Leukotriene Synthesis Inhibitor Research Articles

Redox processes are major regulators of leukotriene synthesis in neutrophils exposed to bacteria Salmonella typhimurium; the way to manipulate neutrophil swarming.

Neutrophils play a primary role in protecting our body from pathogens. When confronted with invading bacteria, neutrophils begin to produce leukotriene B4, a potent chemoattractant that, in cooperation with the primary bacterial chemoattractant fMLP, stimulates the formation of swarms of neutrophils surrounding pathogens. Here we describe a complex redox regulation that either stimulates or inhibits fMLP-induced leukotriene synthesis in an experimental model of neutrophils interacting with Salmonella typhimurium. The scavenging of mitochondrial reactive oxygen species by mitochondria-targeted antioxidants MitoQ and SkQ1, as well as inhibition of their production by mitochondrial inhibitors, inhibit the synthesis of leukotrienes regardless of the cessation of oxidative phosphorylation. On the contrary, antioxidants N-acetylcysteine and sodium hydrosulfide promoting reductive shift in the reversible thiol-disulfide system stimulate the synthesis of leukotrienes. Diamide that oxidizes glutathione at high concentrations inhibits leukotriene synthesis, and the glutathione precursor S-adenosyl-L-methionine prevents this inhibition. Diamide-dependent inhibition is also prevented by diphenyleneiodonium, presumably through inhibition of NADPH oxidase and NADPH accumulation. Thus, during bacterial infection, maintaining the reduced state of glutathione in neutrophils plays a decisive role in the synthesis of leukotriene B4. Suppression of excess leukotriene synthesis is an effective strategy for treating various inflammatory pathologies. Our data suggest that the use of mitochondria-targeted antioxidants may be promising for this purpose, whereas known thiol-based antioxidants, such as N-acetylcysteine, may dangerously stimulate leukotriene synthesis by neutrophils during severe pathogenic infection.

Effectiveness of Histopathological Changes of Induced Thin Layer Endometrium by Pentoxifylline and Pentoxifylline-Loaded Poly Lactic-co-Glycolic Acid on Female Rats

Pentoxifylline (PTXF) is a vasoactive agent that plays a significant role in the treatment of thin-layer endometrium cases. The PTXF, also identified as oxpentifylline, is a member of xanthine derivatives and a competitive nonselective phosphodiesterase inhibitor leading to the elevation of intracellular cAMP, inhibition of tumor necrosis factor and leukotriene synthesis, activation of protein kinase A, and reduction of inflammation and innate immunity. Moreover, it is used as an agent to relieve muscle pain in people with peripheral artery disease (vascular irregularities). It is also an acceptable choice for the treatment of radiation-induced fibrosis. Therefore, the present study aimed to determine the advantageous impact of PTXF and PTXF-loaded poly lactic-co-glycolic acid (PLGA) on female rats after being exposed to ethanol to create a thin layer of the endometrium. For this purpose, 50 female rats were selected and divided into five groups (G1: negative normal control, G2: positive control, G3: PLGA only, G4: preference PTXF, and G5: PLGA-PTXF groups) for a 20-day treatment period. In this study, the histopathological section revealed a perfect improvement in the tissues of the uterine horn of female rats that induced endometria and were treated with PLGA-PTXF. In this group of rats, clear healing was achieved and there was an increase in the thickness of endometrium and myometrium, compared to the ordinary PTXF-treated group which had the lowest recovery characteristics. However, the positive control group underwent a significant decrease in terms of endometrium and myometrium thickness as well as vascular and glandular density. This study showed that the PTXF-loaded PLGA had the capacity to heal the thin layer of the endometrium by improving the levels of histopathological changes, especially regarding the thickness of the endometrium and myometrium more than the ordinary PTXF.

Mitochondria-targeted antioxidant SkQ1 inhibits leukotriene synthesis in human neutrophils.

Leukotrienes are among the most potent mediators of inflammation, and inhibition of their biosynthesis, is becoming increasingly important in the treatment of many pathologies. In this work, we demonstrated that preincubation of human neutrophils with the mitochondria targeted antioxidant SkQ1 (100nM) strongly inhibits leukotriene synthesis induced by three different stimuli: the Ca2+ ionophore A23187, the chemotactic formyl-peptide fMLP in combination with cytocholasin B, and opsonized zymosan. The SkQ1 analogue lacking the antioxidant quinone moiety (C12TPP) was ineffective, suggesting that mitochondrial production of reactive oxygen species (ROS) is critical for activating of leukotriene synthesis in human neutrophils. The uncoupler of oxidative phosphorylation FCCP also inhibits leukotriene synthesis, indicating that a high membrane potential is a prerequisite for stimulating leukotriene synthesis in neutrophils. Our data show that activation of mitogen-activated protein kinases p38 and ERK1/2, which is important for leukotriene synthesis in neutrophils is a target for SkQ1: 1) the selective p38 inhibitor SB203580 inhibited fMLP-induced leukotriene synthesis, while the ERK1/2 activation inhibitor U0126 suppressed leukotriene synthesis induced by any of the three stimuli; 2) SkQ1 effectively prevents p38 and ERK1/2 activation (accumulation of phosphorylated forms) induced by all three stimuli. This is the first study pointing to the involvement of mitochondrial reactive oxygen species in the activation of leukotriene synthesis in human neutrophils. The use of mitochondria-targeted antioxidants can be considered as a promising strategy for inhibiting leukotriene synthesis and treating various inflammatory pathologies.

Extract matrix composition does not affect in vitro leukotriene inhibitory effects of the Petasites hybridus extract Ze 339

It has been shown that a lipophilic CO2-extract prepared from the leaves of Petasites hybridus (Ze 339) inhibited leukotriene synthesis in vitro and ex vivo. The inhibition of the leukotriene synthesis was solely attributed to the sum of the petasins, namely petasin and its isomers isopetasin and neopetasin. To further investigate the influence of the extract matrix on leukotriene synthesis inhibition, we compared twelve selected batches of Ze 339 that differed significantly in the composition of the extract matrix. Quantitative analysis of the twelve extract batches revealed high contents of petasins [28.8–41.9%], fatty acids [17.1–27.2%] and crude oil and fat [17.7–44.2%]. The amount of sterols ranged between 3.0 and 4.9% and that of essential oils between 1.3 and 10.5%. Based on the quantitative analysis, 97–100% of the extract mass could be attributed to the above mentioned groups of ingredients. Despite significant differences in extract matrix composition, only the content of petasins was critical for the dose-dependent inhibition of leukotriene synthesis. However, at equal concentrations of petasins, no significant differences in 5-LOX, LTC4 synthase and LTA4 hydrolase inhibition were detected between the selected extract batches, despite differences in the composition of the petasin isomers. Our data suggest that the extract matrix of Ze 339 has no effect on leukotriene inhibitory effects of the petasins.

Eicosanoid‐induced calcium signaling mediates cellular immune responses of Tenebrio molitor

AbstractCalcium signaling is associated with actin cytoskeleton rearrangement. It is required for expressing cellular immune responses of insect hemocytes. Eicosanoids mediate immune responses by cytoskeleton rearrangement against various pathogen infections in insects. The objective of this study was to investigate cellular immune responses of a mealworm, Tenebrio molitor L. (Coleoptera: Tenebrionidae). The hypothesis tested was that immune responses would be mediated by calcium signaling associated with eicosanoid mediation. Larvae of T. molitor possessed at least four morphological types of hemocytes, most (almost 75%) of which were granulocytes and plasmatocytes. They all exhibited a hemocyte‐spreading behavior by F‐actin extension. Upon bacterial infection, hemocytes exhibited phagocytosis and formed hemocytic nodules. Intracellular calcium was detected in hemocytes. Its amount increased with increasing incubation time after bacterial infection. Inhibition of calcium influx or release from endoplasmic reticulum using specific inhibitors prevented cellular immune responses. Interestingly, treatment with an eicosanoid biosynthesis inhibitor suppressed calcium signals induced by bacterial challenge. Furthermore, treatment with naproxen, a prostaglandin (PG) synthesis inhibitor, or esculetin, a leukotriene synthesis inhibitor, also inhibited the increase of calcium concentration in hemocytes. Among eicosanoids, PGE2 highly stimulated the increase of calcium signals. These results suggest that cellular immune responses of T. molitor are triggered by calcium signaling, which is up‐regulated by eicosanoids.

Current perspective on eicosanoids in asthma and allergic diseases: EAACI Task Force consensus report, part I.

Eicosanoids are biologically active lipid mediators, comprising prostaglandins, leukotrienes, thromboxanes, and lipoxins, involved in several pathophysiological processes relevant to asthma, allergies, and allied diseases. Prostaglandins and leukotrienes are the most studied eicosanoids and established inducers of airway pathophysiology including bronchoconstriction and airway inflammation. Drugs inhibiting the synthesis of lipid mediators or their effects, such as leukotriene synthesis inhibitors, leukotriene receptors antagonists, and more recently prostaglandin D2 receptor antagonists, have been shown to modulate features of asthma and allergic diseases. This review, produced by an European Academy of Allergy and Clinical Immunology (EAACI) task force, highlights our current understanding of eicosanoid biology and its role in mediating human pathology, with a focus on new findings relevant for clinical practice, development of novel therapeutics, and future research opportunities.

Synthetic Oligodeoxynucleotides in the Regulation of Leukotriene Synthesis in Human Neutrophils

Polymorphonuclear leukocytes (PMNLs, neutrophils) play a central role in the defense against microbial infections. In the immune response to bacterial and fungal infections neutrophils eliminate pathogens through phagocytosis. During phagocytosis neutrophils produce physiologically active compounds called leukotrienes. Neutrophil production of leukoriene B4 is responsible for a second wave of neutrophil recruitment during inflammation. In the activation of neutrophils, not only the bacteria themselves play a role, but also pathogen associated molecular patterns, in particular, bacterial DNA and its fragments. Neutrophil priming with bacterial products makes neutrophils more responsive to activating stimuli. Synthetic CpG‐oligodeoxynucleotides (CpG‐ODNs) mimic microbial DNA and are now widely used to study DNA‐mediated cellular events. In our study we compared the effects of synthetic oligodeoxynucleotides (ODNs) of different structure on leukotriene synthesis in neutrophils during Salmonella bacteria phagocytosis. We treated PMNLs with opsonized S. typhimurium at a ratio of bacteria:PMNLs in the range 20–25:1. Leukotrienes and other 5‐lipoxygenase products were detected after priming neutrophils by 30 min incubation with 1 μM ODN and further stimulation for 15 min with opsonized Salmonella bacteria. The neutrophil exposure to A‐class CpG‐ODN, with phosphodiester inner core, inhibited leukotriene synthesis in neutrophil interaction with bacteria Salmonella typhimurium. Sequences, containing the human telomeric (TTAGGG)n repeats, on the contrary, activated leukotriene synthesis. Effects of A‐class CpG‐ODNs were sensitive to inhibitors of endosomal acidification and probably induced intracellular signaling through binding to toll like receptor TLR9. Synthetic DNA fragments containing stimulating CpG motifs initiate TLR9 signals, which lead to activation of the transcription factor NF‐kB. In our assays NF‐kB inhibitor BAY11‐7082 abolished the effects of A‐class CpG ODNs and increased the effects of telomeric ODNs on leukotriene synthesis. The results of our study revealed that the signal to inhibition of leukotriene synthesis by A‐class CpG‐ODNs and to activation of leukotriene synthesis by telomeric ODNs may be due to interaction of both classes of ODNs with TLR9 on neutrophils.Ethics statement. The authors prepared neutrophils from the blood of healthy volunteers. Blood was collected via venous puncture, as approved by the Ministry of Public Health Service of the Russian Federation. Experimental and the subject consent procedures were approved by the Ethics Committee of the A. N. Belozersky Institute of Physico‐Chemical Biology, Moscow State University. Fully informed consent was obtained, and all investigations were conducted according to the principles laid down in the Declaration of Helsinki.Support or Funding InformationThis study was funded by a grant from the Russian Foundation for Basic Research (17‐04‐01491)

Nitrosative Stress and Lipid Homeostasis as a Mechanism for Zileuton Hepatotoxicity and Resistance in Genetically Sensitive Mice.

Zileuton is an orally active inhibitor of leukotriene synthesis for maintenance treatment of asthma, for which clinical usage has been associated with idiosyncratic liver injury. Mechanistic understanding of zileuton toxicity is hampered by the rarity of the cases and lack of an animal model. A promising model for mechanistic study of rare liver injury is the Diversity Outbred (J:DO) mouse population, with genetic variation similar to that found in humans. In this study, female DO mice were administered zileuton or vehicle daily for 7 days (i.g.). Serum liver enzymes were elevated in the zileuton group, with marked interindividual variability in response. Zileuton exposure-induced findings in susceptible DO mice included microvesicular fatty change, hepatocellular mitosis, and hepatocellular necrosis. Inducible nitric oxide synthase and nitrotyrosine abundance were increased in livers of animals with necrosis and those with fatty change, implicating nitrosative stress as a possible injury mechanism. Conversely, DO mice lacking adverse liver pathology following zileuton exposure experienced decreased hepatic concentrations of resistin and increased concentrations of insulin and leptin, providing potential clues into mechanisms of toxicity resistance. Transcriptome pathway analysis highlighted mitochondrial dysfunction and altered fatty acid oxidation as key molecular perturbations associated with zileuton exposure, and suggested that interindividual differences in cytochrome P450 metabolism, glutathione-mediated detoxification, and farnesoid X receptor signaling may contribute to zileuton-induced liver injury (ZILI). Taken together, DO mice provided a platform for investigating mechanisms of toxicity and resistance in context of ZILI which may lead to targeted therapeutic interventions.

Targeting Leukotrienes as a Therapeutic Strategy to Prevent Comorbidities Associated with Metabolic Stress.

Leukotrienes (LTs) are potent lipid mediators that exert a variety of functions, ranging from maintaining the tone of the homeostatic immune response to exerting potent proinflammatory effects. Therefore,LTs are essential elements in the development and maintenance of different chronic diseases, such as asthma, arthritis, and atherosclerosis. Due to the pleiotropic effects of LTs in the pathogenesis of inflammatory diseases, studies are needed to discover potent and specific LT synthesis inhibitors and LT receptor antagonists. Even though most clinical trials using LT inhibitors or antagonists have failed due to low efficacy and/or toxicity, new drug development strategies are driving the discovery for LT inhibitors to prevent inflammatory diseases. A newly important detrimental role for LTs in comorbidities associated with metabolic stress has emerged in the last few years and managing LT production and/or actions could represent an exciting new strategy to prevent or treat inflammatory diseases associated with metabolic disorders. This review is intended to shed light on the synthesis and actions of leukotrienes, the most common drugs used in clinical trials, and discuss the therapeutic potential of preventing LT function in obesity, diabetes, and hyperlipidemia.

Leukotriene Synthesis Is Critical for Medulloblastoma Progression.

Here, we examined the role of leukotrienes, well-known inflammatory mediators, in the tumorigenesis of hedgehog pathway-associated medulloblastoma, and tested the efficacies of antagonists of leukotriene biosynthesis in medulloblastoma treatment.Experimental Design: We examined the leukotriene levels in medulloblastoma cells by ELISA. We next tested whether leukotriene synthesis in medulloblastoma cells relied on activation of hedgehog pathway, or the presence of hedgehog ligand secreted by astrocytes. We then investigated whether leukotriene mediated hedgehog-induced Nestin expression in tumor cells. The functions of leukotriene in tumor cell proliferation and tumor growth in medulloblastoma were determined through knocking down 5-lipoxygenase (a critical enzyme for leukotriene synthesis) by shRNAs, or using 5-lipoxygenase-deficient mice. Finally, the efficacies of antagonists of leukotriene synthesis in medulloblastoma treatment were tested in vivo and in vitro. Leukotriene was significantly upregulated in medulloblastoma cells. Increased leukotriene synthesis relied on hedgehog ligand secreted by astrocytes, a major component of medulloblastoma microenvironment. Leukotriene stimulated tumor cells to express Nestin, a cytoskeletal protein essential for medulloblastoma growth. Genetic blockage of leukotriene synthesis dramatically suppressed medulloblastoma cell proliferation and tumor growth in vivo. Pharmaceutical inhibition of leukotriene synthesis markedly repressed medulloblastoma cell proliferation, but had no effect on proliferation of normal neuronal progenitors. Moreover, antagonists of leukotriene synthesis exhibited promising tumor inhibitory efficacies on drug-resistant medulloblastoma. Our findings reveal a novel signaling pathway that is critical for medulloblastoma cell proliferation and tumor progression, and that leukotriene biosynthesis represents a promising therapeutic target for medulloblastoma treatment.

Targeting lipid mediators in asthma: time for reappraisal.

In the past decades, cysteinyl leukotrienes (CysLTs) and prostaglandin D2 have been recognized as key mediators of asthma and comorbid conditions for their potent broncho-active and proinflammatory properties. However, both the development and initial positioning of small molecules targeting these lipid mediators [i.e., leukotriene-synthesis inhibitors, CysLT-antagonists, and chemoattractant receptor homologous molecule on T-helper2-cells (CRTH2) antagonists] experienced drawbacks by lacking adequate biomarkers to define potential responders. New insights into the mechanisms of airway inflammation in asthma including the interaction of leukotrienes and prostanoids has uncovered potential therapeutic targets. Emerging application of biomarkers in more recent clinical studies helped identify responders to therapies targeting lipid mediators and demonstrated their clinical efficacy in distinct asthma phenotypes and endotypes. Interest in small molecules targeting lipid mediators in asthma and related conditions is emerging. Several clinical trials evaluating the efficacy and safety of CRTH2 (Prostaglandin D2 receptor 2) antagonists are ongoing. There is an urgent need for sensitive biomarkers to identify responders to such therapies and for monitoring of (long-term) effects. Furthermore, evaluation of effectiveness of combining different agents targeting lipid mediators or combining them with available or emerging biologics may uncover other potential benefits in certain asthma populations warranting future research.

Therapeutic effect of 28-homobrassinolide on leukotriene synthesis in leukemia cells.

The present study was aimed to investigate the effect of 28-homobrassinolide on leukotriene synthesis in the 2H3 cells. Cell viability was determined by using sulforhodamine B (SRB) assay. Leukotriene C4 (LTC4) and Leukotriene B4 (LTB4) were determined in the cell and cell lysates. Intracellular Ca2+ was determined in the intact cells. Phospholipases A2 (PLA2) expression was determined in the cells using immunofluorescence. LTC4 and LTB4 were tremendously increased in IgE-loaded 2H3 cells. However, these levels were significantly reduced following treatment with 28-homobrassinolide. The intracellular Ca2+ level was not altered by treatment. Expression of PLA2 was significantly reduced following treatment with 28-homobrassinolide. Taking all these data together, it is suggested that the 28-homobrassinolide may be a potential therapeutic agent to inhibit leukotriene synthesis in 2H3 cells.

Ceruloplasmin-derived peptide is the strongest regulator of oxidative stress and leukotriene synthesis in neutrophils.

Ceruloplasmin, an acute-phase protein, can affect the activity of leukocytes through its various enzymatic activities and protein-protein interactions (with lactoferrin, myeloperoxidase, eosinophil peroxidase, serprocidins, and 5-lipoxygenase (5-LOX), among others). However, the molecular mechanisms of ceruloplasmin activity are not clearly understood. In this study, we tested the ability of two synthetic peptides, RPYLKVFNPR (883-892) (P1) and RRPYLKVFNPRR (882-893) (P2), corresponding to the indicated fragments of the ceruloplasmin sequence, to affect neutrophil activation. Leukotriene (LT) B4 is the primary eicosanoid product of polymorphonuclear leukocytes (PMNLs, neutrophils). We studied leukotriene synthesis in PMNLs upon interaction with Salmonella enterica serovar Typhimurium. Priming of neutrophils with phorbol 12-myristate 13-acetate (PMA) elicited the strong regulatory function of P2 peptide as a superoxide formation inducer and leukotriene synthesis inhibitor. Ceruloplasmin-derived P2 peptide appeared to be a strong inhibitor of 5-LOX product synthesis under conditions of oxidative stress.

The hallucinogenic diterpene salvinorin A inhibits leukotriene synthesis in experimental models of inflammation

Leukotrienes (LTs) are lipid mediators derived from arachidonic acid (AA) involved in a number of autoimmune/inflammatory disorders including asthma, allergic rhinitis and cardiovascular diseases. Salvinorin A (SA), a diterpene isolated from the hallucinogenic plant Salvia divinorum, is a well-established analgesic compound, but its anti-inflammatory properties are under-researched and its effects on LT production is unknown to date. Here, we studied the possible effect of SA on LT production and verified its actions on experimental models of inflammation in which LTs play a prominent role.Peritoneal macrophages (PM) stimulated by calcium ionophore A23187 were chosen as in vitro system to evaluate the effect of SA on LT production. Zymosan-induced peritonitis in mice and carrageenan-induced pleurisy in rats were selected as LT-related models to evaluate the effect of SA on inflammation as well as on LT biosynthesis.SA inhibited, in a concentration-dependent manner, A23187-induced LTB4 biosynthesis in isolated PM. In zymosan-induced peritonitis, SA inhibited cell infiltration, myeloperoxidase activity, vascular permeability and LTC4 production in the peritoneal cavity without decreasing the production of prostaglandin E2. In carrageenan-induced pleurisy in rats, a more sophisticated model of acute inflammation related to LTs, SA significantly inhibited LTB4 production in the inflammatory exudates, along with reducing the phlogistic process in the lung.In conclusion, SA inhibited LT production and it was effective in experimental models of inflammation in which LTs play a pivotal role. SA might be considered as a lead compound for the development of drugs useful in LTs-related diseases.

Boswellic Acids and Their Role in Chronic Inflammatory Diseases.

Whereas KBA is absorbed reaching blood levels being close to in vitro IC50, AKBA which is more active in in vitro studies than KBA, but undergoes much less absorption than KBA. However, absorption of both is increased more than twice when taken together with a high-fat meal.Clinical Studies There are a variety of chronic inflammatory diseases which respond to treatment with extracts from the resin of Boswellia species. Though, the number of cases is small in related clinical studies, their results are convincing and supported by the preclinical data. These studies include rheumatoid arthritis, osteoarthritis, chronic colitis, ulcerative colitis, collagenous colitis, Crohn's disease and bronchial asthma. It can not be expected that there is cure from these diseases but at least improvement of symptoms in about 60-70% of the cases. Side Effects The number and severity of side effects is extremely low. The most reported complaints are gastrointestinal symptoms. Allergic reactions are rare. And most authors report, that treatment with BEs is well tolerated and the registered side effects in BE- and placebo groups are similar.

Antileukotrienes in upper airway inflammatory diseases.

Leukotrienes (LTs) are a family of inflammatory mediators including LTA4, LTB4, LTC4, LTD4, and LTE4. By competitive binding to the cysteinyl LT1 (CysLT1) receptor, LT receptor antagonist drugs, such as montelukast, zafirlukast, and pranlukast, block the effects of CysLTs, improving the symptoms of some chronic respiratory diseases, particularly bronchial asthma and allergic rhinitis. We reviewed the efficacy of antileukotrienes in upper airway inflammatory diseases. An update on the use of antileukotrienes in upper airway diseases in children and adults is presented with a detailed literature survey. Data on LTs, antileukotrienes, and antileukotrienes in chronic rhinosinusitis and nasal polyps, asthma, and allergic rhinitis are presented. Antileukotriene drugs are classified into two groups: CysLT receptor antagonists (zafirlukast, pranlukast, and montelukast) and LT synthesis inhibitors (5-lipoxygenase inhibitors such as zileuton, ZD2138, Bay X 1005, and MK-0591). CysLTs have important proinflammatory and profibrotic effects that contribute to the extensive hyperplastic rhinosinusitis and nasal polyposis (NP) that characterise these disorders. Patients who receive zafirlukast or zileuton tend to show objective improvements in, or at least stabilisation of, NP. Montelukast treatment may lead to clinical subjective improvement in NP. Montelukast treatment after sinus surgery can lead to a significant reduction in eosinophilic cationic protein levels in serum, with a beneficial effect on nasal and pulmonary symptoms and less impact in NP. Combined inhaled corticosteroids and long-acting β-agonists treatments are most effective for preventing exacerbations among paediatric asthma patients. Treatments with medium- or high-dose inhaled corticosteroids, combined inhaled corticosteroids and LT receptor antagonists, and low-dose inhaled corticosteroids have been reported to be equally effective. Antileukotrienes have also been reported to be effective for allergic rhinitis.

Selenium supplementation in thyroid associated ophthalmopathy: an update.

The therapeutic effect of selenium (Se) has already been proven in thyroid disease and thyroid associated ophthalmopathy (TAO). In spite of clear scientific proof of its benefits in TAO, there appears to be no clear agreement among the clinicians regarding its optimum dose, duration of the treatment, efficacy and safety to date. In this review, the author summarises the findings of 135 English language articles published on this subject over the past four decades from 1973 to 2013. The regulation and metabolism of thyroid hormones require a steady supply of Se and recent studies have revealed several possible mechanisms by which Se improves the severity of thyroid disease and TAO. These mechanisms include 1) inhibitory effect of HLA-DR molecule expression on thyrocytes; 2) profound reductions of thyroid stimulating hormone (TSH) receptor antibodies (TSHR-Ab) and TPO antibodies (TPO-Ab); 3) prevention of dysregulation of cell-mediated immunity and B cell function; 4) neutralising reactive oxygen species (ROS) and inhibition of redox control processes required for the activation, differentiation and action of lymphocytes, macrophages, neutrophils, natural killer cells involved in both acute and chronic orbital inflammation in TAO; 5) inhibition of expression of pro-inflammatory cytokines and 6) inhibition of prostaglandin and leukotriene synthesis. An increased oxidative stress has been observed in both acute and chronic phases of thyroid disease with raised tissue concentrations of ROS. The benefits of Se supplementation in individuals with TAO appear to be proportionate to the degree of systemic activity of the thyroid disease. The maximal benefit of Se supplementation is therefore seen in the subjects who are hyperthyroid. Restoration of euthyroidism is one of the main goals in the management of TAO and when anti-thyroid drugs are combined with Se, the patients with Graves' disease (GD) and autoimmune thyroiditis (AIT) achieved euthyroidism faster than those treated with anti-thyroid drugs alone. Se status of normal adult humans can vary widely and Se supplementation may confer benefit only if serum Se levels are insufficient. The author recommends that serum Se levels of patients with TAO to be assessed prior to and during Se supplementation at regular intervals to avoid potential iatrogenic chronic Se overdose.

Understanding the Mechanisms Controlling Leishmania amazonensis Infection In Vitro: The Role of LTB4 Derived From Human Neutrophils

Neutrophils are rapidly recruited to the site of Leishmania infection and play an active role in capturing and killing parasites. They are the main source of leukotriene B4 (LTB4), a potent proinflammatory lipid mediator. However, the role of LTB4 in neutrophil infection by Leishmania amazonensis is not clear. In this study, we show that L. amazonensis or its lipophosphoglycan can induce neutrophil activation, degranulation, and LTB4 production. Using pharmacological inhibitors of leukotriene synthesis, our findings reveal an LTB4-driven autocrine/paracrine regulatory effect. In particular, neutrophil-derived LTB4 controls L. amazonensis killing, degranulation, and reactive oxygen species production. In addition, L. amazonensis infection induces an early increase in Toll-like receptor 2 expression, which facilitates parasite internalization. Nuclear factor kappa B (NFkB) pathway activation represents a required upstream event for L. amazonensis–induced LTB4 synthesis. These leishmanicidal mechanisms mediated by neutrophil-derived LTB4 act through activation of its receptor, B leukotriene receptor 1 (BLT1).

Pivotal Role of the 5-Lipoxygenase Pathway in Lung Injury after Experimental Sepsis

Postsepsis lung injury is a common clinical problem associated with significant morbidity and mortality. Leukotrienes (LTs) are important lipid mediators of infection and inflammation derived from the 5-lipoxygenase (5-LO) metabolism of arachidonate with the potential to contribute to lung damage after sepsis. To test the hypothesis that LTs are mediators of lung injury after sepsis, we assessed lung structure, inflammatory mediators, and mechanical changes after cecal ligation and puncture surgery in wild-type (WT) and 5-LO knockout (5-LO(-/-)) mice and in WT mice treated with a pharmacologic LT synthesis inhibitor (MK886) and LT receptor antagonists (CP105,696 and montelukast). Sixteen hours after surgery, WT animals exhibited severe lung injury (by histological analysis), substantial mechanical impairment (i.e., an increase in static lung elastance), an increase in neutrophil infiltration, and high levels of LTB4, cysteinyl-LTs (cys-LTs), prostaglandin E2, IL-1β, IL-6, IL-10, IL-17, KC (CXCL1), and monocyte chemotactic protein-1 (CCL2) in lung tissue and plasma. 5-LO(-/-) mice and WT mice treated with a pharmacologic 5-LO inhibitor were significantly protected from lung inflammation and injury. Selective antagonists for BLT1 or cys-LT1, the high-affinity receptors for LTB4 and cys-LTs, respectively, were insufficient to provide protection when used alone. These results point to an important role for 5-LO products in sepsis-induced lung injury and suggest that the use of 5-LO inhibitors may be of therapeutic benefit clinically.

Emerging Anti-inflammatory Therapies for Atherosclerosis

Atherosclerosis remains one of the main causes of cardiovascular disease, which is the leading cause of death worldwide. It is now accepted that atherosclerosis is an inflammatory, dynamic and complex disease involving multiple cell types, and many antiinflammatory strategies have recently emerged as potential therapeutic approaches for atherosclerotic disease. In this review, we discuss the most recent progress in the development of anti-inflammatory strategies. We highlight the beneficial effects of potent antiinflammatory drugs, including recently developed biologics, and we describe diverse emerging approaches that target inflammatory processes involved in atherosclerosis including tumor necrosis factor antagonists, anti-interleukins, viral-derived serpins, P-selectin inhibition and leukotriene synthesis inhibition.