Targeting leukotriene B<sub>4</sub>in inflammation

Gennaro, Antonio Di; Haeggström, Jesper Z.

doi:10.1517/14728222.2013.843671

Cited by 35 publications

(26 citation statements)

References 123 publications

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“…Dual inhibition of COXs and 5-LOX has advantage over COXs inhibitors in that blocking both prostaglandin and leukotriene formation likely not only results in more potent anti-inflammatory effects than inhibition of either pro-inflammatory pathway, but also reduces adverse effects compared with commonly-used NSAIDs. This is because a selective shutdown of COX pathway (by COX inhibitors) causes alternative metabolism of arachidonic acid via the 5-LOX pathway to increase leukotrienes, which are pro-inflammatory and promote gastrotoxicity, tumorigenesis and atherogenesis [155–157]. …”

Section: Summary and Conclusion Remarksmentioning

confidence: 99%

Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy

Jiang

2014

Free Radical Biology and Medicine

717

579

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The Vitamin E family consists of four tocopherols and four tocotrienols. α-Tocopherol (αT) is the predominant form of vitamin E in tissues and its deficiency leads to ataxia in humans. However, results from many clinical studies do not support protective roles of αT in disease prevention in people with adequate nutrient status. On the other hand, recent mechanistic studies indicate that other forms of vitamin E such as γ-tocopherol (γT), δ-tocopherol (δT) and γ-tocotrienol (γTE) have unique antioxidant and anti-inflammatory properties that are superior to αT in prevention and therapy against chronic diseases. These vitamin E forms scavenge reactive nitrogen species, inhibit cyclooxygenase- and 5-lipoxygenase-catalyzed eicosanoids and suppress pro-inflammatory signaling such as NF-κB and STAT3/6. Unlike αT, other vitamin E forms are significantly metabolized to carboxychromanols via cytochrome P-450 (CYP4F2)-initiated side-chain ω-oxidation. Long-chain carboxychromanols, esp.13’-carboxychromanols, are shown to have stronger anti-inflammatory effects than un-metabolized vitamins and may therefore contribute to beneficial effects of vitamin E forms in vivo. Consistent with mechanistic findings, animal and human studies show that γT and tocotrienols may be useful against inflammation-associated diseases. This review focuses on non-αT forms of vitamin E with respect to their metabolism, anti-inflammatory effects and mechanisms and in vivo efficacy in preclinical models as well as human clinical intervention studies.

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Section: Summary and Conclusion Remarksmentioning

confidence: 99%

Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy

Jiang

2014

Free Radical Biology and Medicine

717

579

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“…These gaps are critical because although LTB 4 is crucial for host defense, exuberant production underlies the basis for several inflammatory diseases and impairs endogenous resolution programs (11,18). Moreover, complete blockade of LTB 4 biosynthetic enzymes may compromise host defense; thus, understanding new mechanisms that temper LTB 4 production is essential for translational research in this area (19).…”

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confidence: 99%

Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B ₄ synthesis by inhibiting a calcium-activated kinase pathway

Fredman

Özcan

Spolitu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

169

157

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Imbalances between proinflammatory and proresolving mediators can lead to chronic inflammatory diseases. The balance of arachidonic acid-derived mediators in leukocytes is thought to be achieved through intracellular localization of 5-lipoxygenase (5-LOX): nuclear 5-LOX favors the biosynthesis of proinflammatory leukotriene B 4 (LTB 4 ), whereas, in theory, cytoplasmic 5-LOX could favor the biosynthesis of proresolving lipoxin A 4 (LXA 4 ). This balance is shifted in favor of LXA 4 by resolvin D1 (RvD1), a specialized proresolving mediator derived from docosahexaenoic acid, but the mechanism is not known. Here we report a new pathway through which RvD1 promotes nuclear exclusion of 5-LOX and thereby suppresses LTB 4 and enhances LXA 4 in macrophages. RvD1, by activating its receptor formyl peptide receptor2/lipoxin A 4 receptor, suppresses cytosolic calcium and decreases activation of the calcium-sensitive kinase calcium-calmodulin-dependent protein kinase II (CaMKII). CaMKII inhibition suppresses activation P38 and mitogen-activated protein kinase-activated protein kinase 2 kinases, which reduces Ser271 phosphorylation of 5-LOX and shifts 5-LOX from the nucleus to the cytoplasm. As such, RvD1's ability to decrease nuclear 5-LOX and the LTB 4 :LXA 4 ratio in vitro and in vivo was mimicked by macrophages lacking CaMKII or expressing S271A-5-LOX. These findings provide mechanistic insight into how a specialized proresolving mediator from the docosahexaenoic acid pathway shifts the balance toward resolution in the arachidonic acid pathway. Knowledge of this mechanism may provide new strategies for promoting inflammation resolution in chronic inflammatory diseases.P ersistent inflammation and its failed resolution underlie the pathophysiology of prevalent human diseases, including cancer, diabetes, and atherosclerosis (1). Hence, uncovering mechanisms to suppress inflammation and enhance resolution is of immense interest (2-5). Resolution is orchestrated in part by specialized proresolving mediators (SPMs), including lipoxins, resolvins, protectins, and maresins (2), and by protein and peptide mediators (6). A common protective function of SPMs is their ability to limit excessive proinflammatory leukotriene formation without being immunosuppressive (2, 7). Specifically, resolvin D1 (RvD1) is protective in several disease models (8) and limits excessive leukotriene B 4 (LTB 4 ) production without compromising host defense (7, 9). However, the mechanism underlying these actions of RvD1 is not well understood.Arachidonic acid (AA) is first converted into 5-hydroperoxyeicosatetraenoicacid (5-HPETE) and then into leukotriene A 4 (LTA 4 ) by 5-lipoxygenase (5-LOX) (10, 11). Subsequent hydrolysis of LTA 4 by LTA 4 hydrolase yields LTB 4 (10, 11). During inflammation, 5-LOX is phosphorylated and translocates to the nuclear membrane, which favors the biosynthesis of LTB 4 (12-17). However, major gaps remain in our understanding of the relevance of this pathway to primary cells and animal models and how they are regulated by...

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“…Leukotrienes are fatty acid-derived mediators of inflammation implicated in the pathogenesis of several chronic inflammatory disorders (85). Arachidonic acid is metabolized by 5-Lipoxygenase (5LPO) generating several forms of hydroperoxyeicosatetranoic acid known as HPETE (86).…”

Section: Introductionmentioning

confidence: 99%

Inflammatory targets of therapy in sickle cell disease

Owusu-Ansah

Ihunnah

Walker

et al. 2016

Translational Research

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Sickle cell disease (SCD) is a monogenic globin disorder characterized by the production of a structurally abnormal hemoglobin (Hb) variant Hb S, which causes severe hemolytic anemia, episodic painful vaso-occlusion and ultimately end-organ damage. The primary disease pathophysiology is intracellular Hb S polymerization and consequent sickling of erythrocytes. It has become evident over several decades that a more complex disease process contributes to the myriad of clinical complications seen in SCD patients with inflammation playing a central role. Drugs targeting specific inflammatory pathways therefore offer an attractive therapeutic strategy to ameliorate many of the clinical events in SCD. In addition they are useful tools to dissecting the molecular and cellular mechanisms that promote individual clinical events, and for developing improved therapeutics to address more challenging clinical dilemmas such as refractoriness to opioids or hyperalgesia. Here, we discuss the prospect of targeting multiple inflammatory pathways implicated in the pathogenesis of SCD with a focus on new therapeutics, striving to link the actions of the anti-inflammatory agents to a defined pathobiology, and specific clinical manifestations of SCD. We also review the anti-inflammatory attributes and the cognate inflammatory targets of hydroxyurea, the only FDA approved drug for SCD.

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Targeting leukotriene B₄in inflammation

Cited by 35 publications

References 123 publications

Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy

Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy

Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B ₄ synthesis by inhibiting a calcium-activated kinase pathway

Inflammatory targets of therapy in sickle cell disease

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Targeting leukotriene B4in inflammation

Cited by 35 publications

References 123 publications

Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy

Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy

Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B 4 synthesis by inhibiting a calcium-activated kinase pathway

Inflammatory targets of therapy in sickle cell disease

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Targeting leukotriene B₄in inflammation

Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B ₄ synthesis by inhibiting a calcium-activated kinase pathway