals" for neutrophils in inflammation (Serhan, 1994). Thus, it is of particular interest that aspirin (ASA), a widely used NSAID with many beneficial properties (Marcus, 1995) in addition to its well-appreciated action to inhibit prostaglandins (Vane, 1982), also triggers the endogenous generation of 15-epimeric LX via acetylation of cyclooxygenase 2 (COX-2) that have both anti-inflammatory and antiproliferative properties (Clària and Serhan, 1995, 1996; Fierro et al., 2002) at sites of inflammation in vivo (Chiang et al., 1998). This pathway is a previously unappreciated and novel mechanism of drug action that has intriguing implications for targeted drug design as well as the use of ASA. More importantly, LX illustrate the importance of endogenous generation of lipid mediators with anti-inflammatory pro-resolving properties. The emergence of endogenous mechanisms involved in counter-regulation of responses that may lead to tissue injury and acute inflammation not only begins to chart a relatively unappreciated side of human biology (Serhan et al., 1995, 1997), but also provides an opportunity for the exploration of new therapeutic approaches based on endogenous pathways that may reduce the possibilities for unwanted toxic side-effects (Levy et al., 2001; Qui et al., 2001).
Neutrophils (PMN) are within the first line of host defense, and, by their ability to phagocytize microbes, they can protect the host from infection. They can also give rise to PMN-dependent vascular injury and contribute to increased vascular permeability, edema, and further release of chemoattractants. Leukotriene B4 (LTB4) is among the most potent PMN stimuli and thus participates in tissue injury by recruiting PMN in pathophysiological scenarios (Varani and Ward, 1994). Lipoxins are trihydroxytetraene-containing members of the family of eicosanoids that are rapidly produced within vascular lumen, primarily via platelet-leukocyte transcellular biosynthesis, or in tissues by leukocyte endothelial cell transcellular biosynthesis (et al, 1990; Edenius et al., 1991). Pathways that are activated during multicellular responses, such as inflammation, atherosclerosis, and thrombosis, are now known to be controlled by cell-cell interactions (for a recent review, see Serhan, 1997). Cell-cell interactions that occur during these events can evoke transcellular biosynthetic routes that lead to amplification signals, such as leukotrienes (Brady and Serhan, 1992) and prostaglandins (Herschman, 1998), or to braking signals, such as LX or other novel compounds that have yet to be uncovered (Figs. 1 , 2). Thus, these LX branches involve cell-cell interactions that appear to be highly redundant and produce "endogenous stop signals" and/or "anti-inflammatory signals" that are pro-resolution, whereas the pathways that generate leukotrienes, for example, evoke cellular events that are considered to advance inflammation, namely, pro-inflammatory mediators (Samuelsson, 1982; Gallin et al., 1999; Serhan and Prescott, 2000).
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Figure 1. Lipid mediators derived from arachidonic acid in inflammation. Prostaglandins and leukotrienes generated by cyclooxygenase (COX) and the 5, 12, and 15 lipoxygenases amplify inflammation. Lipoxins are generated through transcellular biosynthetic routes through the action of two lipoxygenases on the same arachidonic acid molecule to act as endogenous stop signals in inflammation. NSAID: Non-steroidal anti-inflammatory drug.
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NEUTROPHIL FUNCTION AND DYSFUNCTION IN PERIODONTITIS
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Functional abnormalities of neutrophils have been shown to be important in various diseases. These disorders can be associated with absent or reduced respiratory burst and related intracellular killing (chronic granulomatous disease, myeloperoxidase deficiency, glutathione synthetase deficiency), defective adherence (leukocyte adhesion deficiency), disordered chemotaxis (Wiskott Aldrich syndrome), altered opsonization, or defective degranulation (Chediak-Higashi syndrome) (Lakshman and Finn, 2001). Most of these disorders are rare but expose the patients to severe infections. It is interesting to note that in addition to the systemic outcomes (such as poor wound healing and abscesses), oral ulcers, gingivitis, and recurrent oral infections in general can accompany neutrophil abnormalities.
However, in addition to the direct involvement of neutrophils in the defense against invading pathogens, the neutrophils’ role in mediating tissue destruction in inflammatory diseases is also a significant parameter in pathogenesis (Weiss, 1989; Baumann and Gauldie, 1994). Neutrophil-mediated tissue injury plays an important role in the pathogenesis of several important diseases. Understanding the mechanism is critical to the design of new therapeutic interventions that reduce the adverse effects of neutrophils without impairing protective functions (Hansen, 1995).
The Table (A) summarizes the clinical conditions in which host tissues are damaged by the activation of neutrophils. Among these, reperfusion injury has been widely investigated. Reperfusion is considered to be the most effective means of preventing progression of ischemic cell necrosis after coronary artery occlusion. This procedure involves prompt reopening of the occluded vessel, either by thrombolytic therapy or primary angioplasty, and is performed whenever possible in patients with acute myocardial infarction. However, reperfusion of the previously ischemic myocardium may also introduce an injurious component that may partly counteract the beneficial effects of the restoration of blood flow. This unwanted phenomenon is known as "reperfusion injury", and the principal mediators that lead to tissue damage are oxygen radicals from the neutrophils that are re-introduced (Ambrosio and Tritto, 1999; Jordan et al., 1999). Introduction of neutrophils is accompanied by activation, with subsequent adhesion to endothelial surfaces and migration into tissues. Activated neutrophils release oxygen radicals and proteolytic enzymes, which can directly induce tissue damage (Entman and Smith, 1994; Hansen, 1995). Neutrophils may also plug capillaries and mechanically block flow. Finally, neutrophils may release pro-inflammatory mediators (such as platelet-activating factor, thromboxane, and leukotrienes) that amplify the local inflammatory reaction, further promoting leukocyte and platelet recruitment. The role of these cells in the pathogenesis of tissue injury has been confirmed in several experimental models showing that various anti-neutrophil interventions can reduce ischemia-reperfusion injury in the heart (Entman and Smith, 1994).
Oxygen radical species produced by PMNs can attack every biologically relevant molecule, including proteins, lipids, carbohydrates, and nucleic acids (Badwey and Karnovsky, 1980). These molecules include superoxide, hydrogen peroxide, and hydroxyl radicals. Superoxide anion (O2-) is the initial product generated by the reduction of molecular oxygen (O2) by NADPH oxidase. This process is initiated by a respiratory burst characterized by a marked increase in cellular oxygen consumption, activation of several G proteins located on the cell surface, which begins a cascade of events that leads to the cell response (Badwey and Karnovsky, 1980). Superoxide anions are converted into hydrogen peroxide by superoxide dismutase. In addition, PMNs also contain myeloperoxidase (MPO) in the azurophilic granules. MPO catalyzes the conversion of hydrogen peroxide into hypochlorous acid. Hypochlorous acid is considered to be the primary product responsible for cytotoxicity of neutrophils (Badwey and Karnovsky, 1980; Weiss, 1989; Baumann and Gauldie, 1994). This cytotoxicity derives from the resultant production of powerfully oxidizing chloramines (Entman and Smith, 1994). In addition to their direct oxidative attack, oxygen radicals can also modulate various cellular activities that are important mediators in the sequence of events leading to tissue injury. Superoxide radical inactivates nitric oxide (NO), the endothelial mediator of vascular relaxation, whereas hydrogen peroxide can induce adherence of neutrophils to intact vessels via intracellular adhesion molecule-1 and CD18 interactions (Gasic et al., 1991). Exposure to radicals can stimulate the production of platelet-activating factor by endothelial cells and reduce its catabolism; it can induce generation of neutrophil chemotactic substances from plasma, and it can also stimulate tissue factor synthesis and exposure in endothelial cells, thus promoting intravascular thrombosis (Golino et al., 1996).
Neutrophil-mediated tissue damage in the periodontium was first demonstrated by Deguchi et al. (1990). Similar findings were reported for neutrophil and gingival epithelial cell interactions (Altman et al., 1992), where it was demonstrated that human neutrophils lyse epithelial cells in an in vitro model mediated by myeloperoxidase-hydrogen peroxide interactions. In addition to the direct deleterious activities of neutrophils on host periodontal tissues, superoxide generation was shown to be elevated in both resting and stimulated aggressive periodontitis neutrophils (Van Dyke et al., 1986). Pre-incubation of neutrophils from rapidly progressive periodontitis (RPP) patients with lipopolysaccharide (LPS) extracted from Porphyromonas gingivalis (P. gingivalis) primed the neutrophils for enhanced FMLP-stimulated superoxide production in a dose-dependent manner (Shapira et al., 1991). Furthermore, incubation of control neutrophils with P. gingivalis LPS in the presence of serum from RPP patients generated a higher response as compared with incubation with control serum (Shapira et al., 1991).
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CONTROLLING THE NEUTROPHIL RESPONSE
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Transcellular Biosynthesis of Lipoxins (LX) and 15-epi-LX
15-LO-initiated LX production is clearly demonstrated by airway epithelial cells, monocytes, or eosinophils, which up-regulate 15-LO when exposed to cytokines such as IL-4 or IL-13 (Levy et al., 1993a; Nassar et al., 1994). When these cell types are activated, they generate and release 15S-HETE, which is rapidly taken up and converted by neutrophils to lipoxins via the action of their 5-LO (Fig. 2A, right pathway). This event not only leads to LX biosynthesis, but also "turns off" leukotriene formation. 5-LO conversion of 15R-HETE also results in inhibition of leukotriene biosynthesis. 15R-HETE is a major product of arachidonic acid in several cell types when cyclooxygenase-2 (COX-2) is up-regulated after acetylation by aspirin. Thus, it is possible that aspirin can regulate the in vivo production of leukotrienes by 15R-HETE conversion to 15-epi-LX, and that 15-epi-LX can in turn also regulate the cellular actions of leukotrienes.
Native LXs regulate human PMN responses that are relevant to inflammation. These include: (a) inhibition of FMLP and LTB4-induced chemotaxis (Lee et al., 1989); (b) adhesion and transmigration with endothelial cells (Papayianni et al., 1996), inhibition of cytokine formation such as IL-1β (Hachicha et al., 1999); and (c) transmigration through epithelial cells (Colgan et al., 1993). These actions of LXA4 and aspirin-triggered lipoxins (ATL), their endogenous epimeric counterpart (15-epi-LX), were first demonstrated in experiments with isolated cell types in vitro (Serhan et al., 1995) and were also confirmed and demonstrated in several acute murine models of inflammation and second-organ reperfusion injury (see Table, C , and Takano et al., 1997, 1998; Chiang et al., 1998; 1999; Clish et al., 1999; Hachicha et al., 1999). Some general points can now be made as follows. First, PMN infiltration in vivo to lung, skin, and sites of wound healing is dramatically and potently inhibited by both intravenous and topical application of stable analogues of both LXA4 and aspirin-triggered 15-epi-LXA4 (ATL); second, 15-epi-LXA4 and LXA4 analogs inhibit IL-lβ, TNF , and IL-8 expression while stimulating IL-4 release in vivo (Hachicha et al., 1999; Gronert et al., 2001), and interact in a stereoselective fashion with a common receptor on human and murine leukocytes; and third, bioactive ATL and LXA4 analogues compete with [3H]-LXA4 binding to LXA4 receptors (ALX) (Takano et al., 1998). Thus, these inhibitory actions of LX and ATL analogues are likely to be mediated by these specific LX receptors present in rodent and human cells (Gronert et al., 2001).
Aspirin-triggered 15-epi-lipoxin Circuit
Another major group of tetraene-containing eicosanoids was recently discovered that are products of an unanticipated origin (Clària and Serhan, 1995; Clària et al., 1996) (see Fig. 2). In this biosynthetic scheme, cyclooxygenase-2 (COX-2), expressed in either endothelial cells or epithelial cells after exposure to pro-inflammatory cytokines such as IL-1β, LPS, or TNF, switches its catalytic activity in the presence of aspirin, generating 15-R-HETE instead of prostaglandin intermediates. In this setting, aspirin inhibits prostaglandin biosynthesis by both COX-1 and COX-2 (reviewed in Herschman, 1996). COX-2, when acetylated in endothelial or epithelial cells, is not enzymatically inactive. Instead, this isozyme converts endogenous arachidonic acid to 15R-HETE, which is released and transformed via transcellular routes to form 15-epi-LXs by nearby leukocytes. The activated and, in most instances, adherent leukocytes in this scenario possess 5-LO and transform 15R-HETE to a 5(6)-epoxytetraene within leukocytes, which carries its C15 position alcohol in the R configuration. This proposed common intermediate leads to the formation of both 15-epi-lipoxin A4 and 15-epi-lipoxin B4, which carry the R configuration at C15 (Fig. 2). 15-epi-LXA4 proves to be more potent than native LXA4 in inhibiting neutrophil adhesion (Serhan,et al 1995; Clària et al., 1996), and 15-epi LXB4 inhibits cell proliferation (Clària et al., 1996). The R configuration increases the bioactivity in both molecules.
We are accustomed to thinking of aspirin as simply an inhibitor of eicosanoid biosynthesis (Fig. 2B), and these new results clearly establish that aspirin can trigger the biosynthesis of novel compounds, namely, the ATL, which can serve as potential endogenous anti-inflammatory signals or mediators of some of aspirin’s newly recognized beneficial actions. These relatively recently recognized beneficial actions of ASA include prevention of myocardial infarction (Hennekens et al., 1994; Savage et al., 1995) and protection from colorectal adenoma, as well as other forms of cancer (Giovannucci et al., 1995; Levy, 1997). The mechanism of ASA’s beneficial actions is likely to include the biosynthesis of 15-epi-LX and related compounds and could represent a novel mechanism for this "old drug" for which a wealth of toxicology data is available worldwide. Because of ASA’s widespread use and an absence of a unifying mechanism to explain its many newly appreciated actions, it is important to gain a more complete understanding of its cellular impact and potential site(s) of additional therapeutic value.
15-Lipoxygenase-initiated Pathway
LX biosynthetic pathways were first reported in 1984. LXs were shown to be generated by routes involving insertion of molecular oxygen into the carbon (C) 15 position of arachidonic acid, predominantly in the S configuration. This pathway implicated the involvement of a 15-lipoxygenase in the generation of bioactive molecules (Serhan et al., 1984), and was of interest not only because of the new trihydroxytetraene structures found, but also because the role of the human 15-LO was not known. Subsequently, human 15-LO was found to be abundant in human eosinophils, alveolar macrophages, monocytes, and epithelial cells, is controlled by cytokines, and is regulated primarily by IL-4 and IL-13 (Levy et al., 1993a; Katoh et al., 1994; Nassar et al., 1994; Sigal and Conrad, 1994). These two cytokines are implicated as negative regulators of the inflammatory response or anti-inflammatory cytokines (Anderson and Coyle, 1994). Studies on the actions of lipoxin implicate LXA4 and LXB4 as potential anti-inflammatory compounds, findings that appear to be substantiated with the use of LX analogs in in vivo animal models (Table, B).
The oxygenation of arachidonic acid at the C15 position generates 15-HpETE. The 15S-hydroperoxy form and/or 15S-HETE, the reduced alcohol form, can each serve as a substrate for 5-lipoxygenase in leukocytes. These transformations can occur within the cell type of origin or via transcellular biosynthetic routes in humans. The initial product of the 5-lipoxygenase’s action on 15-HpETE is a 5S-hydroperoxy, 15S-hydro(peroxy)-DiH(p)ETE, which is converted to a 5,6 epoxytetraene. The 5-lipoxygenase is also regulated by cytokines such as GM-CSF and IL-3 (Pouliot et al., 1994; L’Heureux et al., 1995; Ring et al., 1996), and 5-LO is highly expressed in human neutrophils and monocytes. Once formed, the 5(6)-epoxytetraene is rapidly converted by hydrolases to either 5S, 6R, 15S-trihydroxy-7, 9, 13-trans-11-cis-eicosatetraenoic acid, termed lipoxin A4, and/or, via lipoxin B4 hydrolase, to 5S, 14R, 155-trihydroxy-6,10,12-trans-8-cis-eicosatetraenoic acid, termed lipoxin B4. LXA4 and B4 are both vasoactive—primarily vasodilatory in most isolated organs and in vivo models tested (Lefer et al., 1988; Dahlén and Serhan, 1991)—and they both regulate leukocyte functions (Badr et al., 1989; Lee et al., 1991; etal, 1995), perhaps serving as down-regulatory molecules. They required µM levels, however, to give vasoactions, and thus, since only nano-subnanomolar amounts are needed for leukocyte actions, their main role appears to be that of regulating Ieukocyte responses. Concomitant with the biosynthesis of lipoxins by the 15-LO-initiated route, leukotriene biosynthesis is blocked at the 5-lipoxygenase level (Serhan, 1994; Clària et al., 1996), resulting in an inverse relationship between leukotriene and LX biosynthesis. Thus, when LXs are generated by neutrophils from conversion of extra-PMN 15-HETE carrying its alcohol in either the R or S configuration, leukotriene formation is dramatically reduced, while LXs and 15-epi-LX are formed and released.
Single-cell-type Origins of LX
Analysis of available data suggests that primed leukocytes from individuals with inflammatory disorders such as asthma who are exposed to various cytokines and other inflammatory stimuli in vivo generate LXs entirely from endogenous sources of arachidonic acid from a single cell type. The finding that primed cells (Chavis et al., 1995, 1996; Thomas et al., 1995; Fierro et al., 2002) and cells from peripheral blood of individuals with various diseases can generate LXs from endogenous sources of arachidonic acid raises questions with respect to our current understanding of the generation of eicosanoids in inflammatory diseases, namely, what is the temporal relationship between each of the classes of eicosanoid during the progression of an inflammatory response from acute to chronic status? Does diet affect the temporal relationships between classes? Information along these lines will help in understanding the biological impact of each class of compound, since, in experimental models, they regulate key responses during multicellular events. This is particularly evident in view of findings with transgenic rabbits that express 15-LO in a macrophage-specific fashion (Shen et al., 1996). When the 15-LO-overexpressing rabbits were fed an atherogenic diet, the expression of 15-LO was found to have a protective impact on the development of atherosclerosis. It is likely that this action of 15-LO is causally related to biosynthesis and local anti-inflammatory mediators such as LX.
Temporal and Spatial Considerations in LX Formation and PG/LT
Another source of LX is derived from a new form of "priming" that involves the esterification of 15-HETE in inositol-containing phospholipids within the membranes of human neutrophils (Brezinski and Serhan, 1990). Cells rapidly esterify 15-HETE into their inositol-containing lipids, which, upon subsequent agonist stimulation, release 15-HETE from this source, which is further transformed. The deacylated mono-HETEs are released and transformed, in this case, to LX, or perhaps to other eicosanoids that have yet to be discovered. This pathway, illustrated in Fig. 2B, suggests that precursors of LX biosynthesis can be stored within membranes of inflammatory cells and then released by stimuli activating PLA2 (Brezinski and Serhan, 1990). This form of "membrane priming" to generate bioactive lipid mediators has implications in the second messengers generated, such as 15-hydroxy-PIP2 and diglyceride, which contain 15-HETE that may alter their intracellular signaling activities. As is the case with 15S-HETE, 15R-HETE is also rapidly esterified into membrane phospholipids (Fierro et al., 2002) and could probably serve as a reservoir for 15-epi-LX formation. In this context, LXs appear in experimental models of inflammation after both prostanoids and leukotrienes in exudates begin to resolve (Malaviya and Abraham, 2000).
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LIPOXINS IN HUMAN DISEASES: LXA4 AND ATL STABLE ANALOGUES IN DISEASE MODELS
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Lipoxins are found in a variety of inflammatory events and are known to be generated in human organs (Lee et al., 1990). LXA4 and LXB4 are formed in nasal polyps (Edenius et al., 1990) and, of interest, LXA4 is generated in nasal lavage from aspirin (ASA)-sensitive asthmatics (Levy et al., 1993b) and in experimental nephritis (Papayianni et al., 1995). Along these lines, Chavis et al. (1995) proposed that LXs are useful biomarkers of asthma, and Thomas et al. (1995) proposed that LXs are biomarkers of long-term clinical improvement in arthritic patients. The list of diseases and tissues in Table (C) is not exhaustive, and is likely to represent examples of in vivo scenarios where cell-cell interaction is accelerated and the generation of LXs is detected because of the abundance of cytokines and cell-cell interactions in these settings. Rupture of the atherosclerotic plaque leads to rapid generation of lipoxin A4 in the intracoronary artery (Brezinksi et al., 1992). LXs are also generated by normal human bone marrow (Lee et al., 1990; Stenke et al., 1994). During chronic myelocytic leukemia, platelets lose 12-LO. They also lose their ability to generate LX, and this finding may be related to the blast crisis observed in chronic myelocytic leukemia (Stenke et al., 1994).
Because enzyme inhibitors of LT synthesis and LT receptor antagonists find limited use and only in certain clinical settings (Gallin et al., 1999), we evaluated other approaches and prepared, for in vivo studies, LX stable analogues that were designed as potential mimetics of the inhibitory actions noted for LXA4 (Serhan et al., 1995) and, more recently, for LXB4 (Maddox et al., 1998) in vitro. Several LXA4 and ATL stable analogues were strategically synthesized by means of a recombinant dehydrogenase screen assay (etal, 1995) as a relatively inexpensive and rapid screen to design suitable analogues that might function in vivo. Several of these analogs were scaled up via total organic synthesis for more detailed examination and were tested for their ability to inhibit PMN infiltration and changes in vascular permeability in vivo in several murine models (Table, C). 15(R/S)-methyl-LXA4, having a methyl group at the C-15 position (racemate 15R/S), is an analogue of both the aspirin-triggered 15-epi-LXA4 and native LXA4; and 16-phenoxy-LXA4, which has a phenoxy group at the C-16 position, is an analogue of native LXA4 that prevents enzymatic inactivation with recombinant 15-prostaglandin dehydrogenase in vitro (Serhan et al., 1995; see Table, B, and references within). The analogues that proved active also act via competition at LXA4 receptors (Papayianni et al., 1996) and receptor chimeras (Chiang et al., 2000).
For example, when applied topically to mouse ears, these LX stable analogues inhibit both PMN infiltration and vascular permeability changes in a concentration-dependent fashion (Corey and Mehrotra, 1986; Lindgren and Edenius, 1993). At 130 nmol per ear, the degree of inhibition of PMN infiltration was more than 90% for both analogues, with apparent IC50s noted at 13-26 nmol per ear range for each analogue. In the same concentration range, these two LXA4 stable analogues also inhibited vascular permeability, namely, extravasation of Evans blue. At 130 nmol per ear, the inhibition of vascular permeability change was > 98% for 15(R/S)-methyl-LXA4 and 87% for 16-phenoxy-LXA4, respectively, and their impact was noted visually. The inhibition of vascular permeability changes paralleled inhibition of PMN infiltration with both the ATL and LX analogues.
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CAN LIPOXINS BE USEFUL IN THE MANAGEMENT OF PERIODONTAL DISEASES?
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The new paradigm posed at the beginning of this review suggests that periodontitis results from the lack of resolution of inflammation at the site of chronic infection. Faulty resolution is likely the result of failure of endogenous counter-regulatory mechanisms leading to overt chronic inflammation, as seen in certain periodontal diseases. Neutrophil-mediated tissue injury followed by a chronic inflammatory lesion is the result. We hypothesized that limiting the destructive aspects of the inflammatory response without ablation of host defense could be accomplished by treatment with lipoxins and their analogs, resulting in the prevention of the onset of periodontal lesions. To test this hypothesis, we recently developed a rabbit ligature model of periodontal infection with P. gingivalis that produced significant, reproducible, periodontal lesions (Serhan et al., 2002). In this model, rabbit teeth are ligatured and P.g. placed on the ligatures three times a week for 6 wks. During the course of the experiment, the animals experience 50% bone loss on infected ligatured teeth. Ligature alone or concurrent treatment with metronidizole did not result in bone loss, demonstrating the infectious nature of the lesion. In a parallel design experiment, two groups of animals received ligatures and P.g. One group received lipoxin topically applied in vehicle (6 µg in 6 µL) three times a week, and the other group received ethanol alone following the same regimen. At 6 wks, animals were killed and jaws harvested for x-ray analysis of bone loss, histology, and direct bone measurements. Results revealed a marked and statistically significant reduction in all disease parameters in the lipoxin-treated group. Topical application of lipoxin inhibited bone loss > 90%, inhibited connective tissue destruction, and limited connective tissue infiltration by inflammatory and immune cells. However, there was no evidence of direct tissue invasion or damage from the topically applied P.g., suggesting that the micro-organism was cleared normally. Lipoxins have no innate antibacterial activity.
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SUMMARY AND CONCLUSIONS
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Our understanding of the pathogenesis of periodontitis has continued to evolve as our understanding of the underlying mechanisms of the inflammatory response has become more sophisticated. There have been major advances recently that have led to a change in the way we think about inflammation and the pathology that results from inflammation. The new paradigm is the resolution of inflammation as a natural step in the inflammatory process, which leads to the concept that tissue injury mediated by inflammation is a consequence of the inability of the host to resolve the inflammation, not the initial inflammation itself. This is an important distinction, because inflammation is necessary to protect the host from infection, but persistent inflammation can also cause disease—hence the notion that, in a disease such as periodontitis, resolution of inflammation in a timely fashion will protect the host from tissue injury, while the infectious agent is still cleared. The working hypothesis is that periodontal disease reflects an inability to resolve inflammation, which also may have a genetic phenotype, and predisposition. Future studies should be directed toward evaluating this hypothesis.
A large body of recent work suggests that the lipoxins, as a class of eicosanoids associated with inflammation, are the molecules responsible for the resolution of inflammation. These molecules have been demonstrated to be important in a variety of disease processes, and their therapeutic potential has been identified in a variety of model systems. We have demonstrated that resolution of inflammation in periodontitis through lipoxin-mediated pathways offers potential for the prevention and perhaps treatment of periodontal lesions. Future studies will focus on the applicability of lipoxin therapies in humans for the prevention and treatment of the periodontal diseases.
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ACKNOWLEDGMENTS
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The NIH PO1-DE13499 supported this manuscript.
Received for publication June 7, 2002.
Revision received October 25, 2002.
Accepted for publication November 11, 2002.
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Journal of Dental Research, Vol. 82, No. 2,
82-90 (2003)
DOI: 10.1177/154405910308200202
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ABSTRACT
INTRODUCTION
