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Biomedical subjects

C N Serhan

Publications and source records attributed to C N Serhan.

At least 19 recordsLinked to original sources
PubMed2005

RvE1 protects from local inflammation and osteoclast- mediated bone destruction in periodontitis.

Periodontitis is a well-appreciated example of leukocyte-mediated bone loss and inflammation that has pathogenic features similar to those observed in other inflammatory diseases such as arthritis. Resolvins are a new family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammatory signals. Because it is now increasingly apparent that local inflammation plays a critical role in many diseases, including cardiovascular disease, atherosclerosis, and asthma, experiments were undertaken to evaluate the actions of the newly described EPA-derived Resolvin E1 (RvE1) in regulation of neutrophil tissue destruction and resolution of inflammation. The actions of an aspirin-triggered lipoxin (LX) analog and RvE1 in a human disease, localized aggressive periodontitis (LAP), were determined. Results indicate that neutrophils from LAP are refractory to anti-inflammatory molecules of the LX series, whereas LAP neutrophils respond to RvE1. In addition, RvE1 specifically binds to human neutrophils at a site that is functionally distinct from the LX receptor. Consistent with these potent actions, topical application of RvE1 in rabbit periodontitis conferred dramatic protection against inflammation induced tissue and bone loss associated with periodontitis.

Administration, Topical↗
PubMed2004

Interactions between lipoxin A4, the stable analogue 16-phenoxy-lipoxin A4 and leukotriene B4 in cytokine generation by human monocytes.

Lipoxins display both stimulatory and inhibitory actions with leucocytes that are cell-type dependent. We tested whether lipoxin A4 (LXA4) and its stable synthetic analogue 16-phenoxy-17-18,19,20-tetranor-lipoxin-A4 (16-phe-LXA4) modulated the ability of human blood monocytes (MO) to express mRNA and proteins for interleukin-1beta (IL-1beta), IL-6 and IL-1 receptor antagonist (IL-1Ra) in vitro and compared their actions with lipopolysaccharide (LPS) and leukotriene B4 (LTB4). 16-phe-LXA4, LPS and LTB4, but not LXA4, induced gene expression of IL-1beta in MO. IL-1beta protein synthesis increased by LPS (1500-fold), LTB4 (280-fold) and 16-phe-LXA4 (30-fold). Although the IL-1Ra gene was constitutively activated, mRNA concentration not affected by any of the stimulants, IL-Ra protein synthesis was increased by LPS (with 74%), 16-phe-LXA4 (35%) and LTB4 (20%), but not by LXA4. Each of these stimuli upregulated the IL-6 gene. Increases of IL-6 protein were 3000-fold for LPS, threefold for 16-phe-LXA4, eightfold for LXA(4 and) twofold for LTB4. Prior exposure of MO to 16-phe-LXA4, but not LXA4, reduced LTB4 induced synthesis of IL-1beta with 66%, IL-6 with 20% and IL-1Ra with 29%. Thus, a stable LXA analogue, that resists rapid inactivation by monocytes, displays novel actions in cytokine generation, intimately involved in the regulation of inflammation.

Cytokines↗
PubMed2003

Expression of BPI (bactericidal/permeability-increasing protein) in human mucosal epithelia.

Among the antimicrobial proteins and peptides of humans is the cationic 55 kDa bactericidal/permeability-increasing protein (BPI), which possesses antibacterial, endotoxin-neutralizing and opsonic activity against Gram-negative bacteria. Although identified originally as an abundant constituent of neutrophil granules, we have recently identified functional expression of BPI by human mucosal epithelia. BPI expression was markedly up-regulated by exposure of epithelia to lipoxins, endogenous anti-inflammatory eicosanoids that are generated in vivo in the context of aspirin treatment (aspirin-triggered lipoxins). Epithelial BPI was found to be surface expressed and fully functional, as measured by antibacterial activity against Salmonella typhimurium as well as lipopolysaccharide (LPS; endotoxin)-neutralizing activity. These results suggest a role for BPI as an effector of epithelial antibacterial activity and as a modulator of epithelial responses to LPS. Both BPI and the lipoxins are currently the subject of intensive biopharmaceutical development, raising the possibility that therapeutic use of BPI or modulation of epithelial BPI expression may be a useful adjunctive therapy for conditions in which epithelial inflammation is associated with Gram-negative infections and/or endotoxin.

Antimicrobial Cationic Peptides↗
PubMed2003

Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases.

The periodontal diseases are infectious diseases caused by predominantly Gram-negative bacteria. However, as our understanding of the pathogenesis of the periodontal diseases grows, it is becoming clear that most of the tissue damage that characterizes periodontal disease is caused by the host response to infection, not by the infectious agent directly. Investigation into the mechanism of action of host-mediated tissue injury has revealed that the neutrophil plays an important role in destruction of host tissues. In this paper, we review the biochemical pathways and molecular mediators that are responsible for regulation of the inflammatory response in diseases such as periodontitis, with a focus on lipid mediators of inflammation. Pro-inflammatory mediators, such as prostaglandins and leukotrienes, are balanced by counter-regulatory signals provided by a class of molecules called lipoxins. The role of lipoxins in the control and resolution of inflammation is discussed, as is the possibility of the development of new therapeutic strategies for the control and prevention of neutrophil-mediated tissue injury in inflammatory diseases like periodontitis.

Animals↗
PubMed2002

The fibrinolytic receptor for urokinase activates the G protein-coupled chemotactic receptor FPRL1/LXA4R.

The function of urokinase and its receptor is essential for cell migration in pathological conditions, as shown by the analysis of knockout mice phenotypes. How a protease of a fibrinolytic pathway can induce migration is not understood and no link between this protease and migration-promoting G protein-coupled receptors has been described. We now show that FPRL1/LXA4R, a G protein-coupled receptor for a number of polypeptides and for the endogenous lipoxin A4 (LXA4), is the link between urokinase-type plasminogen activator (uPA) and migration as it directly interacts with an activated, soluble, cleaved form of uPA receptor (uPAR) (D2D3(88-274)) to induce chemotaxis. In this article we show that (i) both uPAR and FPRL1/LXA4R are necessary for the chemotactic activity of uPA whereas FPRL1/LXA4R is sufficient to mediate D2D3(88-274)-induced cell migration. (ii) Inhibition or desensitization of FPRL1/LXA4R by antibodies or specific ligands specifically prevents chemotaxis induced by D2D3(88-274) in THP-1 cells and human peripheral blood monocytes. (iii) Desensitization of FPRL1/LXA4R prevents the activation of tyrosine kinase Hck induced by D2D3(88-274). (iv) D2D3(88-274) directly binds to FPRL1/LXA4R and is competed by two specific FPRL1/LXA4R agonists, the synthetic MMK-1 peptide and a stable analog of LXA4. Thus, a naturally produced cleaved form of uPAR is a unique endogenous chemotactic agonist for FPRL1/LXA4R receptor and its activity can be antagonized by specific ligands. These results provide the first direct link, to our knowledge, between the fibrinolytic machinery and the inflammatory response, demonstrating that uPA-derived peptide fragments can activate a specific chemotactic receptor.

Animals↗
PubMed2002

Polyisoprenyl phosphates: natural antiinflammatory lipid signals.

Lipoxins (LX) and aspirin-triggered 15-epimer LX are leukocyte-derived eicosanoids generated during host defense that serve as down-regulatory signals. The specific intracellular events that govern cellular responses to inhibitory extracellular signals are of wide interest in order to understand pivotal intracellular events in diseases characterized by enhanced inflammatory responses, such as asthma, rheumatoid arthritis and atherosclerosis. We recently uncovered a novel role for polyisoprenyl phosphates, in particular presqualene diphosphate (PSDP), as natural down-regulatory signals in human neutrophils that directly inhibit phospholipase D and superoxide anion generation. Activation of LXA4 receptors (ALXR) reverses proinflammatory receptor-initiated decrements in PSDP and inhibits cellular responses. These findings represent evidence for a novel paradigm for lipid-protein interactions in the control of cellular responses, namely receptor-initiated degradation of repressor lipids that is subject to regulation by aspirin treatment via the actions of aspirin-triggered 15-epimer LX at the ALXR, and identify new templates for antiinflammatory drugs by design.

Anti-Inflammatory Agents↗
PubMed2001

Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity.

Lipoxins are eicosanoid mediators that show potent inhibitory effects on the acute inflammatory process. We show here that the induction of lipoxin A(4) (LXA(4)) accompanied the in vivo suppression of interleukin 12 (IL-12) responsiveness of murine splenic dendritic cells (DCs) after microbial stimulation with an extract of Toxoplasma gondii. This paralysis of DC function could not be triggered in mice that were deficient in a key lipoxygenase involved in LXA(4) biosynthesis. In addition, DCs pre-treated with LXA(4) became refractory to microbial stimulation for IL-12 production in vitro and mice injected with a stable LXA(4) analog showed reduced splenic DC mobilization and IL-12 responses in vivo. Together, these findings indicate that the induction of lipoxins in response to microbial stimulation can provide a potent mechanism for regulating DC function during the innate response to pathogens.

Animals↗
PubMed2001

Identification of dual cyclooxygenase-eicosanoid oxidoreductase inhibitors: NSAIDs that inhibit PG-LX reductase/LTB(4) dehydrogenase.

Eicosanoids play key roles in many physiologic and disease processes, and their regulation by nonsteroidal anti-inflammatory drugs (NSAIDs) is critical to many therapeutic approaches. These autacoids are rapidly inactivated by specific enzymes such as 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and 15-oxoprostaglandin 13-reductase/leukotriene B(4) 12-hydroxydehydrogenase (PGR/LTB(4)DH) that act on main series of eicosanoids (i.e., leukotrienes, prostaglandins), and recently found to act in lipoxin inactivation. Here, a panel of NSAIDs was assessed to determine each compound's ability to inhibit eicosanoid-directed activities of either the recombinant 15-PGDH or the PG-LXR/LTB(4)DH. The recombinant 15-PGDH that acts on both prostaglandin E(2) (PGE(2)) and lipoxin A(4) (LXA(4)) was not significantly inhibited by the NSAIDs tested. In contrast, several of the widely used NSAIDs were potent inhibitors of the PG-LXR/LTB(4)DH that metabolizes 15-oxo-PGE(2), and LTB(4) as well as 15-oxo-LXA(4). Diclofenac and indomethacin each inhibited PG-LXR/LTB(4)DH-catalyzed conversion of 15-oxo-PGE(2) to 13,14-dihydro-15-oxo-PGE(2) by 70 and 95%, respectively. Also, a COX-2 inhibitor, niflumic acid, inhibited the PG-LXR/LTB(4)DH eicosanoid oxidoreductase (EOR) by 80% while other COX-2 inhibitors such as nimesulide and NS-398 did not inhibit this enzyme. These results indicate that certain clinically useful NSAIDs such as diclofenac and indomethacin, in addition to inhibiting cyclooxygenases (1 and 2), also interfere with eicosanoid degradation by blocking PG-LXR/LTB(4)DH (EOR) and are members of a new class of dual cyclooxygenase (COX)-EOR inhibitors. Moreover, they suggest that the impact of NSAIDs on PG-LXR/LTB(4)DH activities as targets in the local tissue regulation of eicosanoid-mediated processes should be taken into account.

15-Oxoprostaglandin 13-Reductase↗
PubMed2001

Aspirin-triggered lipoxin A4 and lipoxin A4 up-regulate transcriptional corepressor NAB1 in human neutrophils.

Aspirin-triggered 15-epi-lipoxin A4 (ATL) is an endogenous lipid mediator that mimics the actions of native lipoxin A4, a putative "stop signal" involved in regulating resolution of inflammation. A metabolically more stable analog of ATL, 15-epi-16-(para-fluoro)-phenoxy-lipoxin A4 analog (ATLa), inhibits neutrophil recruitment in vitro and in vivo and displays potent anti-inflammatory actions. ATLa binds with high affinity to the lipoxin A4 receptor, a G protein-coupled receptor on the surface of leukocytes. In this study, we used freshly isolated human neutrophils to examine ATLa's potential for initiating rapid nuclear responses. Using differential display reverse transcription polymerase chain reaction, we identified a subset of genes that was selectively up-regulated upon short exposure of polymorphonuclear leukocytes to ATLa but not to the chemoattractant leukotriene B4 or vehicle alone. We further investigated ATLa regulation of one of the genes, NAB1, a transcriptional corepressor identified previously as a glucocorticoid-responsive gene in hamster smooth muscle cells. Treatment of human neutrophils with pertussis toxin blocked ATLa up-regulation of NAB1. In addition, ATLa stimulated NAB1 gene expression in murine lung vascular smooth muscle in vivo. These findings provide evidence for rapid transcriptional induction of a cassette of genes via an ATLa-stimulated G protein-coupled receptor pathway that is potentially protective and overlaps with the anti-inflammatory glucocorticoid regulatory circuit.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Cutting edge: nociceptin stimulates neutrophil chemotaxis and recruitment: inhibition by aspirin-triggered-15-epi-lipoxin A4.

The nociceptin receptor (Noci-R) is a G protein-coupled receptor present in neural tissues and its activation by nociceptin is involved in the processing of pain signals. Here, we report that Noci-R is present and functional on peripheral blood polymorphonuclear leukocytes (PMN). Human PMN express mRNA for Noci-R, its nucleotide sequence determined, and specific binding with [(125)I]-labeled nociceptin gave an apparent K(d) approximately 1.5 nM for this PMN opioid receptor. Nociceptin evoked PMN chemotaxis with maximal activity at 100 pM, without intracellular Ca(2+) mobilization. When injected in murine air pouches, nociceptin elicited leukocyte infiltration in a concentration-dependent fashion. Nociceptin-stimulated PMN infiltration was inhibited by treating mice with a synthetic analog of the aspirin-triggered lipid mediator 15-epi-lipoxin A(4). The present results identify nociceptin as a potent chemoattractant and provide a novel link between the neural and immune systems that are blocked by aspirin-triggered lipid mediators and may be relevant in neurogenic inflammation.

Animals↗
PubMed2001

Selectivity of recombinant human leukotriene D(4), leukotriene B(4), and lipoxin A(4) receptors with aspirin-triggered 15-epi-LXA(4) and regulation of vascular and inflammatory responses.

Aspirin-triggered lipoxin A(4) (ATL, 15-epi-LXA(4)) and leukotriene D(4) (LTD(4)) possess opposing vascular actions mediated via receptors distinct from the LXA(4) receptor (ALX) that is involved in leukocyte trafficking. Here, we identified these receptors by nucleotide sequencing and demonstrate that LTD(4) receptor (CysLT(1)) is induced in human vascular endothelia by interleukin-1beta. Recombinant CysLT(1) receptor gave stereospecific binding with both [(3)H]-LTD(4) and a novel labeled mimetic of ATL ([(3)H]-ATLa) that was displaced with LTD(4) and ATLa ( approximately IC(50) 0.2 to 0.9 nmol/L), but not with a bioinactive ATL isomer. The clinically used CysLT(1) receptor antagonist, Singulair, showed a lower rank order for competition with [(3)H]-ATLa (IC(50) approximately 8.3 nmol/L). In contrast, LTD(4) was an ineffective competitive ligand for recombinant ALX receptor with [(3)H]-ATLa, and ATLa did not compete for [(3)H]-LTB(4) binding with recombinant LTB(4) receptor. Endogenous murine CysLT(1) receptors also gave specific [(3)H]-ATLa binding that was displaced with essentially equal affinity by LTD(4) or ATLa. Systemic ATLa proved to be a potent inhibitor (>50%) of CysLT(1)-mediated vascular leakage in murine skin (200 microg/kg) in addition to its ability to block polymorphonuclear leukocyte recruitment to dorsal air pouch (4 microg/kg). These results indicate that ATL and LTD(4) bind and compete with equal affinity at CysLT(1), providing a molecular basis for aspirin-triggered LXs serving as a local damper of both vascular CysLT(1) signals as well as ALX receptor-regulated polymorphonuclear leukocyte traffic.

Animals↗
PubMed2001

Lipid mediator class switching during acute inflammation: signals in resolution.

Leukotrienes (LTs) and prostaglandins (PGs) amplify acute inflammation, whereas lipoxins (LXs) have unique anti-inflammatory actions. Temporal analyses of these eicosanoids in clinical and experimental exudates showed early coordinate appearance of LT and PG with polymorphonuclear neutrophil (PMN) recruitment. This was followed by LX biosynthesis, which was concurrent with spontaneous resolution. Human peripheral blood PMNs exposed to PGE2 (as in exudates) switched eicosanoid biosynthesis from predominantly LTB4 and 5-lipoxygenase (5-LO)-initiated pathways to LXA4, a 15-LO product that "stopped" PMN infiltration. These results indicate that first-phase eicosanoids promote a shift to anti-inflammatory lipids: functionally distinct lipid-mediator profiles switch during acute exudate formation to "reprogram" the exudate PMNs to promote resolution.

Animals↗
PubMed2001

Inosine monophosphate and aspirin-triggered 15-epi-lipoxin A4 act in concert to regulate neutrophil trafficking: additive actions of two new endogenous anti-inflammatory mediators.

Regulation of neutrophil (PMN) trafficking by soluble mediators is a critical component in the outcome of host defense, inflammation resolution, and neutrophil-mediated tissue injury. Elucidation of the endogenous mediators that protect tissues from excess leukocyte traffic and aberrant PMN activation that can lead to tissue damage and chronic inflammation is of considerable interest, especially the endogenous mechanisms of anti-inflammation. To this end, we recently uncovered two new classes of mediators: inosine monophosphate (IMP) and aspirin-triggered 15(R)-epimers of native lipoxin A(4). Here, we examined the combined actions of both classes of compounds in regulating key events in neutrophil trafficking. Neutrophil rolling in mouse microvessels was inhibited by both IMP or 5S,6R,15R-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid (15-epi-LXA(4)) in a concentration-dependent fashion. When combined, IMP (300 nM) and 15-epi-LX (10 nM) demonstrated additive inhibition of neutrophil rolling in microvessels. IMP and 15-epi-LX also significantly inhibited tumor necrosis factor-alpha (TNF-alpha)-induced neutrophil accumulation into the mouse air pouch in a dose-dependent manner. Again, the combination of low dose IMP (10 microg) and LX analog (5 microg) gave additive inhibition of neutrophil accumulation in this model. These results demonstrate the inhibition of neutrophil trafficking in two separate models by two different classes of small endogenous molecules. The additive inhibition by IMP and aspirin-triggered LX may represent key pathways that protect and resolve inflammatory responses that could be harnessed for treatment.

Animals↗
PubMed2001

Mechanisms in anti-inflammation and resolution: the role of lipoxins and aspirin-triggered lipoxins.

Multicellular host responses to infection, injury or inflammatory stimuli lead to the formation of a broad range of chemical mediators by the host. The integrated response of the host is essential to health and disease; thus it is important to achieve a more complete understanding of the molecular and cellular events governing the formation and actions of endogenous mediators of resolution that appear to control the duration of inflammation. Lipoxins are trihydroxytetraene-containing lipid mediators that can be formed during cell-cell interactions and are predominantly counterregulators of some well-known mediators of inflammation. Since this circuit of lipoxin formation and action appears to be of physiological relevance for the resolution of inflammation, therapeutic modalities targeted at this system are likely to have fewer unwanted side effects than other candidates and current anti-inflammatory therapies. Here, we present an overview of the recent knowledge about the biosynthesis and bioactions of these anti-inflammatory lipid mediators.

Animals↗
PubMed2001

Lipoxins and aspirin-triggered 15-epi-lipoxins are endogenous components of antiinflammation: emergence of the counterregulatory side.

Eicosanoids are known to play important roles in cell-cell communications and as intracellular signals that are critical components of multi-cellular responses such as acute inflammation and reperfusion injury. Recent findings have given rise to several new concepts that are reviewed here regarding the generation of eicosanoids and their impact in inflammation. Lipoxins (LX) are trihydroxytetraene-containing eicosanoids that can be generated within the vascular lumen during platelet-leukocyte interactions and at mucosal surfaces via leukocyte-epithelial cell interactions. During these cell-cell interactions, transcellular biosynthetic pathways are used as major LX biosynthetic routes, and thus, in humans, LX are formed in vivo during multi-cellular responses such as inflammation, atherosclerosis, and in asthma. This branch of the eicosanoid cascade generates specific tetraene-containing products that serve as stop signals, in that they regulate key steps in leukocyte trafficking and prevent leukocyte-mediated acute tissue injury. Of interest here are recent results indicating that aspirin's mechanism of action also involves the triggering of novel carbon 15 epimers of LX or 15-epi-LX that mimic the bioactions of native LX. Here, an overview of these recent developments is presented, with a focus on the cellular and molecular interactions of these novel antiinflammatory lipid mediators.

Animals↗
PubMed2000

Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing.

Aspirin therapy inhibits prostaglandin biosynthesis without directly acting on lipoxygenases, yet via acetylation of cyclooxygenase 2 (COX-2) it leads to bioactive lipoxins (LXs) epimeric at carbon 15 (15-epi-LX, also termed aspirin-triggered LX [ATL]). Here, we report that inflammatory exudates from mice treated with omega-3 polyunsaturated fatty acid and aspirin (ASA) generate a novel array of bioactive lipid signals. Human endothelial cells with upregulated COX-2 treated with ASA converted C20:5 omega-3 to 18R-hydroxyeicosapentaenoic acid (HEPE) and 15R-HEPE. Each was used by polymorphonuclear leukocytes to generate separate classes of novel trihydroxy-containing mediators, including 5-series 15R-LX(5) and 5,12,18R-triHEPE. These new compounds proved to be potent inhibitors of human polymorphonuclear leukocyte transendothelial migration and infiltration in vivo (ATL analogue > 5,12,18R-triHEPE > 18R-HEPE). Acetaminophen and indomethacin also permitted 18R-HEPE and 15R-HEPE generation with recombinant COX-2 as well as omega-5 and omega-9 oxygenations of other fatty acids that act on hematologic cells. These findings establish new transcellular routes for producing arrays of bioactive lipid mediators via COX-2-nonsteroidal antiinflammatory drug-dependent oxygenations and cell-cell interactions that impact microinflammation. The generation of these and related compounds provides a novel mechanism(s) for the therapeutic benefits of omega-3 dietary supplementation, which may be important in inflammation, neoplasia, and vascular diseases.

Acetaminophen↗