Resolution-Based Therapies: The Potential of Lipoxins to Treat Human Diseases.

Inflammation is an a physiological response instead an essential response of the organism to injury and its adequate resolution is essential to restore homeostasis. However, defective resolution can be the precursor of severe forms of chronic inflammation and fibrosis. Nowadays, it is known that an excessive inflammatory response underlies the most prevalent human pathologies worldwide. Therefore, great biomedical research efforts have been driven toward discovering new strategies to promote the resolution of inflammation with fewer side-effects and more specificity than the available anti-inflammatory treatments. In this line, the use of endogenous specialized pro-resolving mediators (SPMs) has gained a prominent interest. Among the different SPMs described, lipoxins stand out as one of the most studied and their deficiency has been widely associated with a wide range of pathologies. In this review, we examined the current knowledge on the therapeutic potential of lipoxins to treat diseases characterized by a severe inflammatory background affecting main physiological systems, paying special attention to the signaling pathways involved. Altogether, we provide an updated overview of the evidence suggesting that increasing endogenously generated lipoxins may emerge as a new therapeutic approach to prevent and treat many of the most prevalent diseases underpinned by an increased inflammatory response.

Deletion of 12/15-lipoxygenase accelerates the development of aging-associated and instability-induced osteoarthritis.

OBJECTIVE: 12/15-Lipoxygenase (12/15-LOX) catalyzes the generation of various anti-inflammatory lipid mediators, and has been implicated in several inflammatory and degenerative diseases. However, there is currently no evidence that 12/15-LOX has a role in osteoarthritis (OA). The aim of this study was to investigate the role of 12/15-LOX in the pathogenesis of OA. METHODS: The development of aging-associated and destabilization of the medial meniscus (DMM)-induced OA were compared in 12/15-LOX-deficient (12/15-LOX-/-) and wild-type (WT) mice. The extent of cartilage damage was evaluated by histology. The expression of OA markers was evaluated by immunohistochemistry and RT-PCR. Cartilage explants were stimulated with IL-1α in the absence or presence of the 12/15-LOX metabolites, 15-hydroxyeicosatetraenoic acids (15-HETE), 13-hydroxyoctadecadienoic acid (13-HODE) or lipoxin A4 (LXA4), and the levels of matrix metalloproteinases-13 (MMP-13), Nitric oxide (NO) and prostaglandin E2 (PGE2) were determined. The effect of LXA4 on the progression of OA was evaluated in wild type (WT) mice. RESULTS: The expression of 12/15-LOX in cartilage increased during the progression of DMM-induced OA and with aging in WT mice. Cartilage degeneration was more severe in 12/15-LOX-/- mice compared to WT mice in both models of OA, and this was associated with increased expression of MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs, aggrecanases (ADAMTS5), inducible NO synthases (iNOS), and mPGES-1. Treatment of cartilage explants with 12/15-LOX metabolites, suppressed IL-1α-induced production of MMP-13, NO and PGE2, with LXA4 being the most potent. Intra-peritoneal injection of LXA4 reduced the severity of DMM-induced cartilage degradation. CONCLUSIONS: These data suggest an important role of 12/15-LOX in the pathogenesis of OA. They also suggest that activation of this pathway may provide a novel strategy for prevention and treatment of OA.

Resolving inflammation by using nutrition therapy: roles for specialized proresolving mediators.

PURPOSE OF REVIEW: Inflammation is a unifying component of many of the diseases that afflict Western civilizations. Nutrition therapy and, in particular, essential fatty acid supplementation is one of the approaches that is currently in use for the treatment and management of many inflammatory conditions. The purpose of the present review is to discuss the recent literature in light of the discovery that essential fatty acids are converted by the body to a novel genus of lipid mediators, termed specialized proresolving mediators (SPMs). RECENT FINDINGS: The SPM genus is composed of four mediator families - the lipoxins, resolvins, protectins, and maresins. These molecules potently and stereoselectively promote the termination of inflammation, tissue repair, and regeneration. Recent studies indicate that in disease, SPM production becomes dysregulated giving rise to a status of failed resolution. Of note, several studies found that omega-3 fatty acid supplementation, at doses within the recommended daily allowance, led to increases in several SPM families that correlate with enhanced white blood cell responses in humans and reduced inflammation in mice. SUMMARY: Given the potent biological actions of SPM in organ protection and promoting bacterial clearance, nutritional therapies enriched in omega-3 fatty acids hold promise as a potential co-therapy approach when coupled with functional lipid mediator profiling.

Proresolution mediators and receptors: novel drug targets for enhancing pharmacological armamentarium against periodontal inflammation.

Periodontal diseases are comprised of a group of inflammatory conditions that result in the destruction of the supporting structures of the dentition. Emphasis has traditionally been placed on the deleterious actions of lipid mediators, such as prostanoids and leukotrienes, in propagating the inflammatory response and enhancing tissue destruction. Recently, the emerging understanding of the molecular basis of inflammation has elucidated that return of tissue homeostasis, triggered as part of a normal inflammatory response i.e. resolution of inflammation is an active, agonist-mediated, well-orchestrated phenomenon. The naturally-occurring pro-resolution lipid mediators, lipoxins, resolvins, protectins, maresins etc. have been identified as a novel genus of potent and stereoselective players that counter-regulate excessive acute inflammation and stimulate molecular and cellular events that define resolution. In this Review, we provide an update and overview of newly identified mediators that play pivotal roles in resolution and focus on the emerging appreciation of the endogenous pathways and mediators that control timely resolution which can be exploited as novel drug targets to extend the pharamaceutical armamentarium to combat chronic inflammation, thus controlling periodontal inflammation and the associated systemic inflammatory effects on the body, in general.

Lipoxins, resolvins, and protectins in the prevention and treatment of diabetic macular edema and retinopathy.

Diabetic macular edema and retinopathy are low-grade inflammatory conditions. Infusions of antitumor necrosis factor-α (anti-TNF-α) antibody and antivascular endothelial growth factor (anti-VEGF) antibody have been shown to be at least partly effective in the treatment of diabetic macular edema and proliferative diabetic retinopathy. Intravitreal therapy of diabetic macular edema by the anti-TNF-α antibody has been found to produce significant side effects and anti-VEGF therapy to be ineffective. Nevertheless, these studies have indicated that the suppression of TNF-α and other proinflammatory cytokines and VEGF could be of benefit in diabetic macular edema and retinopathy. The retina is rich in polyunsaturated fatty acids, especially in ω-3, and several studies have shown that polyunsaturated fatty acids prevent diabetic retinopathy. Lipoxins, resolvins, and protectins derived from various polyunsaturated fatty acids possess anti-inflammatory actions and suppress the production of interleukin-6, and TNF-α and VEGF have antiangiogenic actions. In view of these evidences, I propose that lipoxins, resolvins, and protectins could be of significant benefit in the prevention and management of diabetic macular edema and retinopathy.

Paradigm shift in the pharmacological management of periodontal diseases.

It is becoming clear that variations in inflammatory response are a major determinant in susceptibility to periodontitis. However, our understanding of the relationship of the causal agents in periodontitis to the pathogenesis is not as clear as we once thought, and thus therapies based on etiopathogenesis are similarly in question. We are entering a new era of therapeutic discovery that may have a major impact on our management of the periodontal diseases. Fundamentally, periodontitis is an irreversible condition and once both soft and hard tissues are lost, the healthy periodontal architecture cannot be completely or predictably rebuilt. The discovery of new families of lipid mediators of resolution of inflammation (the lipoxins) and eicosapentaenoic-acid- and docosahexaenoic-acid-derived chemical mediators (the resolvins and protectins) opens new avenues to designing resolution-targeted therapies to control the unwanted side effects of excessive inflammation. The novel protective and therapeutic actions of pro-resolution lipid mediators following microbial challenge are mediated by regulation of the local and systemic inflammatory response that has a direct impact on the organization of the biofilm (plaque) and suggests a new paradigm in clinical periodontal therapeutics.

Role of lipoxins, resolvins, and other bioactive lipids in colon and pancreatic cancer.

Unresolved inflammation, due to insufficient production of proresolving anti-inflammatory lipid mediators, can lead to an increased risk of tumorigenesis and tumor cell invasiveness. Various bioactive lipids, particularly those formed by cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, have been well established as therapeutic targets for many epithelial cancers. Emerging studies suggest that there is a role for anti-inflammatory bioactive lipids and their mediators during the resolution phase of inflammation. These proresolving bioactive lipids, including lipoxins (LXs) and resolvins (RVs), have potent anti-inflammatory and anti-carcinogenic properties. The molecular signaling pathways controlling generation and degradation of the proresolving mediators LXs and RVs are now being elucidated, and the component molecules may serve as new targets for regulation of inflammation and inflammation-associated cancers like colon and pancreatic cancers. This review will highlight the recent advances in our understanding of how these bioactive lipids and proresolving mediators may function with various immune cells and cytokines in inhibiting tumor cell proliferation and progression and invasiveness of colon and pancreatic cancers.

Anti-inflammatory and pro-resolving properties of benzo-lipoxin A(4) analogs.

Lipoxins (LXs) are potent endogenous counter-regulatory lipid mediators that dampen acute inflammation and promote its resolution. Here, we present our investigation of a new class of thermally and metabolically stable benzo-LXA(4) analogs that are potently anti-inflammatory and easier to synthesize. Replacement of the tetraene unit of native LXA(4) with a benzo-fused ring system not only increases the thermal stability but also enables highly convergent and efficient syntheses of these analogs. In addition, they resist rapid catalysis and inactivation by eicosanoid oxidoreductase. Like native LXs, o-[9, 12]-benzo-omega6-epi-LXA(4), o-[9, 12]-benzo-deoxy-LXA(4), m-[9, 12]-benzo-omega6-epi-LXA(4) and [9, 14]-benzo-omega6-(R/S)-LXA(4) demonstrated potent time-dependent reduction, at nanogram dosages, of PMN infiltration and pro-inflammatory cytokine generation in vivo in murine peritonitis and were organ protective in hind limb ischemia-reperfusion injury of the lung. The o-[9, 12]-benzo-omega6-epi-LXA(4) and m-[9, 12]-benzo-omega6-epi-LXA(4) were most potent in nanogram doses; both decreased PMN infiltration by approximately 32%, while o-[9, 12]-benzo-deoxy-LXA(4) and [9, 15]-omega6-(R/S)-LXA(4) were less potent. The [9,12]-benzo-omega6-epi-LXA(4) also activated a lipoxin A(4) GPCR and increased macrophage phagocytic activity. Taken together, these findings demonstrate a new generation of LXA(4) stable analogs that are easy to synthesize and anti-inflammatory. These benzo-LXA(4) analogs are promising tools for new therapeutic approaches as well as assessing endogenous mechanisms in anti-inflammation and resolution.

The management of inflammation in periodontal disease.

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.

Lipid mediators: lipoxin and aspirin-triggered 15-epi-lipoxins.

Lipoxins (LX) and their 15-epimers, aspirin triggered lipoxins (ATL) are emerging as major promoters of resolution of the inflammatory reaction. These eicosanoids, that carry a tetraene chromophore, derive from sequential lipoxygenase (LO) metabolism of arachidonic acid. Three principal routes of LX/ATL biosynthesis have been uncovered. One involves cooperation between 15- and 5-LO, one other requires interactions between 12- and 5-LO and a third is characterized by 5-LO transformation of intermediary products generated by aspirin-acetylated cyclooxygenase (COX)-2. Thus, in a large majority of cases the biosynthesis of these eicosanois requires transcellular metabolic exchange during cell-cell interactions. LX and ATL are rapidly metabolized and inactivated by monocyte 15-hydroxyprostaglandin dehydrogenase (PGDH). A number of stable analogs that resist inactivation and retain biological activity has been synthesized. Accumulating evidence suggests that these analogs may have a potential therapeutic impact in a variety of diseases characterized by neutrophil-mediated persistent inflammation, such as reperfusion injury, gastro-intestinal and renal inflammatory disorders, periodontitis. Clinical evaluation of LXA4 and 15-epi-LXA4 formation and their pharmacological regulation may be now achieved using recently developed ELISA assays, that allow large-scale measurements in human biological fluids.