The Experts below are selected from a list of 288 Experts worldwide ranked by ideXlab platform
Charles N Serhan - One of the best experts on this subject based on the ideXlab platform.
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a mosquito Lipoxin lipocalin complex mediates innate immune priming in anopheles gambiae
Nature Communications, 2015Co-Authors: Jose Luis Ramirez, Charles N Serhan, Giselle De Almeida Oliveira, Eric Calvo, Jesmond Dalli, Romain A Colas, Jose M C Ribeiro, Carolina BarillasmuryAbstract:Exposure of Anopheles gambiae mosquitoes to Plasmodium infection enhances the ability of their immune system to respond to subsequent infections. However, the molecular mechanism that allows the insect innate immune system to ‘remember' a previous encounter with a pathogen has not been established. Challenged mosquitoes constitutively release a soluble haemocyte differentiation factor into their haemolymph that, when transferred into Naive mosquitoes, also induces priming. Here we show that this factor consists of a Lipoxin/Lipocalin complex. We demonstrate that innate immune priming in mosquitoes involves a persistent increase in expression of Evokin (a lipid carrier of the lipocalin family), and in their ability to convert arachidonic acid to Lipoxins, predominantly Lipoxin A4. Plasmodium ookinete midgut invasion triggers immune priming by inducing the release of a mosquito Lipoxin/lipocalin complex.
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Lipoxin a modulates adaptive immunity by decreasing memory b cell responses via an alx fpr2 dependent mechanism
European Journal of Immunology, 2014Co-Authors: Sesquile Ramon, Charles N Serhan, Simona Bancos, Richard P PhippsAbstract: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.
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Lipoxin a4 decreases human memory b cell antibody production via an alx fpr2 dependent mechanism a link between resolution signals and adaptive immunity
European Journal of Immunology, 2014Co-Authors: Sesquile Ramon, Charles N Serhan, Simona Bancos, Richard P PhippsAbstract:Summary Specialized proresolving mediators (SPMs) are endogenous bioactive lipid molecules that play a fundamental role in the regulation of inflammation and its resolution. SPMs are classified into Lipoxins, resolvins, protectins and maresins. Lipoxins and other SPMs 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 B cells. LXA4 decreased IgM and IgG production on activated 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 vivo. To our knowledge, this is the first description of the actions of Lipoxins on human B cells, which shows 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.
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aspirin triggered Lipoxin and resolvin e1 modulate vascular smooth muscle phenotype and correlate with peripheral atherosclerosis
American Journal of Pathology, 2010Co-Authors: Matthew Spite, Charles N Serhan, Mark A Creager, Christopher D Owens, Hope Lancero, Alex H K Kroemer, Reena L Pande, Michael S ConteAbstract:Atherosclerosis is a chronic inflammatory disease of the vessel wall. Recent evidence suggests that chronic vascular inflammation ensues as an imbalance between pro- and anti-inflammatory mediators. Recently identified lipid mediators (eg, Lipoxins and resolvins) play active roles in promoting the resolution of inflammation. Alterations in vascular smooth muscle cell (VSMC) phenotype, which manifest as a loss of contractile protein expression and increased proliferation and migration, are prominent mechanistic features of both atherosclerosis and restenosis following various interventions (eg, angioplasty and bypass grafting). We sought to determine whether human atherosclerosis is associated with a “resolution deficit” and whether Lipoxins and resolvins influence VSMC phenotype. Here we report that plasma levels of aspirin-triggered Lipoxin are significantly lower in patients with symptomatic peripheral artery disease than in healthy volunteers. Both aspirin-triggered Lipoxin and resolvin E1 block platelet-derived growth factor-stimulated migration of human saphenous vein SMCs and decrease phosphorylation of the platelet-derived growth factor receptor-β. Importantly, receptors for aspirin-triggered Lipoxin and resolvin E1 (ALX and ChemR23, respectively) were identified in human VSMCs. Overall, these results demonstrate that stimulatory lipid mediators confer a protective phenotypic switch in VSMCs and elucidate new functions for these mediators in the regulation of SMC biology. These results also suggest that peripheral artery disease is associated with an inflammation-resolution deficit and highlight a potential therapeutic opportunity for the regulation of vascular injury responses.
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Lipoxins and aspirin triggered Lipoxin inhibit inflammatory pain processing
Journal of Experimental Medicine, 2007Co-Authors: Camilla I Svensson, Charles N Serhan, Michela ZattoniAbstract:Inflammatory conditions can lead to debilitating and persistent pain. This hyperalgesia reflects sensitization of peripheral terminals and facilitation of pain signaling at the spinal level. Studies of peripheral systems show that tissue injury triggers not only inflammation but also a well-orchestrated series of events that leads to reversal of the inflammatory state. In this regard, Lipoxins represent a unique class of lipid mediators that promote resolution of inflammation. The antiinflammatory role of peripheral Lipoxins raises the hypothesis that similar neuraxial systems may also down-regulate injury-induced spinal facilitation of pain processing. We report that the Lipoxin A4 receptor is expressed on spinal astrocytes both in vivo and in vitro and that spinal delivery of Lipoxin A4, as well as stable analogues, attenuates inflammation-induced pain. Furthermore, activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase in astrocytes, which has been indicated to play an important role in spinal pain processing, was attenuated in the presence of Lipoxins. This linkage opens the possibility that Lipoxins regulate spinal nociceptive processing though their actions upon astrocytic activation. Targeting mechanisms that counterregulate the spinal consequences of persistent peripheral inflammation provide a novel endogenous mechanism by which chronic pain may be controlled.
Niamh E. Kieran - One of the best experts on this subject based on the ideXlab platform.
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Lipoxins: Potential anti-inflammatory, proresolution, and antifibrotic mediators in renal disease
Kidney international, 2004Co-Authors: Niamh E. Kieran, Paola Maderna, Catherine GodsonAbstract:Lipoxins: Potential anti-inflammatory, proresolution, and antifibrotic mediators in renal disease. Lipoxins are lipoxygenase-derived lipid mediators with both anti-inflammatory and proresolution properties that have been demonstrated in vivo and in vitro. The bioactivity profile of Lipoxins in vitro suggests that they have therapeutic potential in acute renal failure and glomerulonephritis; predictions that have been borne out to date in experimental models of renal disease. We review recent developments on the molecular basis of Lipoxin bioactions mediated through receptor crosstalk and the accumulating evidence that Lipoxins may have potential as novel anti-inflammatory agents.
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modification of the transcriptomic response to renal ischemia reperfusion injury by Lipoxin analog
Kidney International, 2003Co-Authors: Niamh E. Kieran, Peter Doran, Susan B. Connolly, Marie Claire GreenanAbstract:Modification of the transcriptomic response to renal ischemia/reperfusion injury by Lipoxin analog. Background Lipoxins are lipoxygenase-derived eicosanoids with anti-inflammatory and proresolution bioactivities in vitro and in vivo. We have previously demonstrated that the stable synthetic LXA 4 analog 15-epi-16-(FPhO)-LXA4-Me is renoprotective in murine renal ischemia/reperfusion injury, as gauged by lower serum creatinine, attenuated leukocyte infiltration, and reduced morphologic tubule injury. Methods We employed complementary oligonucleotide microarray and bioinformatic analyses to probe the transcriptomic events that underpin Lipoxin renoprotection in this setting. Results Microarray-based analysis identified three broad categories of genes whose mRNA levels are altered in response to ischemia/reperfusion injury, including known genes previously implicated in the pathogenesis of ischemia/reperfusion injury [e.g., intercellular adhesion molecule-1 (ICAM-1), p21, KIM-1], known genes not previously associated with ischemia/reperfusion injury, and cDNAs representing yet uncharacterized genes. Characterization of expressed sequence tags (ESTs) displayed on microarrays represents a major challenge in studies of global gene expression. A bioinformatic annotation pipeline successfully annotated a large proportion of ESTs modulated during ischemia/reperfusion injury. The differential expression of a representative group of these ischemia/reperfusion injury–modulated genes was confirmed by real-time polymerase chain reaction. Prominent among the up-regulated genes were claudin-1, -3, and -7, and ADAM8. Interestingly, the former response was claudin-specific and was not observed with other claudins expressed by the kidney (e.g., claudin-8 and -6) or indeed with other components of the renal tight junctions (e.g., occludin and junctional adhesion molecule). Noteworthy among the down-regulated genes was a cluster of transport proteins (e.g., aquaporin-1) and the zinc metalloendopeptidase meprin-1β implicated in renal remodeling. Conclusion Treatment with the Lipoxin analog 15-epi-16-(FPhO)-LXA4-Me prior to injury modified the expression of many differentially expressed pathogenic mediators, including cytokines, growth factors, adhesion molecules, and proteases, suggesting a renoprotective action at the core of the pathophysiology of acute renal failure (ARF). Importantly, this Lipoxin-modulated transcriptomic response included many genes expressed by renal parenchymal cells and was not merely a reflection of a reduced renal mRNA load resulting from attenuated leukocyte recruitment. The data presented herein suggest a framework for understanding drivers of kidney injury in ischemia/reperfusion and the molecular basis for renoprotection by Lipoxins in this setting.
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Modification of the transcriptomic response to renal ischemia/reperfusion injury by Lipoxin analog
Kidney international, 2003Co-Authors: Niamh E. Kieran, Peter Doran, Susan B. Connolly, Marie Claire Greenan, Debra F. Higgins, Martin O. Leonard, Catherine Godson, Cormac T. Taylor, Anna Henger, Matthias KretzlerAbstract:Modification of the transcriptomic response to renal ischemia/reperfusion injury by Lipoxin analog. Background Lipoxins are lipoxygenase-derived eicosanoids with anti-inflammatory and proresolution bioactivities in vitro and in vivo. We have previously demonstrated that the stable synthetic LXA 4 analog 15-epi-16-(FPhO)-LXA4-Me is renoprotective in murine renal ischemia/reperfusion injury, as gauged by lower serum creatinine, attenuated leukocyte infiltration, and reduced morphologic tubule injury. Methods We employed complementary oligonucleotide microarray and bioinformatic analyses to probe the transcriptomic events that underpin Lipoxin renoprotection in this setting. Results Microarray-based analysis identified three broad categories of genes whose mRNA levels are altered in response to ischemia/reperfusion injury, including known genes previously implicated in the pathogenesis of ischemia/reperfusion injury [e.g., intercellular adhesion molecule-1 (ICAM-1), p21, KIM-1], known genes not previously associated with ischemia/reperfusion injury, and cDNAs representing yet uncharacterized genes. Characterization of expressed sequence tags (ESTs) displayed on microarrays represents a major challenge in studies of global gene expression. A bioinformatic annotation pipeline successfully annotated a large proportion of ESTs modulated during ischemia/reperfusion injury. The differential expression of a representative group of these ischemia/reperfusion injury–modulated genes was confirmed by real-time polymerase chain reaction. Prominent among the up-regulated genes were claudin-1, -3, and -7, and ADAM8. Interestingly, the former response was claudin-specific and was not observed with other claudins expressed by the kidney (e.g., claudin-8 and -6) or indeed with other components of the renal tight junctions (e.g., occludin and junctional adhesion molecule). Noteworthy among the down-regulated genes was a cluster of transport proteins (e.g., aquaporin-1) and the zinc metalloendopeptidase meprin-1β implicated in renal remodeling. Conclusion Treatment with the Lipoxin analog 15-epi-16-(FPhO)-LXA4-Me prior to injury modified the expression of many differentially expressed pathogenic mediators, including cytokines, growth factors, adhesion molecules, and proteases, suggesting a renoprotective action at the core of the pathophysiology of acute renal failure (ARF). Importantly, this Lipoxin-modulated transcriptomic response included many genes expressed by renal parenchymal cells and was not merely a reflection of a reduced renal mRNA load resulting from attenuated leukocyte recruitment. The data presented herein suggest a framework for understanding drivers of kidney injury in ischemia/reperfusion and the molecular basis for renoprotection by Lipoxins in this setting.
Susan B. Connolly - One of the best experts on this subject based on the ideXlab platform.
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modification of the transcriptomic response to renal ischemia reperfusion injury by Lipoxin analog
Kidney International, 2003Co-Authors: Niamh E. Kieran, Peter Doran, Susan B. Connolly, Marie Claire GreenanAbstract:Modification of the transcriptomic response to renal ischemia/reperfusion injury by Lipoxin analog. Background Lipoxins are lipoxygenase-derived eicosanoids with anti-inflammatory and proresolution bioactivities in vitro and in vivo. We have previously demonstrated that the stable synthetic LXA 4 analog 15-epi-16-(FPhO)-LXA4-Me is renoprotective in murine renal ischemia/reperfusion injury, as gauged by lower serum creatinine, attenuated leukocyte infiltration, and reduced morphologic tubule injury. Methods We employed complementary oligonucleotide microarray and bioinformatic analyses to probe the transcriptomic events that underpin Lipoxin renoprotection in this setting. Results Microarray-based analysis identified three broad categories of genes whose mRNA levels are altered in response to ischemia/reperfusion injury, including known genes previously implicated in the pathogenesis of ischemia/reperfusion injury [e.g., intercellular adhesion molecule-1 (ICAM-1), p21, KIM-1], known genes not previously associated with ischemia/reperfusion injury, and cDNAs representing yet uncharacterized genes. Characterization of expressed sequence tags (ESTs) displayed on microarrays represents a major challenge in studies of global gene expression. A bioinformatic annotation pipeline successfully annotated a large proportion of ESTs modulated during ischemia/reperfusion injury. The differential expression of a representative group of these ischemia/reperfusion injury–modulated genes was confirmed by real-time polymerase chain reaction. Prominent among the up-regulated genes were claudin-1, -3, and -7, and ADAM8. Interestingly, the former response was claudin-specific and was not observed with other claudins expressed by the kidney (e.g., claudin-8 and -6) or indeed with other components of the renal tight junctions (e.g., occludin and junctional adhesion molecule). Noteworthy among the down-regulated genes was a cluster of transport proteins (e.g., aquaporin-1) and the zinc metalloendopeptidase meprin-1β implicated in renal remodeling. Conclusion Treatment with the Lipoxin analog 15-epi-16-(FPhO)-LXA4-Me prior to injury modified the expression of many differentially expressed pathogenic mediators, including cytokines, growth factors, adhesion molecules, and proteases, suggesting a renoprotective action at the core of the pathophysiology of acute renal failure (ARF). Importantly, this Lipoxin-modulated transcriptomic response included many genes expressed by renal parenchymal cells and was not merely a reflection of a reduced renal mRNA load resulting from attenuated leukocyte recruitment. The data presented herein suggest a framework for understanding drivers of kidney injury in ischemia/reperfusion and the molecular basis for renoprotection by Lipoxins in this setting.
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Modification of the transcriptomic response to renal ischemia/reperfusion injury by Lipoxin analog
Kidney international, 2003Co-Authors: Niamh E. Kieran, Peter Doran, Susan B. Connolly, Marie Claire Greenan, Debra F. Higgins, Martin O. Leonard, Catherine Godson, Cormac T. Taylor, Anna Henger, Matthias KretzlerAbstract:Modification of the transcriptomic response to renal ischemia/reperfusion injury by Lipoxin analog. Background Lipoxins are lipoxygenase-derived eicosanoids with anti-inflammatory and proresolution bioactivities in vitro and in vivo. We have previously demonstrated that the stable synthetic LXA 4 analog 15-epi-16-(FPhO)-LXA4-Me is renoprotective in murine renal ischemia/reperfusion injury, as gauged by lower serum creatinine, attenuated leukocyte infiltration, and reduced morphologic tubule injury. Methods We employed complementary oligonucleotide microarray and bioinformatic analyses to probe the transcriptomic events that underpin Lipoxin renoprotection in this setting. Results Microarray-based analysis identified three broad categories of genes whose mRNA levels are altered in response to ischemia/reperfusion injury, including known genes previously implicated in the pathogenesis of ischemia/reperfusion injury [e.g., intercellular adhesion molecule-1 (ICAM-1), p21, KIM-1], known genes not previously associated with ischemia/reperfusion injury, and cDNAs representing yet uncharacterized genes. Characterization of expressed sequence tags (ESTs) displayed on microarrays represents a major challenge in studies of global gene expression. A bioinformatic annotation pipeline successfully annotated a large proportion of ESTs modulated during ischemia/reperfusion injury. The differential expression of a representative group of these ischemia/reperfusion injury–modulated genes was confirmed by real-time polymerase chain reaction. Prominent among the up-regulated genes were claudin-1, -3, and -7, and ADAM8. Interestingly, the former response was claudin-specific and was not observed with other claudins expressed by the kidney (e.g., claudin-8 and -6) or indeed with other components of the renal tight junctions (e.g., occludin and junctional adhesion molecule). Noteworthy among the down-regulated genes was a cluster of transport proteins (e.g., aquaporin-1) and the zinc metalloendopeptidase meprin-1β implicated in renal remodeling. Conclusion Treatment with the Lipoxin analog 15-epi-16-(FPhO)-LXA4-Me prior to injury modified the expression of many differentially expressed pathogenic mediators, including cytokines, growth factors, adhesion molecules, and proteases, suggesting a renoprotective action at the core of the pathophysiology of acute renal failure (ARF). Importantly, this Lipoxin-modulated transcriptomic response included many genes expressed by renal parenchymal cells and was not merely a reflection of a reduced renal mRNA load resulting from attenuated leukocyte recruitment. The data presented herein suggest a framework for understanding drivers of kidney injury in ischemia/reperfusion and the molecular basis for renoprotection by Lipoxins in this setting.
Peter Doran - One of the best experts on this subject based on the ideXlab platform.
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modification of the transcriptomic response to renal ischemia reperfusion injury by Lipoxin analog
Kidney International, 2003Co-Authors: Niamh E. Kieran, Peter Doran, Susan B. Connolly, Marie Claire GreenanAbstract:Modification of the transcriptomic response to renal ischemia/reperfusion injury by Lipoxin analog. Background Lipoxins are lipoxygenase-derived eicosanoids with anti-inflammatory and proresolution bioactivities in vitro and in vivo. We have previously demonstrated that the stable synthetic LXA 4 analog 15-epi-16-(FPhO)-LXA4-Me is renoprotective in murine renal ischemia/reperfusion injury, as gauged by lower serum creatinine, attenuated leukocyte infiltration, and reduced morphologic tubule injury. Methods We employed complementary oligonucleotide microarray and bioinformatic analyses to probe the transcriptomic events that underpin Lipoxin renoprotection in this setting. Results Microarray-based analysis identified three broad categories of genes whose mRNA levels are altered in response to ischemia/reperfusion injury, including known genes previously implicated in the pathogenesis of ischemia/reperfusion injury [e.g., intercellular adhesion molecule-1 (ICAM-1), p21, KIM-1], known genes not previously associated with ischemia/reperfusion injury, and cDNAs representing yet uncharacterized genes. Characterization of expressed sequence tags (ESTs) displayed on microarrays represents a major challenge in studies of global gene expression. A bioinformatic annotation pipeline successfully annotated a large proportion of ESTs modulated during ischemia/reperfusion injury. The differential expression of a representative group of these ischemia/reperfusion injury–modulated genes was confirmed by real-time polymerase chain reaction. Prominent among the up-regulated genes were claudin-1, -3, and -7, and ADAM8. Interestingly, the former response was claudin-specific and was not observed with other claudins expressed by the kidney (e.g., claudin-8 and -6) or indeed with other components of the renal tight junctions (e.g., occludin and junctional adhesion molecule). Noteworthy among the down-regulated genes was a cluster of transport proteins (e.g., aquaporin-1) and the zinc metalloendopeptidase meprin-1β implicated in renal remodeling. Conclusion Treatment with the Lipoxin analog 15-epi-16-(FPhO)-LXA4-Me prior to injury modified the expression of many differentially expressed pathogenic mediators, including cytokines, growth factors, adhesion molecules, and proteases, suggesting a renoprotective action at the core of the pathophysiology of acute renal failure (ARF). Importantly, this Lipoxin-modulated transcriptomic response included many genes expressed by renal parenchymal cells and was not merely a reflection of a reduced renal mRNA load resulting from attenuated leukocyte recruitment. The data presented herein suggest a framework for understanding drivers of kidney injury in ischemia/reperfusion and the molecular basis for renoprotection by Lipoxins in this setting.
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Modification of the transcriptomic response to renal ischemia/reperfusion injury by Lipoxin analog
Kidney international, 2003Co-Authors: Niamh E. Kieran, Peter Doran, Susan B. Connolly, Marie Claire Greenan, Debra F. Higgins, Martin O. Leonard, Catherine Godson, Cormac T. Taylor, Anna Henger, Matthias KretzlerAbstract:Modification of the transcriptomic response to renal ischemia/reperfusion injury by Lipoxin analog. Background Lipoxins are lipoxygenase-derived eicosanoids with anti-inflammatory and proresolution bioactivities in vitro and in vivo. We have previously demonstrated that the stable synthetic LXA 4 analog 15-epi-16-(FPhO)-LXA4-Me is renoprotective in murine renal ischemia/reperfusion injury, as gauged by lower serum creatinine, attenuated leukocyte infiltration, and reduced morphologic tubule injury. Methods We employed complementary oligonucleotide microarray and bioinformatic analyses to probe the transcriptomic events that underpin Lipoxin renoprotection in this setting. Results Microarray-based analysis identified three broad categories of genes whose mRNA levels are altered in response to ischemia/reperfusion injury, including known genes previously implicated in the pathogenesis of ischemia/reperfusion injury [e.g., intercellular adhesion molecule-1 (ICAM-1), p21, KIM-1], known genes not previously associated with ischemia/reperfusion injury, and cDNAs representing yet uncharacterized genes. Characterization of expressed sequence tags (ESTs) displayed on microarrays represents a major challenge in studies of global gene expression. A bioinformatic annotation pipeline successfully annotated a large proportion of ESTs modulated during ischemia/reperfusion injury. The differential expression of a representative group of these ischemia/reperfusion injury–modulated genes was confirmed by real-time polymerase chain reaction. Prominent among the up-regulated genes were claudin-1, -3, and -7, and ADAM8. Interestingly, the former response was claudin-specific and was not observed with other claudins expressed by the kidney (e.g., claudin-8 and -6) or indeed with other components of the renal tight junctions (e.g., occludin and junctional adhesion molecule). Noteworthy among the down-regulated genes was a cluster of transport proteins (e.g., aquaporin-1) and the zinc metalloendopeptidase meprin-1β implicated in renal remodeling. Conclusion Treatment with the Lipoxin analog 15-epi-16-(FPhO)-LXA4-Me prior to injury modified the expression of many differentially expressed pathogenic mediators, including cytokines, growth factors, adhesion molecules, and proteases, suggesting a renoprotective action at the core of the pathophysiology of acute renal failure (ARF). Importantly, this Lipoxin-modulated transcriptomic response included many genes expressed by renal parenchymal cells and was not merely a reflection of a reduced renal mRNA load resulting from attenuated leukocyte recruitment. The data presented herein suggest a framework for understanding drivers of kidney injury in ischemia/reperfusion and the molecular basis for renoprotection by Lipoxins in this setting.
Catherine Godson - One of the best experts on this subject based on the ideXlab platform.
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Lipoxin a4 attenuates adipose inflammation
The FASEB Journal, 2012Co-Authors: Emma Borgeson, Debra F. Higgins, Fiona C Mcgillicuddy, Karen A Harford, Niamh Corrigan, P Maderna, Helen M Roche, Catherine GodsonAbstract:Aging and adiposity are associated with chronic low-grade inflammation, which underlies the development of obesity-associated complications, including type 2 diabetes mellitus (T2DM). The mechanisms underlying adipose inflammation may include macrophage infiltration and activation, which, in turn, affect insulin sensitivity of adipocytes. There is a growing appreciation that specific lipid mediators (including Lipoxins, resolvins, and protectins) can promote the resolution of inflammation. Here, we investigated the effect of Lipoxin A4 (LXA4), the predominant endogenously generated Lipoxin, on adipose tissue inflammation. Using adipose tissue explants from perigonadal depots of aging female C57BL/6J mice (Animalia, Chordata, Mus musculus) as a model of age-associated adipose inflammation, we report that LXA4 (1 nM) attenuates adipose inflammation, decreasing IL-6 and increasing IL-10 expression (P<0.05). The altered cytokine milieu correlated with increased GLUT-4 and IRS-1 expression, suggesting improved insulin sensitivity. Further investigations revealed the ability of LXA4 to rescue macrophage-induced desensitization to insulin-stimulated signaling and glucose uptake in cultured adipocytes, using vehicle-stimulated cells as controls. This was associated with preservation of Akt activation and reduced secretion of proinflammatory cytokines, including TNF-α. We therefore propose that LXA4 may represent a potentially useful and novel therapeutic strategy to subvert adipose inflammation and insulin resistance, key components of T2DM.
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Aromatic Lipoxin A4 and Lipoxin B4 Analogues Display Potent Biological Activities
Journal of medicinal chemistry, 2007Co-Authors: Timothy P. O'sullivan, Catherine Godson, Paola Maderna, Karl S. A. Vallin, Syed Tasadaque A. Shah, Jérome Fakhry, Michael Scannell, André L. F. Sampaio, Mauro Perretti, Patrick J. GuiryAbstract:Lipoxins are a group of biologically active eicosanoids typically formed by transcellular lipoxygenase activity. Lipoxin A4 (LXA4) and Lipoxin B4 (LXB4) biosynthesis has been detected in a variety of inflammatory conditions. The native Lipoxins LXA4 and LXB4 demonstrate potent antiinflammatory and proresolution bioactions. However, their therapeutic potential is compromised by rapid metabolic inactivation by PG dehydrogenase-mediated oxidation and reduction. Here we report on the stereoselective synthesis of aromatic LXA4 and LXB4 analogues by employing Sharpless epoxidation, Pd-mediated Heck coupling, and diastereoselective reduction as the key transformations. Subsequent biological testing has shown that these analogues display potent biological activities. Phagocytic clearance of apoptotic leukocytes plays a critical role in the resolution of inflammation. Both LXA4 analogues (1R)-3a and (1S)-3a were found to stimulate a significant increase in phagocytosis of apoptotic polymorphonuclear leukocytes (PM...
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Aromatic Lipoxin A4 and Lipoxin B4 Analogues Display Potent Biological Activities
Journal of medicinal chemistry, 2007Co-Authors: Timothy P. O'sullivan, Catherine Godson, Paola Maderna, Karl S. A. Vallin, Syed Tasadaque A. Shah, Jérome Fakhry, Michael Scannell, André L. F. Sampaio, Mauro Perretti, Patrick J. GuiryAbstract:Lipoxins are a group of biologically active eicosanoids typically formed by transcellular lipoxygenase activity. Lipoxin A4 (LXA4) and Lipoxin B4 (LXB4) biosynthesis has been detected in a variety of inflammatory conditions. The native Lipoxins LXA4 and LXB4 demonstrate potent antiinflammatory and proresolution bioactions. However, their therapeutic potential is compromised by rapid metabolic inactivation by PG dehydrogenase-mediated oxidation and reduction. Here we report on the stereoselective synthesis of aromatic LXA4 and LXB4 analogues by employing Sharpless epoxidation, Pd-mediated Heck coupling, and diastereoselective reduction as the key transformations. Subsequent biological testing has shown that these analogues display potent biological activities. Phagocytic clearance of apoptotic leukocytes plays a critical role in the resolution of inflammation. Both LXA4 analogues (1R)-3a and (1S)-3a were found to stimulate a significant increase in phagocytosis of apoptotic polymorphonuclear leukocytes (PMN) by macrophages, with comparable efficacy to the effect of native LXA4, albeit greater potency, while the LXB4 analogue also stimulated phagocytosis with a maximum effect observed at 10-11 M. LX-stimulated phagocytosis was associated with rearrangement of the actin cytoskeleton consistent with that reported for native Lipoxins. Using zymosan-induced peritonitis as a murine model of acute inflammation (1R)-3a significantly reduced PMN accumulation.
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Taking insult from injury: Lipoxins and Lipoxin receptor agonists and phagocytosis of apoptotic cells.
Prostaglandins leukotrienes and essential fatty acids, 2005Co-Authors: Paola Maderna, Catherine GodsonAbstract:Phagocytic clearance of apoptotic cells plays a pivotal role in the resolution of inflammation. Recent evidence has shown that such processes can be regulated by endogenous mediators, suggesting that specific mimetics may have therapeutic potential in chronic inflammation and autoimmune disorders. Here we review the mechanisms underlying recognition and engulfment of apoptotic cells and regulation of these processes by Lipoxins and Lipoxin receptor agonists.
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Lipoxins: Potential anti-inflammatory, proresolution, and antifibrotic mediators in renal disease
Kidney international, 2004Co-Authors: Niamh E. Kieran, Paola Maderna, Catherine GodsonAbstract:Lipoxins: Potential anti-inflammatory, proresolution, and antifibrotic mediators in renal disease. Lipoxins are lipoxygenase-derived lipid mediators with both anti-inflammatory and proresolution properties that have been demonstrated in vivo and in vitro. The bioactivity profile of Lipoxins in vitro suggests that they have therapeutic potential in acute renal failure and glomerulonephritis; predictions that have been borne out to date in experimental models of renal disease. We review recent developments on the molecular basis of Lipoxin bioactions mediated through receptor crosstalk and the accumulating evidence that Lipoxins may have potential as novel anti-inflammatory agents.