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Identification of Proteomic Features To Distinguish Benign Pulmonary Nodules from Lung Adenocarcinoma.
Codreanu SG, Hoeksema MD, Slebos RJC, Zimmerman LJ, Rahman SMJ, Li M, Chen SC, Chen H, Eisenberg R, Liebler DC, Massion PP
(2017) J Proteome Res 16: 3266-3276
MeSH Terms: 5-Lipoxygenase-Activating Proteins, Adenocarcinoma, Adenocarcinoma of Lung, Adult, Aged, Antigens, CD, Arachidonate 5-Lipoxygenase, Biomarkers, Tumor, CD11 Antigens, Cell Adhesion Molecules, Diagnosis, Differential, Female, GPI-Linked Proteins, Gene Expression Regulation, Neoplastic, Glucose Transporter Type 3, Humans, Integrin alpha Chains, Lung Neoplasms, Male, Middle Aged, Neoplasm Proteins, Proteomics, Respiratory Mucosa, Solitary Pulmonary Nodule, Tandem Mass Spectrometry, Tissue Array Analysis, Transcriptome
Show Abstract · Added January 29, 2018
We hypothesized that distinct protein expression features of benign and malignant pulmonary nodules may reveal novel candidate biomarkers for the early detection of lung cancer. We performed proteome profiling by liquid chromatography-tandem mass spectrometry to characterize 34 resected benign lung nodules, 24 untreated lung adenocarcinomas (ADCs), and biopsies of bronchial epithelium. Group comparisons identified 65 proteins that differentiate nodules from ADCs and normal bronchial epithelium and 66 proteins that differentiate ADCs from nodules and normal bronchial epithelium. We developed a multiplexed parallel reaction monitoring (PRM) assay to quantify a subset of 43 of these candidate biomarkers in an independent cohort of 20 benign nodules, 21 ADCs, and 20 normal bronchial biopsies. PRM analyses confirmed significant nodule-specific abundance of 10 proteins including ALOX5, ALOX5AP, CCL19, CILP1, COL5A2, ITGB2, ITGAX, PTPRE, S100A12, and SLC2A3 and significant ADC-specific abundance of CEACAM6, CRABP2, LAD1, PLOD2, and TMEM110-MUSTN1. Immunohistochemistry analyses for seven selected proteins performed on an independent set of tissue microarrays confirmed nodule-specific expression of ALOX5, ALOX5AP, ITGAX, and SLC2A3 and cancer-specific expression of CEACAM6. These studies illustrate the value of global and targeted proteomics in a systematic process to identify and qualify candidate biomarkers for noninvasive molecular diagnosis of lung cancer.
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27 MeSH Terms
Opposing roles of LTB4 and PGE2 in regulating the inflammasome-dependent scorpion venom-induced mortality.
Zoccal KF, Sorgi CA, Hori JI, Paula-Silva FW, Arantes EC, Serezani CH, Zamboni DS, Faccioli LH
(2016) Nat Commun 7: 10760
MeSH Terms: Animals, Arachidonate 5-Lipoxygenase, Blotting, Western, Carrier Proteins, Celecoxib, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Cyclooxygenase Inhibitors, Dinoprostone, In Vitro Techniques, Indoles, Indomethacin, Inflammasomes, Interleukin-1beta, Leukotriene B4, Lipoxygenase Inhibitors, Macrophages, Macrophages, Peritoneal, Mice, Mice, Knockout, NF-kappa B, NLR Family, Pyrin Domain-Containing 3 Protein, Phosphoproteins, Prostaglandin Antagonists, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype, Reverse Transcriptase Polymerase Chain Reaction, Scorpion Stings, Scorpion Venoms, Scorpions, Xanthones
Show Abstract · Added May 4, 2017
Tityus serrulatus sting causes thousands of deaths annually worldwide. T. serrulatus-envenomed victims exhibit local or systemic reaction that culminates in pulmonary oedema, potentially leading to death. However, the molecular mechanisms underlying T. serrulatus venom (TsV) activity remain unknown. Here we show that TsV triggers NLRP3 inflammasome activation via K(+) efflux. Mechanistically, TsV triggers lung-resident cells to release PGE2, which induces IL-1β production via E prostanoid receptor 2/4-cAMP-PKA-NFκB-dependent mechanisms. IL-1β/IL-1R actions account for oedema and neutrophil recruitment to the lungs, leading to TsV-induced mortality. Inflammasome activation triggers LTB4 production and further PGE2 via IL-1β/IL-1R signalling. Activation of LTB4-BLT1/2 pathway decreases cAMP generation, controlling TsV-induced inflammation. Exogenous administration confirms LTB4 anti-inflammatory activity and abrogates TsV-induced mortality. These results suggest that the balance between LTB4 and PGE2 determines the amount of IL-1β inflammasome-dependent release and the outcome of envenomation. We suggest COX1/2 inhibition as an effective therapeutic intervention for scorpion envenomation.
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31 MeSH Terms
Lipoxin Inhibits Fungal Uptake by Macrophages and Reduces the Severity of Acute Pulmonary Infection Caused by Paracoccidioides brasiliensis.
Ribeiro LR, Loures FV, de Araújo EF, Feriotti C, Costa TA, Serezani CH, Jancar S, Calich VL
(2015) Mediators Inflamm 2015: 852574
MeSH Terms: Acetates, Animals, Arachidonate 5-Lipoxygenase, Dinoprostone, Inflammation Mediators, Leukotriene Antagonists, Leukotriene C4, Lipoxins, Macrophages, Alveolar, Male, Mice, Mice, 129 Strain, Mice, Inbred A, Mice, Knockout, Paracoccidioides, Paracoccidioidomycosis, Quinolines, Receptors, Leukotriene, Receptors, Pattern Recognition
Show Abstract · Added May 4, 2017
Cysteinyl leukotrienes (CysLTs) and lipoxins (LXs) are lipid mediators that control inflammation, with the former inducing and the latter inhibiting this process. Because the role played by these mediators in paracoccidioidomycosis was not investigated, we aimed to characterize the role of CysLT in the pulmonary infection developed by resistant (A/J) and susceptible (B10.A) mice. 48 h after infection, elevated levels of pulmonary LTC4 and LXA4 were produced by both mouse strains, but higher levels were found in the lungs of susceptible mice. Blocking the CysLTs receptor by MTL reduced fungal loads in B10.A, but not in A/J mice. In susceptible mice, MLT treatment led to reduced influx of PMN leukocytes, increased recruitment of monocytes, predominant synthesis of anti-inflammatory cytokines, and augmented expression of 5- and 15-lipoxygenase mRNA, suggesting a prevalent LXA4 activity. In agreement, MTL-treated macrophages showed reduced fungal burdens associated with decreased ingestion of fungal cells. Furthermore, the addition of exogenous LX reduced, and the specific blockade of the LX receptor increased the fungal loads of B10.A macrophages. This study showed for the first time that inhibition of CysLTs signaling results in less severe pulmonary paracoccidioidomycosis that occurs in parallel with elevated LX activity and reduced infection of macrophages.
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19 MeSH Terms
Leukotriene B4-mediated sterile inflammation promotes susceptibility to sepsis in a mouse model of type 1 diabetes.
Filgueiras LR, Brandt SL, Wang S, Wang Z, Morris DL, Evans-Molina C, Mirmira RG, Jancar S, Serezani CH
(2015) Sci Signal 8: ra10
MeSH Terms: Analysis of Variance, Animals, Arachidonate 5-Lipoxygenase, Chromatin Immunoprecipitation, Cytokines, Diabetes Mellitus, Type 1, Female, Gene Expression Regulation, Immunoblotting, Inflammation, Inflammation Mediators, Insulin, Leukotriene B4, Macrophages, Mice, Mice, Knockout, Myeloid Differentiation Factor 88, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, STAT1 Transcription Factor, Sepsis
Show Abstract · Added May 4, 2017
Type 1 diabetes mellitus (T1DM) is associated with chronic systemic inflammation and enhanced susceptibility to systemic bacterial infection (sepsis). We hypothesized that low insulin concentrations in T1DM trigger the enzyme 5-lipoxygenase (5-LO) to produce the lipid mediator leukotriene B4 (LTB4), which triggers systemic inflammation that may increase susceptibility to polymicrobial sepsis. Consistent with chronic inflammation, peritoneal macrophages from two mouse models of T1DM had greater abundance of the adaptor MyD88 (myeloid differentiation factor 88) and its direct transcriptional effector STAT-1 (signal transducer and activator of transcription 1) than macrophages from nondiabetic mice. Expression of Alox5, which encodes 5-LO, and the concentration of the proinflammatory cytokine interleukin-1β (IL-1β) were also increased in peritoneal macrophages and serum from T1DM mice. Insulin treatment reduced LTB4 concentrations in the circulation and Myd88 and Stat1 expression in the macrophages from T1DM mice. T1DM mice treated with a 5-LO inhibitor had reduced Myd88 mRNA in macrophages and increased abundance of IL-1 receptor antagonist and reduced production of IL-β in the circulation. T1DM mice lacking 5-LO or the receptor for LTB4 also produced less proinflammatory cytokines. Compared to wild-type or untreated diabetic mice, T1DM mice lacking the receptor for LTB4 or treated with a 5-LO inhibitor survived polymicrobial sepsis, had reduced production of proinflammatory cytokines, and had decreased bacterial counts. These results uncover a role for LTB4 in promoting sterile inflammation in diabetes and the enhanced susceptibility to sepsis in T1DM.
Copyright © 2015, American Association for the Advancement of Science.
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21 MeSH Terms
Inhibitors of the 5-lipoxygenase arachidonic acid pathway induce ATP release and ATP-dependent organic cation transport in macrophages.
da Silva-Souza HA, Lira MN, Costa-Junior HM, da Cruz CM, Vasconcellos JS, Mendes AN, Pimenta-Reis G, Alvarez CL, Faccioli LH, Serezani CH, Schachter J, Persechini PM
(2014) Biochim Biophys Acta 1838: 1967-77
MeSH Terms: Adenosine Triphosphate, Animals, Arachidonate 5-Lipoxygenase, Calcium, Cations, Ion Transport, Lipoxygenase Inhibitors, Macrophages, Mice, Mice, Inbred C57BL, Phospholipases A2, Receptors, Purinergic P2X7
Show Abstract · Added May 4, 2017
We have previously described that arachidonic acid (AA)-5-lipoxygenase (5-LO) metabolism inhibitors such as NDGA and MK886, inhibit cell death by apoptosis, but not by necrosis, induced by extracellular ATP (ATPe) binding to P2X7 receptors in macrophages. ATPe binding to P2X7 also induces large cationic and anionic organic molecules uptake in these cells, a process that involves at least two distinct transport mechanisms: one for cations and another for anions. Here we show that inhibitors of the AA-5-LO pathway do not inhibit P2X7 receptors, as judged by the maintenance of the ATPe-induced uptake of fluorescent anionic dyes. In addition, we describe two new transport phenomena induced by these inhibitors in macrophages: a cation-selective uptake of fluorescent dyes and the release of ATP. The cation uptake requires secreted ATPe, but, differently from the P2X7/ATPe-induced phenomena, it is also present in macrophages derived from mice deficient in the P2X7 gene. Inhibitors of phospholipase A2 and of the AA-cyclooxygenase pathway did not induce the cation uptake. The uptake of non-organic cations was investigated by measuring the free intracellular Ca(2+) concentration ([Ca(2+)]i) by Fura-2 fluorescence. NDGA, but not MK886, induced an increase in [Ca(2+)]i. Chelating Ca(2+) ions in the extracellular medium suppressed the intracellular Ca(2+) signal without interfering in the uptake of cationic dyes. We conclude that inhibitors of the AA-5-LO pathway do not block P2X7 receptors, trigger the release of ATP, and induce an ATP-dependent uptake of organic cations by a Ca(2+)- and P2X7-independent transport mechanism in macrophages.
Copyright © 2014 Elsevier B.V. All rights reserved.
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12 MeSH Terms
The leukotriene B₄/BLT₁ axis is a key determinant in susceptibility and resistance to histoplasmosis.
Secatto A, Soares EM, Locachevic GA, Assis PA, Paula-Silva FW, Serezani CH, de Medeiros AI, Faccioli LH
(2014) PLoS One 9: e85083
MeSH Terms: Animals, Arachidonate 5-Lipoxygenase, Disease Susceptibility, Enzyme Inhibitors, Gene Expression, Histoplasma, Histoplasmosis, Host Specificity, Host-Pathogen Interactions, Leukotriene B4, Lung, Macrophages, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Phagocytosis, Receptors, Leukotriene B4, Rodent Diseases, Signal Transduction, Spleen
Show Abstract · Added May 4, 2017
The bioactive lipid mediator leukotriene B4 (LTB4) greatly enhances phagocyte antimicrobial functions against a myriad of pathogens. In murine histoplasmosis, inhibition of the LT-generating enzyme 5-lypoxigenase (5-LO) increases the susceptibility of the host to infection. In this study, we investigated whether murine resistance or susceptibility to Histoplasma capsulatum infection is associated with leukotriene production and an enhancement of in vivo and/or in vitro antimicrobial effector function. We show that susceptible C57BL/6 mice exhibit a higher fungal burden in the lung and spleen, increased mortality, lower expression levels of 5-LO and leukotriene B4 receptor 1 (BLT1) and decreased LTB4 production compared to the resistant 129/Sv mice. Moreover, we demonstrate that endogenous and exogenous LTs are required for the optimal phagocytosis of H. capsulatum by macrophages from both murine strains, although C57BL/6 macrophages are more sensitive to the effects of LTB4 than 129/Sv macrophages. Therefore, our results provide novel evidence that LTB4 production and BLT1 signaling are required for a histoplasmosis-resistant phenotype.
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20 MeSH Terms
Effect of zileuton and celecoxib on urinary LTE4 and PGE-M levels in smokers.
Mohebati A, Milne GL, Zhou XK, Duffield-Lillico AJ, Boyle JO, Knutson A, Bosworth BP, Kingsley PJ, Marnett LJ, Brown PH, Akpa EG, Szabo E, Dannenberg AJ
(2013) Cancer Prev Res (Phila) 6: 646-55
MeSH Terms: Adult, Arachidonate 5-Lipoxygenase, Biomarkers, Celecoxib, Chromatography, Liquid, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Female, Humans, Hydroxyurea, Leukotriene E4, Lipoxygenase Inhibitors, Male, Maximum Tolerated Dose, Prognosis, Prostaglandins, Pyrazoles, Smoking, Sulfonamides, Tandem Mass Spectrometry
Show Abstract · Added March 7, 2014
COX-2 and 5-lipoxygenase (5-LO) use arachidonic acid for the synthesis of eicosanoids that have been implicated in carcinogenesis and cardiovascular disease. The ability of celecoxib, a selective COX-2 inhibitor, to redirect arachidonic acid into the 5-LO pathway can potentially reduce its efficacy as a chemopreventive agent and increase the risk of cardiovascular complications. Levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E4 (LTE4), biomarkers of the COX and 5-LO pathways, are elevated in smokers. Here, we investigated the effects of zileuton, a 5-LO inhibitor, versus zileuton and celecoxib for 6 ± 1 days on urinary PGE-M and LTE4 levels in smokers. Treatment with zileuton led to an 18% decrease in PGE-M levels (P = 0.03); the combination of zileuton and celecoxib led to a 62% reduction in PGE-M levels (P < 0.001). Levels of LTE4 decreased by 61% in subjects treated with zileuton alone (P < 0.001) and were unaffected by the addition of celecoxib. Although zileuton use was associated with a small overall decrease in PGE-M levels, increased PGE-M levels were found in a subset (19 of 52) of subjects. Notably, the addition of celecoxib to the 5-LO inhibitor protected against the increase in urinary PGE-M levels (P = 0.03). In conclusion, zileuton was an effective inhibitor of 5-LO activity resulting in marked suppression of urinary LTE4 levels and possible redirection of arachidonic acid into the COX-2 pathway in a subset of subjects. Combining celecoxib and zileuton was associated with inhibition of both the COX-2 and 5-LO pathways manifested as reduced levels of urinary PGE-M and LTE4.
©2013 AACR.
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20 MeSH Terms
Leukotriene B4 enhances innate immune defense against the puerperal sepsis agent Streptococcus pyogenes.
Soares EM, Mason KL, Rogers LM, Serezani CH, Faccioli LH, Aronoff DM
(2013) J Immunol 190: 1614-22
MeSH Terms: Adolescent, Adult, Animals, Arachidonate 5-Lipoxygenase, Cells, Cultured, Female, Genetic Predisposition to Disease, Humans, Immunity, Innate, Leukotriene B4, Mice, Mice, Inbred C57BL, Mice, Knockout, Puerperal Infection, Sepsis, Streptococcal Infections, Up-Regulation, Young Adult
Show Abstract · Added May 4, 2017
Puerperal sepsis is a leading cause of maternal mortality worldwide. Streptococcus pyogenes [group A Streptococcus; (GAS)] is a major etiologic agent of severe postpartum sepsis, yet little is known regarding the pathogenesis of these infections. Tissue macrophages provide innate defense against GAS, and their actions are highly regulated. The intracellular second messenger cAMP can negatively regulate macrophage actions against GAS. Because leukotriene (LT) B(4) has been shown to suppress intracellular cAMP in macrophages, we hypothesized that it could enhance innate defenses against GAS. We assessed the capacity of LTB(4) to modulate antistreptococcal actions of human macrophages, including placental and decidual macrophages and used a novel intrauterine infection model of GAS in mice lacking the 5-lipoxygenase enzyme to determine the role of endogenous LTs in host defense against this pathogen. Animals lacking 5-lipoxygenase were significantly more vulnerable to intrauterine GAS infection than were wild-type mice and showed enhanced dissemination of bacteria out of the uterus and a more robust inflammatory response than did wild-type mice. In addition, LTB(4) reduced intracellular cAMP levels via the BLT1 receptor and was a potent stimulant of macrophage phagocytosis and NADPH oxidase-dependent intracellular killing of GAS. Importantly, interference was observed between the macrophage immunomodulatory actions of LTB(4) and the cAMP-inducing lipid PGE(2), suggesting that interplay between pro- and anti-inflammatory compounds may be important in vivo. This work underscores the potential for pharmacological targeting of lipid mediator signaling cascades in the treatment of invasive GAS infections.
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18 MeSH Terms
Conversion of human 5-lipoxygenase to a 15-lipoxygenase by a point mutation to mimic phosphorylation at Serine-663.
Gilbert NC, Rui Z, Neau DB, Waight MT, Bartlett SG, Boeglin WE, Brash AR, Newcomer ME
(2012) FASEB J 26: 3222-9
MeSH Terms: Arachidonate 15-Lipoxygenase, Arachidonate 5-Lipoxygenase, Arachidonic Acid, Humans, Lipoxins, Models, Molecular, Phosphorylation, Point Mutation, Serine
Show Abstract · Added January 21, 2015
The enzyme 5-lipoxygenase (5-LOX) initiates biosynthesis of the proinflammatory leukotriene lipid mediators and, together with 15-LOX, is also required for synthesis of the anti-inflammatory lipoxins. The catalytic activity of 5-LOX is regulated through multiple mechanisms, including Ca(2+)-targeted membrane binding and phosphorylation at specific serine residues. To investigate the consequences of phosphorylation at S663, we mutated the residue to the phosphorylation mimic Asp, providing a homogenous preparation suitable for catalytic and structural studies. The S663D enzyme exhibits robust 15-LOX activity, as determined by spectrophotometric and HPLC analyses, with only traces of 5-LOX activity remaining; synthesis of the anti-inflammatory lipoxin A(4) from arachidonic acid is also detected. The crystal structure of the S663D mutant in the absence and presence of arachidonic acid (in the context of the previously reported Stable-5-LOX) reveals substantial remodeling of helices that define the active site so that the once fully encapsulated catalytic machinery is solvent accessible. Our results suggest that phosphorylation of 5-LOX at S663 could not only down-regulate leukotriene synthesis but also stimulate lipoxin production in inflammatory cells that do not express 15-LOX, thus redirecting lipid mediator biosynthesis to the production of proresolving mediators of inflammation.
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9 MeSH Terms
5-Lipoxygenase deficiency impairs innate and adaptive immune responses during fungal infection.
Secatto A, Rodrigues LC, Serezani CH, Ramos SG, Dias-Baruffi M, Faccioli LH, Medeiros AI
(2012) PLoS One 7: e31701
MeSH Terms: Animals, Arachidonate 5-Lipoxygenase, Cell Proliferation, Cells, Cultured, Cytotoxicity, Immunologic, Flow Cytometry, Histoplasma, Histoplasmosis, Immunity, Humoral, Immunity, Innate, Leukotriene B4, Leukotriene C4, Lung, Lymphocyte Activation, Macrophages, Peritoneal, Mice, Mice, Knockout, Nitric Oxide, Phagocytosis, Survival Rate, T-Lymphocytes
Show Abstract · Added May 4, 2017
5-Lipoxygenase-derived products have been implicated in both the inhibition and promotion of chronic infection. Here, we sought to investigate the roles of endogenous 5-lipoxygenase products and exogenous leukotrienes during Histoplasma capsulatum infection in vivo and in vitro. 5-LO deficiency led to increased lung CFU, decreased nitric oxide production and a deficient primary immune response during active fungal infection. Moreover, H. capsulatum-infected 5-LO(-/-) mice showed an intense influx of neutrophils and an impaired ability to generate and recruit effector T cells to the lung. The fungal susceptibility of 5-LO(-/-) mice correlated with a lower rate of macrophage ingestion of IgG-H. capsulatum relative to WT macrophages. Conversely, exogenous LTB4 and LTC4 restored macrophage phagocytosis in 5-LO deficient mice. Our results demonstrate that leukotrienes are required to control chronic fungal infection by amplifying both the innate and adaptive immune response during histoplasmosis.
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21 MeSH Terms