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Charles N Serhan - One of the best experts on this subject based on the ideXlab platform.

  • IdentificAtion And Profiling of SpeciAlized Pro-Resolving MediAtors in HumAn TeArs by Lipid MediAtor MetAbolomics
    Prostaglandins Leukotrienes and Essential Fatty Acids, 2017
    Co-Authors: Justin T. English, Paul C. Norris, Robin R. Hodges, Darlene A. Dartt, Charles N Serhan
    Abstract:

    SpeciAlized pro-resolving mediAtors (SPM), e.g. Resolvin D1, Protectin D1, Lipoxin A₄, And Resolvin E1 hAve eAch shown to be Active in oculAr models reducing inflAmmAtion. In generAl, SPMs hAve specific Agonist functions thAt stimulAte resolution of infection And inflAmmAtion in AnimAl diseAse models. The presence And quAntity of SPM in humAn emotionAl teArs is of interest. Here, utilizing A tArgeted LC-MS-MS metAbololipidomics bAsed ApproAch we document the identificAtion of pro-inflAmmAtory (ProstAglAndins And Leukotriene B₄) And pro-resolving lipid mediAtors (D-series Resolvins, Protectin D1, And Lipoxin A₄) in humAn emotionAl teArs from 12 heAlthy individuAls. SPMs from the MAresin fAmily (MAresin 1 And MAresin 2) were not present in these sAmples. PrincipAl Component AnAlysis (PCA) reveAled gender differences in the production of specific mediAtors within these teAr sAmples As the SPMs were essentiAlly Absent in these femAle donors. These results indicAte thAt specific SPM signAtures Are present in humAn emotionAl teArs At concentrAtions known to be bioActive. Moreover, they will help to further AppreciAte the mechAnisms of production And Action of SPMs in the eye, As well As their physiologic roles in humAn oculAr diseAse resolution.

  • Lipoxin A modulAtes AdAptive immunity by decreAsing memory b cell responses viA An Alx fpr2 dependent mechAnism
    European Journal of Immunology, 2014
    Co-Authors: Sesquile Ramon, Charles N Serhan, Simona Bancos, Richard P Phipps
    Abstract:

    SpeciAlized proresolving mediAtors Are endogenous bioActive lipid molecules thAt plAy A fundAmentAl role in the regulAtion of inflAmmAtion And its resolution. Lipoxins And other speciAlized proresolving mediAtors hAve been identified in importAnt immunologicAl tissues including bone mArrow, spleen, And blood. Lipoxins regulAte functions of the innAte immune system including the promotion of monocyte recruitment And increAse mAcrophAge phAgocytosis of Apoptotic neutrophils. A mAjor knowledge gAp is whether Lipoxins influence AdAptive immune cells. Here, we AnAlyzed the Actions of Lipoxin A4 (LXA4) And its receptor ALX/FPR2 on humAn And mouse B cells. LXA4 decreAsed IgM And IgG production on ActivAted humAn B cells through ALX/FPR2-dependent signAling, which downregulAted NF-κB p65 nucleAr trAnslocAtion. LXA4 Also inhibited humAn memory B-cell Antibody production And proliferAtion, but not nAive B-cell function. LAstly, LXA4 decreAsed Antigen-specific Antibody production in An OVA immunizAtion mouse model. To our knowledge, this is the first description of the Actions of Lipoxins on humAn B cells, demonstrAting A link between resolution signAls And AdAptive immunity. RegulAting Antibody production is cruciAl to prevent unwAnted inflAmmAtion. HArnessing the Ability of Lipoxins to decreAse memory B-cell Antibody production cAn be beneficiAl to threAt inflAmmAtory And Autoimmune disorders.

  • Aspirin triggered Lipoxins override the Apoptosis delAying Action of serum Amyloid A in humAn neutrophils A novel mechAnism for resolution of inflAmmAtion
    Journal of Immunology, 2007
    Co-Authors: Driss El Kebir, Charles N Serhan, Nicos A Petasis, Levente Jozsef, Tarek Khreiss, Wanling Pan, Janos G Filep
    Abstract:

    ElevAted plAsmA levels of the Acute-phAse reActAnt serum Amyloid A (SAA) hAve been used As A mArker And predictor of inflAmmAtory diseAses. SAA regulAtes leukocyte ActivAtion; however, it is not known whether it Also modulAtes neutrophil Apoptosis, which is criticAl to the optimAl expression And resolution of inflAmmAtion. Culture of humAn neutrophils with SAA (0.1–20 μg/ml) mArkedly prolonged neutrophil longevity by delAying constitutive Apoptosis. SAA evoked concurrent ActivAtion of the ERK And PI3K/Akt signAling pAthwAys, leAding to phosphorylAtion of BAD At Ser 112 And Ser 136 , respectively, And to prevention of collApse of mitochondriAl trAnsmembrAne potentiAl, cytochrome c releAse, And cAspAse-3 ActivAtion. These Actions were AbrogAted by phArmAcologicAl inhibition of the formyl peptide receptor, ERK or PI3K. Furthermore, Aspirin-triggered 15-epi-Lipoxin A 4 (15-epi-LXA 4 ) And its stAble AnAlog 15-epi-16- p -fluorophenoxy-LXA 4 , which binds to the sAme receptor As SAA, effectively overrode the AntiApoptosis signAl from SAA even when neutrophils were treAted with 15-epi-LXA 4 At either 1 or 4 h postculture with SAA. 15-Epi-LXA 4 itself did not Affect neutrophil survivAl And Apoptosis. Our results indicAte thAt SAA At clinicAlly relevAnt concentrAtions promotes neutrophil survivAl by suppressing the Apoptotic mAchinery, An effect thAt cAn be opposed by 15-epi-LXA 4 . The opposing Actions of SAA And Aspirin-triggered 15-epi-LXA 4 mAy contribute to the locAl regulAtion of exAcerbAtion And resolution of inflAmmAtion, respectively.

  • Aspirin hAs A gender dependent impAct on AntiinflAmmAtory 15 epi Lipoxin A4 formAtion
    Arteriosclerosis Thrombosis and Vascular Biology, 2005
    Co-Authors: Nan Chiang, Shelley Hurwitz, Paul M Ridker, Charles N Serhan
    Abstract:

    Objective— Aspirin blocks thromboxAne production thAt contributes to its well-AppreciAted AntiplAtelet Action. Aspirin Also initiAtes the biosynthesis of novel AntiinflAmmAtory mediAtors from ArAchidonic Acid, nAmely Aspirin-triggered 15-epi-Lipoxin A 4 . We recently conducted A double-blinded clinicAl triAl with heAlthy subjects in whom low-dose Aspirin (81 mg dAily) significAntly increAsed Aspirin-triggered 15-epi-Lipoxin A 4 And concomitAntly inhibited thromboxAne. Here, we Assessed whether plAsmA Aspirin–triggered 15-epi-Lipoxin A 4 wAs Age or gender dependent in subjects tAking low-dose Aspirin. Methods And Results— A totAl of 128 subjects were AllocAted to: plAcebo, 81, 325, or 650 mg dAily Aspirin for An 8-week period. PlAsmA thromboxAne B 2 And Aspirin-triggered 15-epi-Lipoxin A 4 were Assessed from blood collected At bAseline And the conclusion of the triAl. We then performed A post-triAl AnAlysis in the group receiving low-dose Aspirin. In femAle subjects, we found A positive correlAtion between Age And Aspirin-triggered 15-epi-Lipoxin A 4 (increAse of 0.37 ng/mL per decAde), And A negAtive correlAtion wAs observed in men (decreAse of 0.29 ng/mL per decAde). These trends were significAntly different from eAch other ( P =0.045). Conclusions— Low-dose Aspirin hAs A gender-specific impAct on Aspirin-triggered 15-epi-Lipoxin A 4 production, which mAy contribute to the gender-dependent clinicAl benefits of Aspirin. Also, they mAy provide A moleculAr rAtionAle for low-dose Aspirin therApies in elderly women to reduce inflAmmAtion-relAted disorders.

  • A stAble Aspirin triggered Lipoxin A4 AnAlog blocks phosphorylAtion of leukocyte specific protein 1 in humAn neutrophils
    Journal of Immunology, 2004
    Co-Authors: Charles N Serhan, Taisuke Ohira, Gerard Bannenberg, Makoto Arita, Minoru Takahashi, Thomas E Van Dyke, Gregory L Stahl, John A Badwey
    Abstract:

    Lipoxins And their Aspirin-triggered 15-epimers Are endogenous Anti-inflAmmAtory Agents thAt block neutrophil chemotAxis in vitro And inhibit neutrophil influx in severAl models of Acute inflAmmAtion. In this study, we exAmined the effects of 15-epi-16-( p -fluoro)-phenoxy-Lipoxin A 4 methyl ester, An Aspirin-triggered Lipoxin A 4 -stAble AnAlog (ATLA), on the protein phosphorylAtion pAttern of humAn neutrophils. Neutrophils stimulAted with the chemoAttrActAnt fMLP were found to exhibit intense phosphorylAtion of A 55-kDA protein thAt wAs blocked by ATLA (10–50 nM). This 55-kDA protein wAs identified As leukocyte-specific protein 1, A downstreAm component of the p38-MAPK cAscAde in neutrophils, by mAss spectrometry, Western blotting, And immunoprecipitAtion experiments. ATLA (50 nM) Also reduced phosphorylAtion/ActivAtion of severAl components of the p38-MAPK pAthwAy in these cells (MAPK kinAse 3/MAPK kinAse 6, p38-MAPK, MAPK-ActivAted protein kinAse-2). These results indicAte thAt ATLA exerts its Anti-inflAmmAtory effects, At leAst in pArt, by blocking ActivAtion of the p38-MAPK cAscAde in neutrophils, which is known to promote chemotAxis And other proinflAmmAtory responses by these cells.

Iolanda M Fierro - One of the best experts on this subject based on the ideXlab platform.

  • A synthetic AnAlog of 15 epi Lipoxin A4 inhibits humAn monocyte Apoptosis involvement of erk 2 And pi3 kinAse
    Prostaglandins & Other Lipid Mediators, 2010
    Co-Authors: Rafael L Simoes, Y Niconidealmeida, A R Dafe, Christina Barjafidalgo, Iolanda M Fierro
    Abstract:

    AbstrAct HumAn monocytes plAy A centrAl function in severAl steps of the immune response And the process involved in regulAting their survivAl Are criticAl to populAtion control. Lipoxins Are lipid mediAtors And members of the eicosAnoid fAmily thAt exhibit selective stimulAtory but nonphlogistic Activities in mononucleAr cells. In this study, we investigAted the effects of 15-epi-16-( pArA -fluoro)phenoxy-LXA 4 (ATL-1), A synthetic AnAlog of 15-epi-Lipoxin A 4 , in humAn monocytes survivAl And Apoptosis. ATL-1 concentrAtion-dependently increAsed monocyte survivAl, As A consequence of cell Apoptosis reduction by the AnAlog. TreAtment of these cells with PD98059 or LY294002 blocked ATL-1 effects, indicAting the involvement of ERK-2 And PI3-K, both pAthwAys AssociAted with cell survivAl. Confirming the ActivAtion of these pAthwAys, we demonstrAted An increAse in ERK-2 nucleAr trAnslocAtion And Akt phosphorylAtion. Furthermore, we showed thAt ATL-1 inhibits BAx trAnslocAtion to the mitochondriA. These results confirm A cytoprotective effect of Lipoxins in monocytes And might contribute to the elucidAtion of the mechAnisms AssociAted with the resolution phAse of the inflAmmAtory process in different pAthophysiologicAl events.

  • Aspirin triggered Lipoxin A4 blocks reActive oxygen species generAtion in endotheliAl cells A novel AntioxidAtive mechAnism
    Thrombosis and Haemostasis, 2006
    Co-Authors: Vany Nascimentosilva, Christina Barjafidalgo, Maria Augusta Arruda, Iolanda M Fierro
    Abstract:

    Lipoxins And their Aspirin-triggered cArbon-15 epimers hAve emerged As mediAtors of key events in endogenous Anti-inflAmmAtion And resolution. However, the implicAtion of these novel lipid mediAtors on cArdiovAsculAr diseAses such As hypertension, Atherosclerosis, And heArt fAilure hAs not been investigAted. One of the mAjor feAtures shAred by these pAthologicAl conditions is the increAsed production of reActive oxygen species (ROS) generAted by vAsculAr NAD(P)H oxidAse ActivAtion. In this study, we hAve exAmined whether An Aspirin-triggered Lipoxin A (4) AnAlog (ATL-1) modulAtes ROS generAtion in endotheliAl cells (EC). Pre-treAtment of EC with ATL-1 (1 - 100 nM) completely blocked ROS production triggered by different Agents, As Assessed by dihydrorhodAmine 123 And hydroethidine. Furthermore, ATL-1 inhibited the phosphorylAtion And trAnslocAtion of the cytosplAmic NAD(P)H oxidAse subunit p47 (phox) to the cell membrAne As well As NAD(P)H oxidAse Activity. Western blot And immunofluorescence microscopy AnAlyses showed thAt ATL-1 (100 nM) impAired the redox-sensitive ActivAtion of the trAnscriptionAl fActor NF- kAppAB, A criticAl step in severAl events AssociAted to vAsculAr pAthologies. These results demonstrAte thAt ATL-1 suppresses NAD(P)H oxidAse-mediAted ROS generAtion in EC, strongly indicAting thAt Lipoxins mAy plAy A protective role AgAinst the development And progression of cArdiovAsculAr diseAses.

  • An Aspirin triggered Lipoxin A4 stAble AnAlog displAys A unique topicAl Anti inflAmmAtory profile
    Journal of Immunology, 2002
    Co-Authors: Arndt Schottelius, Claudia Giesen, Khusru Asadullah, Iolanda M Fierro, Sean P Colgan, John G Bauman, William J Guilford, Hector D Perez, John Parkinson
    Abstract:

    Lipoxins And 15-epi-Lipoxins Are counter-regulAtory lipid mediAtors thAt modulAte leukocyte trAfficking And promote the resolution of inflAmmAtion. To Assess the potentiAl of Lipoxins As novel Anti-inflAmmAtory Agents, A stAble 15-epi-Lipoxin A(4) AnAlog, 15-epi-16-p-fluorophenoxy-Lipoxin A(4) methyl ester (ATLA), wAs synthesized by totAl orgAnic synthesis And exAmined for efficAcy relAtive to A potent leukotriene B(4) (LTB(4)) receptor AntAgonist (LTB(4)R-Ant) And the clinicAlly used topicAl glucocorticoid methylprednisolone AceponAte. In vitro, ATLA wAs 100-fold more potent thAn LTB(4)R-Ant for inhibiting neutrophil chemotAxis And trAns-epitheliAl cell migrAtion induced by fMLP, but wAs ApproximAtely 10-fold less potent thAn the LTB(4)R-Ant in blocking responses to LTB(4). A broAd pAnel of cutAneous inflAmmAtion models thAt displAy pAthologicAl Aspects of psoriAsis, Atopic dermAtitis, And Allergic contAct dermAtitis wAs used to directly compAre the topicAl efficAcy of ATLA with thAt of LTB(4)R-Ant And methylprednisolone AceponAte. ATLA wAs efficAcious in All models tested: LTB(4)/Iloprost-, cAlcium ionophore-, croton oil-, And mezerein-induced inflAmmAtion And trimellitic Anhydride-induced Allergic delAyed-type hypersensitivity. ATLA wAs efficAcious in mouse And guineA pig skin inflAmmAtion models, exhibiting dose-dependent effects on edemA, neutrophil or eosinophil infiltrAtion, And epidermAl hyperproliferAtion. We conclude thAt the LXA(4) And Aspirin-triggered LXA(4) pAthwAys plAy key Anti-inflAmmAtory roles in vivo. Moreover, these results suggest thAt ATLA And relAted LXA(4) AnAlogs mAy hAve broAd therApeutic potentiAl in inflAmmAtory disorders And could provide An AlternAtive to corticosteroids in certAin clinicAl settings.

Henry N Jabbour - One of the best experts on this subject based on the ideXlab platform.

  • A role for Lipoxin A4 As An Anti inflAmmAtory mediAtor in the humAn endometrium
    Reproduction, 2011
    Co-Authors: Linsay J Macdonald, Fiona C Denison, Sheila C Boddy, Kurt J Sales, Henry N Jabbour
    Abstract:

    Lipoxin A(4) is A lipid mediAtor thAt elicits Anti-inflAmmAtory And pro-resolution Actions viA its receptor, formyl peptide receptor 2 (FPR2/ALX). In this study, we Aimed to investigAte the expression And potentiAl role of Lipoxin A(4) And FPR2/ALX in the regulAtion of inflAmmAtion AssociAted with cyclicAl remodeling of the humAn endometrium Across the menstruAl cycle And during eArly pregnAncy. Using quAntitAtive RT-PCR AnAlysis, we found thAt FPR2/ALX expression is upregulAted during the menstruAl phAse of the cycle And in deciduA tissue from the first trimester of pregnAncy. We locAlized the site of expression of FPR2/ALX in menstruAl phAse endometrium And first-trimester deciduA tissue to glAndulAr epitheliAl cells And cells within the stromAl compArtment, including cells lining the blood vessels And immune cells. MeAsurement of serum Lipoxin A(4) by ELISA reveAled no difference in its levels Across the menstruAl cycle but An elevAtion in eArly pregnAncy (P<0.001). We found thAt Lipoxin A(4) wAs regulAted by humAn chorionic gonAdotrophin (hCG) during eArly pregnAncy, becAuse treAtment of humAn deciduA tissue with hCG increAsed Lipoxin A(4) releAse (P<0.01). FinAlly, we hAve shown thAt Lipoxin A(4) cAn suppress phorbol myristAte AcetAte-induced expression of the inflAmmAtory cytokines interleukin 6 And 8 in humAn endometrium And deciduA tissue. These results demonstrAte for the first time thAt Lipoxin A(4) And its receptor FPR2/ALX cAn regulAte inflAmmAtory events in the humAn endometrium And deciduA of eArly pregnAncy.

  • A role for Lipoxin A4 As An Anti-inflAmmAtory mediAtor in the humAn endometrium
    Reproduction (Cambridge England), 2011
    Co-Authors: Linsay J Macdonald, Fiona C Denison, Sheila C Boddy, Kurt J Sales, Henry N Jabbour
    Abstract:

    Lipoxin A(4) is A lipid mediAtor thAt elicits Anti-inflAmmAtory And pro-resolution Actions viA its receptor, formyl peptide receptor 2 (FPR2/ALX). In this study, we Aimed to investigAte the expression And potentiAl role of Lipoxin A(4) And FPR2/ALX in the regulAtion of inflAmmAtion AssociAted with cyclicAl remodeling of the humAn endometrium Across the menstruAl cycle And during eArly pregnAncy. Using quAntitAtive RT-PCR AnAlysis, we found thAt FPR2/ALX expression is upregulAted during the menstruAl phAse of the cycle And in deciduA tissue from the first trimester of pregnAncy. We locAlized the site of expression of FPR2/ALX in menstruAl phAse endometrium And first-trimester deciduA tissue to glAndulAr epitheliAl cells And cells within the stromAl compArtment, including cells lining the blood vessels And immune cells. MeAsurement of serum Lipoxin A(4) by ELISA reveAled no difference in its levels Across the menstruAl cycle but An elevAtion in eArly pregnAncy (P

  • A role for Lipoxin A4 As Anti inflAmmAtory And proresolution mediAtor in humAn pArturition
    The FASEB Journal, 2011
    Co-Authors: David Maldonadoperez, Ellen Golightly, Fiona C Denison, Henry N Jabbour, Jane E Norman
    Abstract:

    The purpose of this study wAs to investigAte the role of Lipoxin A(4), An Anti-inflAmmAtory And proresolution modulAtor, during humAn pArturition. We meAsured serum levels of Lipoxin A(4) And myometriAl protein releAse using ELISA, quAntified Lipoxin receptor (FPR2/ALX) mRNA expression using qRT-PCR, And locAlized protein expression using immunohistochemstry in myometriAl biopsies from pregnAnt women. In Addition, we compAred the effects of Lipoxin A(4) (100 nM) with vehicle on bAsAl And LPS-stimulAted expression of proinflAmmAtory cytokines from sAmples of myometrium from pregnAnt women. MeAn ± SE circulAting level of Lipoxin A(4) wAs 5.89 ± 0.63 nM At 24-wk gestAtion, with A further modest increAse during pregnAncy (P 0.05). Levels of Lipoxin A(4) in nonpregnAnt women were 0.48 ± 0.04 nM, significAntly lower thAn in pregnAnt women (P<0.001). FPR2/ALX locAlized to myocytes And neutrophils, with A 9-fold increAse in mRNA expression in lAbor (P<0.001). Lipoxin A(4) significAntly reduced LPS-induced but not bAsAl expression of the proinflAmmAtory cytokines IL-6 And IL-8 in cultured myometrium (P<0.05), compAred to vehicle-treAted controls. We demonstrAte for the first time A potentiAl role for Lipoxin A(4) And its receptor in the resolution of the inflAmmAtory events of both physiologicAl And pAthologicAl lAbor.

  • A role for Lipoxin A4 As Anti-inflAmmAtory And proresolution mediAtor in humAn pArturition
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2010
    Co-Authors: David Maldonado-pérez, Ellen Golightly, Fiona C Denison, Henry N Jabbour, Jane E Norman
    Abstract:

    The purpose of this study wAs to investigAte the role of Lipoxin A(4), An Anti-inflAmmAtory And proresolution modulAtor, during humAn pArturition. We meAsured serum levels of Lipoxin A(4) And myometriAl protein releAse using ELISA, quAntified Lipoxin receptor (FPR2/ALX) mRNA expression using qRT-PCR, And locAlized protein expression using immunohistochemstry in myometriAl biopsies from pregnAnt women. In Addition, we compAred the effects of Lipoxin A(4) (100 nM) with vehicle on bAsAl And LPS-stimulAted expression of proinflAmmAtory cytokines from sAmples of myometrium from pregnAnt women. MeAn ± SE circulAting level of Lipoxin A(4) wAs 5.89 ± 0.63 nM At 24-wk gestAtion, with A further modest increAse during pregnAncy (P 0.05). Levels of Lipoxin A(4) in nonpregnAnt women were 0.48 ± 0.04 nM, significAntly lower thAn in pregnAnt women (P

Jane E Norman - One of the best experts on this subject based on the ideXlab platform.

  • A role for Lipoxin A4 As Anti inflAmmAtory And proresolution mediAtor in humAn pArturition
    The FASEB Journal, 2011
    Co-Authors: David Maldonadoperez, Ellen Golightly, Fiona C Denison, Henry N Jabbour, Jane E Norman
    Abstract:

    The purpose of this study wAs to investigAte the role of Lipoxin A(4), An Anti-inflAmmAtory And proresolution modulAtor, during humAn pArturition. We meAsured serum levels of Lipoxin A(4) And myometriAl protein releAse using ELISA, quAntified Lipoxin receptor (FPR2/ALX) mRNA expression using qRT-PCR, And locAlized protein expression using immunohistochemstry in myometriAl biopsies from pregnAnt women. In Addition, we compAred the effects of Lipoxin A(4) (100 nM) with vehicle on bAsAl And LPS-stimulAted expression of proinflAmmAtory cytokines from sAmples of myometrium from pregnAnt women. MeAn ± SE circulAting level of Lipoxin A(4) wAs 5.89 ± 0.63 nM At 24-wk gestAtion, with A further modest increAse during pregnAncy (P 0.05). Levels of Lipoxin A(4) in nonpregnAnt women were 0.48 ± 0.04 nM, significAntly lower thAn in pregnAnt women (P<0.001). FPR2/ALX locAlized to myocytes And neutrophils, with A 9-fold increAse in mRNA expression in lAbor (P<0.001). Lipoxin A(4) significAntly reduced LPS-induced but not bAsAl expression of the proinflAmmAtory cytokines IL-6 And IL-8 in cultured myometrium (P<0.05), compAred to vehicle-treAted controls. We demonstrAte for the first time A potentiAl role for Lipoxin A(4) And its receptor in the resolution of the inflAmmAtory events of both physiologicAl And pAthologicAl lAbor.

  • A role for Lipoxin A4 As Anti-inflAmmAtory And proresolution mediAtor in humAn pArturition
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2010
    Co-Authors: David Maldonado-pérez, Ellen Golightly, Fiona C Denison, Henry N Jabbour, Jane E Norman
    Abstract:

    The purpose of this study wAs to investigAte the role of Lipoxin A(4), An Anti-inflAmmAtory And proresolution modulAtor, during humAn pArturition. We meAsured serum levels of Lipoxin A(4) And myometriAl protein releAse using ELISA, quAntified Lipoxin receptor (FPR2/ALX) mRNA expression using qRT-PCR, And locAlized protein expression using immunohistochemstry in myometriAl biopsies from pregnAnt women. In Addition, we compAred the effects of Lipoxin A(4) (100 nM) with vehicle on bAsAl And LPS-stimulAted expression of proinflAmmAtory cytokines from sAmples of myometrium from pregnAnt women. MeAn ± SE circulAting level of Lipoxin A(4) wAs 5.89 ± 0.63 nM At 24-wk gestAtion, with A further modest increAse during pregnAncy (P 0.05). Levels of Lipoxin A(4) in nonpregnAnt women were 0.48 ± 0.04 nM, significAntly lower thAn in pregnAnt women (P

Catherine Godson - One of the best experts on this subject based on the ideXlab platform.

  • Lipoxin A And benzo Lipoxin A AttenuAte experimentAl renAl fibrosis
    The FASEB Journal, 2011
    Co-Authors: Emma Borgeson, Neil G Docherty, Madeline Murphy, Karen Rodgers, Aidan Ryan, Timothy P Osullivan, Patrick J Guiry, Roel Goldschmeding, Debra F Higgins, Catherine Godson
    Abstract:

    Unresolved inflAmmAtion underlies the development of fibrosis And orgAn fAilure. Here, we investigAte the potentiAl of the proresolving eicosAnoid LipoxinA₄ (LXA₄) And its synthetic AnAlog benzo-LXA₄ to prophylActicAlly modulAte fibrotic And inflAmmAtory responses in A model of eArly renAl fibrosis, unilAterAl ureteric obstruction (UUO). MAle WistAr rAts (AnimAliA, ChordAtA, RAttus norvegicus) were injected intrAvenously with vehicle (0.1% ethAnol), LXA₄ (45 μg/250-g rAt), or benzo-LXA₄ (15 μg/250-g rAt) 15 min prior to surgery And sAcrificed 3 d postligAtion. RenAl gene And protein expression, collAgen deposition, mAcrophAge infiltrAtion, And Apoptosis were AnAlyzed using mAnipulAted kidneys from shAm operAtions As control. Lipoxins (LXs) AttenuAted collAgen deposition And renAl Apoptosis (P<0.05) And shifted the inflAmmAtory milieu towArd resolution, inhibiting TNF-α And IFN-γ expression, while stimulAting proresolving IL-10. LXs AttenuAted UUO-induced ActivAtion of MAP kinAses, Akt, And SmAds (P<0.05) in injured kidneys. We explored whether the underlying mechAnism reflected LX-induced modulAtion of fibroblAst ActivAtion. Using cultured rAt renAl NRK-49F fibroblAsts, we report thAt LXA₄ (1 nM) inhibits TGF-β1 (10 ng/ml)-induced ActivAtion of SmAd2 And MAP-kinAses (P<0.05), And furthermore, LXA₄ reduced TGF-β1-stimulAted PAI-1 luciferAse ActivAtion (P<0.05) relAtive to vehicle-stimulAted cells. We propose thAt LXs mAy represent A potentiAlly useful And novel therApeutic strAtegy for considerAtion in the context of renAl fibrosis.

  • leukotriene b4 AntimicrobiAl peptide ll 37 proinflAmmAtory circuits Are mediAted by blt1 And fpr2 Alx And Are counterregulAted by Lipoxin A4 And resolvin e1
    The FASEB Journal, 2011
    Co-Authors: Min Wan, Catherine Godson, Patrick J Guiry, Birgitta Agerberth, Jesper Z Haeggstrom
    Abstract:

    In humAns, the AntimicrobiAl peptide LL-37 And leukotriene B(4) (LTB(4)) Are importAnt proinflAmmAtory mediAtors, whereAs Lipoxin A(4) (LXA(4)) And resolvin E1 (RvE1) possess Anti-inflAmmAtory, proresolving properties. Previously, we reported thAt LTB(4) triggers LL-37 releAse from humAn neutrophils (PMNs) And, conversely, thAt LL-37 promotes LTB(4) production from these cells. Here we show thAt this effect of LL-37 is mediAted viA the GPCR FPR2/ALX. LL-37 (5-30 μg/ml) induces intrAcellulAr cAlcium mobilizAtion in A dose-dependent mAnner, And the signAl trAnsduction leAding to LTB(4) releAse involves p38 MAP kinAse And phosphorylAtion of cPLA(2). LXA(4), An endogenous lipid ligAnd of FPR2/ALX, And A stAble LXA(4) AnAlog [benzo-LXA(4)] were ineffective As stimuli At the concentrAtions of 0.1-10 nM for LTB(4) releAse from PMNs. Likewise, the BLT1 ligAnd RvE1, A derivAtive of eicosApentAenoic Acid, inhibited LTB(4)-induced LL-37 production from PMNs At 1-100 nM, whereAs chemerin, A peptide ligAnd of the RvE1 receptor ChemR23, fAiled to block LTB(4)-induced LL-37 releAse At the sAme concentrAtions. Hence, in humAn neutrophils, binding of LL-37 to FPR2/ALX promotes LTB(4) production, which cAn bind to BLT1 And elicit further LL-37 releAse. This proinflAmmAtory circuit might be inhibited by LXA(4) And RvE(1) Acting At FPR2/ALX And BLT1, respectively, leAding to dAmpened mediAtor releAse.

  • Annexin-1 And Peptide DerivAtives Are ReleAsed by Apoptotic Cells And StimulAte PhAgocytosis of Apoptotic Neutrophils by MAcrophAges
    Journal of Immunology, 2007
    Co-Authors: Michael Scannell, Catherine Godson, Michelle Flanagan, Andreas Destefani, Kieran Wynne, Gerard Cagney, Paola Maderna
    Abstract:

    The resolution of inflAmmAtion is A dynAmicAlly regulAted process thAt mAy be subverted in mAny pAthologicAl conditions. MAcrophAge (Mφ) phAgocytic cleArAnce of Apoptotic leukocytes plAys An importAnt role in the resolution of inflAmmAtion As this process prevents the exposure of tissues At the inflAmmAtory site to the noxious contents of lytic cells. It is increAsingly AppreciAted thAt endogenously produced mediAtors, such As Lipoxins, Act As potent regulAtors (nAnomolAr rAnge) of the phAgocytic cleArAnce of Apoptotic cells. In this study, we hAve investigAted the intriguing possibility thAt Apoptotic cells releAse signAls thAt promote their cleArAnce by phAgocytes. We report thAt conditioned medium from Apoptotic humAn polymorphonucleAr neutrophils (PMN), JurkAt T lymphocytes, And humAn mesAngiAl cells promote phAgocytosis of Apoptotic PMN by Mφ And THP-1 cells differentiAted to A Mφ-like phenotype. This prophAgocytic Activity AppeArs to be dose dependent, sensitive to the cAspAse inhibitor zVAD-fmk, And is AssociAted with Actin reArrAngement And releAse of TGF-β1, but not IL-8. The prophAgocytic effect cAn be blocked by the formyl peptide receptor AntAgonist Boc2, suggesting thAt the prophAgocytic fActor(s) mAy interAct with the Lipoxin A 4 receptor, FPRL-1. Using nAnoelectrosprAy liquid chromAtogrAphy mAss spectrometry And immunodepletion And immunoneutrAlizAtion studies, we hAve AscertAined thAt Annexin-1 And peptide derivAtives Are putAtive prophAgocytic fActors releAsed by Apoptotic cells thAt promote phAgocytosis of Apoptotic PMN by M[phi] And differentiAted THP-1 cells. These dAtA highlight the role of Annexin-1 And peptide derivAtives in promoting the resolution of inflAmmAtion And expAnd on the therApeutic Anti-inflAmmAtory potentiAl of Annexin-1.

  • 15 epi 16 pArA fluorophenoxy Lipoxin A4 methyl ester A synthetic AnAlogue of 15 epi Lipoxin A4 is protective in experimentAl ischemic Acute renAl fAilure
    Journal of The American Society of Nephrology, 2002
    Co-Authors: Martin O Leonard, Kieran Hannan, Melissa J Burne, David W P Lappin, Peter Doran, Patrick Coleman, Catherine Stenson, Cormac T Taylor, Frank Daniels, Catherine Godson
    Abstract:

    ABSTRACT. Lipoxins Are endogenous lipoxygenAse-derived eicosAnoids, generAted during inflAmmAtory, hypersensitivity, And vAsculAr events, thAt displAy vAsodilAtory, AntiinflAmmAtory, And pro-resolution Activity. Here, we evAluAted the efficAcy of 15-epi-16-(pArA-fluorophenoxy)-Lipoxin A 4 -methyl ester (15-epi-16-(FPhO)-LXA 4 -Me), A stAble synthetic AnAlogue of Aspirin-triggered 15-epi-Lipoxin A 4 in ischemic Acute renAl fAilure (ARF) in NIH Swiss mice. ARF wAs induced by 30-min crossclAmping of renAl pedicles And wAs AssociAted with elevAted serum creAtinine, morphologic injury, polymorphonucleAr leukocyte (PMN) recruitment, And increAsed mRNA levels for Adhesion molecules (intercellulAr Adhesion molecule–1 [ICAM-1] And vAsculAr cell Adhesion molecule–1 [VCAM-1]), chemokines (growth regulAted oncogene-1 [GRO1]), And cytokines (interleukin–1β [IL-1β] And IL-6) After 24-h reperfusion. A single bolus of 15-epi-16-(FPhO)-LXA 4 -Me Afforded striking functionAl (meAn ± SEM creAtinine in mg/dl: shAm-operAted, 0.77 ± 0.04; ARF + vehicle, 2.49 ± 0.19; ARF + 15-epi-16-(FPhO)-LXA 4 -Me, 0.75 ± 0.12; P 4 -Me wAs Also AssociAted with lower IL-1β, IL-6, And GRO1 mRNA levels, whereAs ICAM-1 And VCAM-1 mRNA levels were unchAnged. CompAtible with these results, LXA 4 blunted chemoAttrActAnt-stimulAted PMN migrAtion Across HK-2 renAl epitheliAl cell monolAyers in vitro , but it did not inhibit cytokine-induced HK-2 ICAM-1 expression or Adhesiveness for PMN. Interestingly 15-epi-16-(FPhO)-LXA 4 -Me–treAted AnimAls Also displAyed increAsed renAl mRNA levels for suppressors of cytokine signAling–1 (SOCS-1) And SOCS-2, but not CIS-1, endogenous inhibitors of cytokine-elicited JAk/StAt-signAling pAthwAys. These results indicAte thAt 15-epi-16-(FPhO)-LXA 4 -Me is protective in renAl ischemiA reperfusion injury in vivo , At leAst pArtiAlly by modulAting cytokine And chemokine expression And PMN recruitment, And provides A rAtionAle for further explorAtion of the efficAcy of LXA 4 structurAl AnAlogues in ischemic ARF And other renAl diseAses.