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At least 19 recordsLinked to original sources

PubMed1996

Activation of human monocytes and the acute monocytic leukemia cell line (THP-1) by lipoxins involves unique signaling pathways for lipoxin A4 versus lipoxin B4: evidence for differential Ca2+ mobilization.

Lipoxins are bioactive eicosanoids that are generated during multicellular events such as inflammation, thrombosis, and atherosclerosis. They have selective actions on peripheral blood cells, in that previous results indicate that lipoxin A4 (LXA4) and lipoxin B4 (LXB4) inhibit neutrophil migration while they are both potent stimuli of peripheral blood monocyte (PBM) chemotaxis and adherence. Here, we report the impact of lipoxins on levels of free cytosolic calcium ([Ca2+]i) in PBM and THP-1 cells (acute monocytic leukemia cells) as well as on the functional responses of these cells. LXA4, but not LXB4, induced a concentration-dependent increase in [Ca2+]i in monocytes that was half-maximal at approximately 200 nM. Prior exposure of the cells to EGTA reduced the LXA4-induced increase in [Ca2+]i by approximately 50 to 60%, indicating the contribution of both intracellular mobilization and external influx in LXA4 Ca2+ regulation. A leukotriene B4 receptor antagonist, ONO 4057, did not significantly alter LXA4-induced [Ca2+]i, while it inhibited the action of leukotriene B4. LXA4 also induced a rise in [Ca2+]i in the monocytic leukemia cell line (time to reach maximum = 15.1 +/- 0.87 s), and both LXA4 and LXB4 stimulated a concentration-dependent THP-1 cell adherence to laminin with concentrations as low as 10(-10)M. In contrast to the findings with LXA4, exposure of THP-1 or PBM to LXB4 was not accompanied by mobilization of intracellular Ca2+. Although both LXA4 and LXB4 stimulate adherence of PBM, they did not evoke superoxide anion generation by these cells, nor did they affect the rate of acidification of extracellular medium by monocytes, as monitored using a microphysiometer. Together, these results indicate that an increase in [Ca2+]i is a component of the signal transduction events following monocyte interaction with LXA4, but not LXB4, and that both LXA4 and LXB4 are potent and selective agonists for THP-1 cells and PBM. Moreover, they suggest that LX display a unique profile of actions with mononuclear cells compared with other known agonists of monocytes, and that LX can direct monocyte-mediated events.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1995

Lipoxin A4 receptor activation is distinct from that of the formyl peptide receptor in myeloid cells: inhibition of CD11/18 expression by lipoxin A4-lipoxin A4 receptor interaction.

Lipoxin A4 (LXA4) interacts with high-affinity receptors in human neutrophils and differentiated HL-60 cells. Recently, we characterized a myeloid-derived cDNA that encodes a LXA4 high-affinity receptor (LXA4R) [Fiore, S., Maddox, J. F., Perez, H. D., and Serhan, C. N. (1994) J. Exp. Med. 180, 253-260] denoted earlier as a related N-formyl peptide receptor (RFP). To examine the selectivity of this receptor we tested its preference for specific binding of 3H-LXA4 versus 3H-N-formylmethionyl-leucyl-phenylalanine (3H-FMLP). When receptor-transfected Chinese hamster ovary cells were exposed to either 3H-LXA4 or 3H-FMLP, the receptor affinity for LXA4 exceeded by 1000-fold that of FMLP (6.1 nM vs 5 microM). Upon differentiation, HL-60 cells acquire high-affinity binding sites and respond to both LXA4 and FMLP. Northern blot analysis of differentiated HL-60 cells using an RFP probe showed a characteristic band at 2.1 kb. Differentiated HL-60 cells exposed to an RFP antisense oligonucleotide selectively lost 3H-LXA4 binding as well as LXA4-stimulated lipid remodeling that paralleled the loss of mRNA for LXA4R. In contrast, the specific mRNA for the FMLP receptor, 3H-FMLP specific binding, and FMLP-induced phospholipase D activity were still observed. Treatment of human neutrophils with antisera raised against a peptide in the LXA4R third extracellular domain also resulted in selective abrogation of 3H-LXA4 specific binding with polymorphonuclear leukocytes (PMN) without blocking 3H-FMLP binding. FMLP-stimulated CD11b upregulation as well as homotypic aggregation of PMN was inhibited by LXA4 (which at 10(-9) M gave approximately 1 log unit shift to the right in the FMLP dose-response curve). The addition of LXA4R antisera did not alter FMLP-induced responses in PMN but completely blocked LXA4 actions. These results indicate that altering the expression of the LXA4R protein by blockage of transcriptional mechanisms or hindrance of the LXA4R extracellular domains leads to loss of LXA4 specific binding and blockage of LXA4 signaling. Moreover, they indicate that in myeloid cells LXA4-LXA4R interactions are dissociable from those of FMLP and that LXA4 regulates CD11/18 on the PMN surface.

Animals↗

PubMed2002

Lipoxins, aspirin-triggered epi-lipoxins, lipoxin stable analogues, and the resolution of inflammation: stimulation of macrophage phagocytosis of apoptotic neutrophils in vivo.

Lipoxins (LX) are eicosanoids with antiinflammatory activity in glomerulonephritis (GN) and inflammatory diseases, hypersensitivity, and ischemia reperfusion injury. It has been demonstrated that LXA(4) stimulates non-phlogistic phagocytosis of apoptotic polymorphonuclear neutrophils (PMN) by monocyte-derived macrophages (Mphi) in vitro, suggesting a role for LX as endogenous pro-resolution lipid mediators. It is here reported that LXA(4), LXB(4), the aspirin-triggered LX (ATL) epimer, 15-epi-LXB(4), and a stable synthetic analogue 15(R/S)-methyl-LXA(4) stimulate phagocytosis of exogenously administered excess apoptotic PMN by macrophages (M phi) in vivo in a classic model of acute inflammation, namely thioglycollate-induced peritonitis. Significant enhancement of phagocytosis in vivo was observed with 15-min exposure to LX and with intraperitoneal doses of LXA(4), LXB(4), 15(R/S)-methyl-LXA(4), and 15-epi-LXB(4) of 2.5 to 10 micro g/kg. Non-phlogistic LX-stimulated phagocytosis by M phi was sensitive to inhibition of PKC and PI 3-kinase and associated with increased production of transforming growth factor-beta(1) (TGF-beta(1)). LX-stimulated phagocytosis was not inhibited by phosphatidylserine receptor (PSR) antisera and was abolished by prior exposure of M phi to beta 1,3-glucan, suggesting a novel M phi-PMN recognition mechanism. Interestingly, the recently described peptide agonists of the LXA(4) receptor (MYFINITL and LESIFRSLLFRVM) stimulated phagocytosis through a process associated with increased TGF-beta(1) release. These data provide the first demonstration that LXA(4), LXB(4), ATL, and LX stable analogues rapidly promote M phi phagocytosis of PMN in vivo and support a role for LX as rapidly acting, pro-resolution signals in inflammation. Engagement of the LXR by LX generated during cell-cell interactions in inflammation and by endogenous LXR peptide agonists released from distressed cells may be an important stimulus for clearance of apoptotic cells and may be amenable to pharmacologic mimicry for therapeutic gain.

Anti-Inflammatory Agents↗

PubMed2005

[Transfection of Lipoxin A4 receptor-like protein gene enhanced the inhibitory effect of Lipoxin A4 on human lung fibroblasts proliferation induced by connective tissue growth factor].

OBJECTIVE: Lipoxin A(4) is formed by the metabolism of arachidonic acid. Anti-inflammatory and anti-proliferative effect of lipoxin A(4) has been shown in many human diseases. Recently, as a novel high affinity receptor for ligand lipoxin A(4), Lipoxin A(4) receptor-like protein (LRLP) has been identified. Currently close attention is paid to the important contribution of connective tissue growth factor (CTGF) in lung fibrosis. The purpose of the study was to transfect LRLP gene into human lung fibroblasts and investigate the mechanism of its enhancing antagonistic effect of Lipoxin A(4) on human lung fibroblasts proliferation induced by connective tissue growth factor. METHODS: Eukaryocytic expression vector pEGFP/LRLP which contained LRLP and green fluorescence protein fusion gene (GFP) was constructed and transfected into human lung fibroblasts (HLF). After selecting with G418, HLF/LRLP cell clone which stably expressed LRLP/GFP fusion protein was isolated and characterized by the laser scanning confocal microscope. Cultured HLF and HLF/LRLP were stimulated for 24 h with CTGF (1 microg/ml) in the presence and absence of pretreatment of Lipoxin A(4) (10.0 nmol/L) for 30 min. Inhibition of cell proliferation was determined by MTT assay. Cell cycle analysis was performed by flow cytometry. Western blot was used to detect the expression of cyclin D(1) protein. Electrophoretic mobility shift assay (EMSA) was employed to detect the DNA binding activity of STAT(3). RESULTS: (1) HLF/LRLP cell clone which stably expressed LRLP and GFP fusion protein was successfully obtained. (2) Proliferation of HLF and HLF/LRLP was induced by 1 microg/ml CTGF. Pretreatment with 10 nm Lipoxin A(4) inhibited the proliferation of HLF and HLF/LRLP. And the inhibitory rate of HLF/LRLP was significantly higher than that of HLF [(54.1 +/- 4.2)%, (21.2 +/- 3.7)%, P < 0.05]. (3) The flow cytometry analysis showed that compared with HLF, more HLF/LRLP were arrested at G(0)/G(1) phase in the presence of pretreatment of Lipoxin A(4). [(76.3 +/- 3.5)%, (60.8 +/- 2.0)%, P < 0.05]. (4) Ten nmol/L Lipoxin A(4) antagonized CTGF induced increase of cyclin D(1) protein expression in HLF and HLF/LRLP. And its antagonistic effect on HLR/LRLP was stronger than that on HLF (P < 0.05). (5) Ten nmol/L Lipoxin A(4) antagonized CTGF induced increase of STAT(3) DNA binding activity, and its antagonistic effect on HLF/LRLP was more powerful than that on HLF (P < 0.05). CONCLUSIONS: Transfection of Lipoxin A(4) receptor-like protein gene enhanced the inhibitory effect of Lipoxin A(4) on human lung fibroblasts proliferation induced by CTGF. Its mechanism might be related to regulation of cyclin D(1) protein expression and STAT(3) DNA binding activity.

Connective Tissue Growth Factor↗

PubMed2006

Lipoxin and synthetic lipoxin analogs: an overview of anti-inflammatory functions and new concepts in immunomodulation.

Lipoxin A4 (LXA4) and lipoxin B4 (LXB4) were first identified in 1984 by Serhan and colleagues as 5- and 15-lipoxygenase interaction products of activated leukocytes. Endogenous transcellular biosynthesis of LXA4 and LXB4 occurs via interaction of leukocytes with epithelium, endothelium or platelets. Acetylation of cyclooxygenase-2 (COX-2) by aspirin can trigger 15-epi-LXA4 (ATL) biosynthesis. Elucidating the pharmacological actions of lipoxins and ATL was facilitated by total synthesis of LXA4 in 1988 by Nicolaou and colleagues. In 1994, Fiore and colleagues used [3H]-LXA4 to identify the cDNA for a human G-protein-coupled, high affinity LXA4 and ATL receptor (ALX-R/FPRL-1), providing the first hints for the molecular basis of lipoxin actions. The recognition that lipoxins and ATL undergo rapid, prostaglandin dehydrogenase (PGDH)-mediated metabolic inactivation led do the design and synthesis of first-generation PGDH-resistant LXA4, LXB4 and ATL analogs in 1995-1998 by Serhan, Petasis and colleagues. These relatively stable pharmacological agents, together with myeloid-specific ALX-R-expressing transgenic mice, have provided powerful tools to explore lipoxin functions in vivo. Here we briefly review the substantial body of evidence supporting the lipoxin --> ALX-R pathway as a novel and potent mechanism for preventing/resolving acute inflammation. Emphasis will also be placed on recent findings that lipoxins play new roles in "immunomodulation" via regulation of macrophage, dendritic cell, and T-lymphocyte effector functions in the setting of polarized T-helper cell responses (Th1 and Th2). These studies suggest roles for lipoxins as novel regulators of allergy and adaptive immunity and that lipoxins may have therapeutic potential in chronic immune disorders.

Acetylation↗

PubMed1990

Lipoxin A4 and lipoxin B4 stimulate the release but not the oxygenation of arachidonic acid in human neutrophils: dissociation between lipid remodeling and adhesion.

The profiles of actions of lipoxin A4 (LXA4) and lipoxin B4 (LXB4), two lipoxygenase-derived eicosanoids, were examined with human neutrophils. At nanomolar concentrations, LXA4 and LXB4 each stimulated the release of [1-14C]arachidonic acid from esterified sources in neutrophils. Lipoxin-induced release of [1-14C]arachidonic acid was both dose- and time-dependent and was comparable to that induced by the chemotactic peptide f-met-leu-phe. Time-course studies revealed that lipoxin A4 and lipoxin B4 each induced a biphasic release of [1-14C]arachidonic acid, which was evident within seconds (5-15 sec) in its initial phase and minutes (greater than 30 sec) in the second phase. In contrast, the all-trans isomers of LXA4 and LXB4 did not provoke [1-14C]AA release. Lipoxin-induced release of arachidonic acid was inhibited by prior treatment of the cells with pertussis toxin but not by its beta-oligomers, suggesting the involvement of guaninine nucleotide-binding regulatory proteins in this event. Dual radiolabeling of neutrophil phospholipid classes with [1-14C]arachidonic acid and [3H]palmitic acid showed that phosphatidylcholine was a major source of lipoxin-induced release of [1-14C]arachidonic acid. They also demonstrated that lipoxins rapidly stimulate both formation of phosphatidic acid as well as phospholipid remodeling. Although both LXA4 and LXB4 (10(-8)-10(-6) M) stimulated the release of [1-14C]arachidonic acid, neither compound evoked its oxygenation by either the 5- or 15-lipoxygenase pathways (including the formation of LTB4, 20-COOH-LTB4, 5-HETE, or 15-HETE). LXA4 and LXB4 (10(-7) M) each stimulated the elevation of cytosolic Ca2+ as monitored with Fura 2-loaded cells, albeit to a lesser extent than equimolar concentrations of FMLP. Neither lipoxin altered the binding of [3H]LTB4 to its receptor on neutrophils. In addition, they did not stimulate aggregation or induce adhesion of neutrophils to human endothelial cells. Results indicate that both LXA4 and LXB4 stimulate the rapid remodeling of neutrophil phospholipids to release arachidonic acid without provoking either aggregation or the formation of lipoxygenase-derived products within a similar temporal and dose range. Together they indicate that LXA4 and LXB4 display selective actions with human neutrophils and suggest that these eicosanoids possess unique profiles of action which may regulate neutrophil function during inflammation.

Arachidonic Acids↗

PubMed1988

Conformational analysis of lipoxin A, lipoxin B and their trans-isomers.

Lipoxin A and lipoxin B (LXA and LXB) are formed from the oxygenation of arachidonic acid by interactions between the 5- and 15-lipoxygenases of human leukocytes. Each compound displays highly stereospecific biological actions. Here, we present a computational description of the following compounds: lipoxin A, (5S,6R,15S)-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid; 11-trans-lipoxin A, (5S,6R,15S)-trihydroxy-7,9,11,13-trans-eicosatetraenoic acid; lipoxin B, (5S,14R,15S)-trihydroxy-6,10,12-trans-8-cis-eicosatetraenoic acid; and 8-trans-lipoxin B, (5S,14R,15S)-trihydroxy-6,8,10,12-trans-eicosatetraenoic acid. The analyses considered van der Waals energy, electrostatic interactions, torsional potential, and alterations in electrostatic forces. Additional analyses were carried out with each of the four compounds forming complexes with one calcium ion. Each compound gave very different conformers. Both lipoxin A and lipoxin B can form globular conformations, while their all-trans isomers form rigid extended structures. When complexes with each of these compounds and one calcium ion were examined (i.e., (LXA)2Ca: (11-trans-LXA)2Ca), both LXA and LXB formed several flexible conformations including crumpled, wrapped or extended conformations. In this situation, LXA showed a higher probability than LXB to wrap around one Ca2+. In contrast, the two all-trans isomers always lead to extended conformations. Results from the present study illustrate that changes in the stereochemistry of LXA and LXB lead to unique conformations which may underlie the different biological actions of these compounds. Moreover, they indicate that the conformations of eicosanoids can change while in aqueous or hydrophobic environments (i.e., biomembranes).

Arachidonate 15-Lipoxygenase↗

PubMedDate not supplied

Lipoxin analogs and lipoxin formation in vivo.

The definition of lipoxin bioactions in vivo and of lipoxin levels in humans, under physiological and pathological conditions, represents a main task toward the clinical use of lipoxins. The introduction of lipoxin stable analogs and of new methodology for immunological measurements of lipoxin A4 in human fluids is significantly contributing to fulfill this task. This chapter reviews the current literature on the use of lipoxin analogs, in vivo, and on measurements of lipoxin A4 in health and disease.

Aging↗

PubMed1991

Characterization of lipoxins by combined gas chromatography and electron-capture negative ion chemical ionization mass spectrometry: formation of lipoxin A4 by stimulated human whole blood.

The lipoxins are a recent addition to the family of bioactive products derived from arachidonic acid. Here, we have prepared pentafluorobenzyl ester, trimethylsilyl ether derivatives of lipoxin A4, lipoxin B4 and pentadeuterolipoxin A4 and have characterized these products by electron-capture negative ion chemical ionization gas chromatography/mass spectrometry (NICI GC/MS). Lipoxin A4 (5S,6R,15S-trihydroxy-7,9,13-trans-11-cis-eicosa-tetraenoic acid; LXA4) was quantified following extraction from whole blood by stable isotopic dilution utilizing deuterium-labeled LXA4 as internal standard and selected ion monitoring of the [M--pentafluorobenzyl] anions. Studies with a second tritiated internal standard (e.g. [11,12-3H]LXA4) also showed that the recovery of LXA4 was greater than 80% following solid-phase extraction from whole blood, and greater than 90% from isolated cells. In addition, neither isolated neutrophils nor platelets oxidatively metabolized [11,12-3H]LXA4 when incubated in the presence or absence of stimuli. Whole blood incubated with either the ionophore of divalent cations (A23187), thrombin, or thrombin plus the chemotactic peptide formylmethionyl-leucine-phenylalanine generated both LXA4 and thromboxane, which were quantified by stable isotope dilution. The ratio of thromboxane to LXA4 formed by stimulated whole blood ranged from approximately 2:1 to 20:1. These results indicate that the lipoxins display suitable characteristics as their respective pentafluorobenzyl ester, trimethylsilyl ether derivatives for quantification by electron-capture NICI GC/MS. Moreover, they provide evidence that LXA4 can be generated from endogenous sources in whole blood following exposure to physiologically relevant stimuli.

Adult↗

PubMed1988

Soybean lipoxygenase-catalyzed formation of lipoxin A and lipoxin B isomers from arachidonic acid via 5,15-dihydroperoxyeicosatetraenoic acid.

Soybean lipoxygenase converted arachidonic acid to a group of polar products (lambda max, 300-301 nm), which were increasingly formed during the continued incubation at 20 degrees C after the initial incubation (2 hrs, at 4 degrees C). These products were identified as lipoxin A and B isomers, based on the chromatographic and spectrometric analyses. In further chromatographic analyses, the lipoxin A and B isomers were separated into at least three isomers, respectively. The exposure of 5,15-dihydroperoxyeicosatetraenoic acid to the soybean lipoxygenase produced the identical product profile of chromatography, substantiating the intermediacy of 5,15-dihydroperoxyeicosatetraenoic acid in the soybean lipoxygenase-catalyzed formation of lipoxins. Based on these results, it is proposed that the conversion of arachidonic acid into lipoxins by soybean lipoxygenase may bear a mechanistic resemblance to the formation of lipoxins in the human leukocytes.

Arachidonate 5-Lipoxygenase↗

PubMed2006

Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent.

Control of inflammation is crucial to prevent damage to the host during infection. Lipoxins and aspirin-triggered lipoxins are crucial modulators of proinflammatory responses; however, their intracellular mechanisms have not been completely elucidated. We previously showed that lipoxin A4 (LXA4) controls migration of dendritic cells (DCs) and production of interleukin (IL)-12 in vivo. In the absence of LXA4 biosynthetic pathways, the resulting uncontrolled inflammation during infection is lethal, despite pathogen clearance. Here we show that lipoxins activate two receptors in DCs, AhR and LXAR, and that this activation triggers expression of suppressor of cytokine signaling (SOCS)-2. SOCS-2-deficient DCs are hyper-responsive to microbial stimuli, as well as refractory to the inhibitory actions of LXA4, but not to IL-10. Upon infection with an intracellular pathogen, SOCS-2-deficient mice had uncontrolled production of proinflammatory cytokines, decreased microbial proliferation, aberrant leukocyte infiltration and elevated mortality. We also show that SOCS-2 is a crucial intracellular mediator of the anti-inflammatory actions of aspirin-induced lipoxins in vivo.

Animals↗

PubMed2006

Glucocorticoids co-interact with lipoxin A4 via lipoxin A4 receptor (ALX) up-regulation.

Lipoxin A(4) (LXA(4)) is an eicosanoid which is produced via lipoxygenases and characteristic of its anti-inflammatory effect in many metabolites of arachidonic acid, which are mostly pro-inflammatory. Glucocorticoids are well known also for their strong anti-inflammatory action but induce 5-lipoxygenase, essential to synthesize leukotrienes, which are pro-inflammatory. To elucidate the interaction of glucocorticoids and lipoxin A(4) for anti-inflammation, we analyzed in vitro expression of lipoxin A(4) receptor (ALX) on human neutrophils and the in vivo anti-inflammatory effect of glucocorticoids and LXA(4) using a dermal inflammation mouse model. ALX mRNA was up-regulated by dexamethasone (Dex) in human neutrophils. A glucocorticoid receptor antagonist, mifepristone, suppressed up-regulation of ALX induced by Dex. LXA(4) and/or Dex decreased CD11b expression on human neutrophils and suppressed mouse dermatitis induced by LTB(4). These results suggest that anti-inflammatory effects of glucocorticoids depend at least partly on up-regulation of ALX and that the lipoxin system could be a negative feedback regulator for LTB(4).

Adult↗

PubMed1997

Lipoxins and novel aspirin-triggered 15-epi-lipoxins (ATL): a jungle of cell-cell interactions or a therapeutic opportunity?

Lipid-derived mediators play critical roles in inflammation and other multicellular vascular processes, including atherosclerosis and thrombosis. The lipoxins (LXs) were first isolated in 1984, and have continued to show intriguing and potentially important biological roles. These compounds carry a trihydroxytetraene structure and are both structurally and functionally unique among arachidonic acid-derived bioactive products. The availability of synthetic materials for evaluation of bioactions as well as appropriate methods of detection to determine when and where LX are generated has, in recent studies, catapulted our understanding of the formation and actions of the lipoxins. This mini-review addresses new concepts in the formation and biological roles of these lipid-derived mediators and considers whether the lipoxins and the newly discovered aspirin-triggered lipoxins (ATL) represent novel approaches for therapeutic opportunities. Recent findings indicate that select cytokines and aspirin initiate and regulate LX biosynthetic events. These circuits involve cell-cell interfacing that facilitates transcellular events to form LX that display anti-inflammatory actions in both in vitro and in vivo models. These recent results suggest that LX biosynthetic circuits assemble to evoke anti-inflammatory actions and generate LX that can serve as "stop signals" in appropriate microenvironments.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1989

Identification of a novel 7-cis-11-trans-lipoxin A4 generated by human neutrophils: total synthesis, spasmogenic activities and comparison with other geometric isomers of lipoxins A4 and B4.

Addition of (15S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid (15-HETE) and the ionophore A23187 (2.5 microM) to human neutrophils led to the formation of both lipoxin A4 and lipoxin B4 as well as a novel 5,6,15-trihydroxyeicosatetraenoic acid. The new compound was identified using an improved isolation and detection system and its basic structure was determined by physical methods. On the basis of biosynthetic considerations, geometric isomers of lipoxin A4 and lipoxin B4 were prepared by total synthesis. Comparison of these synthetic materials with the neutrophil-derived product showed that the new compound is (5S,6R,15S)-trihydroxy-9,11,13-trans-7-cis-eicosatetraenoic acid or the 7-cis-11-trans-isomer of LXA4 (7-cis-11-trans-LXA4). LXA4, 11-trans-LXA4, 7-cis-LXA4 and 7-cis-11-trans-LXA4 all evoked dose-dependent (0.1-10 microM) contractions of the guinea pig lung strip, whereas 6-cis-LXB4 and 6-cis-8-trans-LXB4 relaxed this preparation. LXA4 and 7-cis-LXA4 were approx. 10-times more potent than the compounds with 11-trans geometry. However, all four double-bond isomers of LXA4 caused contractions which, based upon pharmacological evidence, appeared to involve specific activation of the same site as cysteinyl-containing leukotrienes. In conclusion, 7-cis-11-trans-LXA4 was isolated and identified as a novel biologically active eicosanoid formed by human neutrophils.

Airway Resistance↗

PubMedDate not supplied

Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution.

Lipoxins (LXs) or the lipoxygenase interaction products are generated from arachidonic acid via sequential actions of lipoxygenases and subsequent reactions to give specific trihydroxytetraene-containing eicosanoids. These unique structures are formed during cell-cell interactions and appear to act at both temporal and spatially distinct sites from other eicosanoids produced during the course of inflammatory responses and to stimulate natural resolution. Lipoxin A4 (LXA4) and lipoxin B4 (LXB4) are positional isomers that each possesses potent cellular and in vivo actions. These LX structures are conserved across species. The results of numerous studies reviewed in this work now confirm that they are the first recognized eicosanoid chemical mediators that display both potent anti-inflammatory and pro-resolving actions in vivo in disease models that include rabbit, rat, and mouse systems. LXs act at specific GPCRs as agonists to regulate cellular responses of interest in inflammation and resolution. Aspirin has a direct impact in the LX circuit by triggering the biosynthesis of endogenous epimers of LX, termed the aspirin-triggered 15-epi-LX, that share the potent anti-inflammatory actions of LX. Stable analogs of LXA4, LXB4, and aspirin-triggered lipoxin were prepared, and several of these display potent actions in vitro and in vivo. The results reviewed herein implicate a role of LX and their analogs in many common human diseases including airway inflammation, asthma, arthritis, cardiovascular disorders, gastrointestinal disease, periodontal disease, kidney diseases and graft-vs.-host disease, as well as others where uncontrolled inflammation plays a key role in disease pathogenesis. Hence, the LX pathways and mechanisms reviewed to date in this work provide a basis for new approaches to treatment of many common human diseases that involve inflammation.

Animals↗

PubMed1988

Determination of picogram amounts of lipoxin A4 and lipoxin B4 by high-performance liquid chromatography with electrochemical detection.

A new method for the determination of lipoxins with electrochemical detection after high-performance liquid chromatography is described. The half-wave potentials of lipoxin A4 and lipoxin B4 at a glassy carbon electrode and a mobile phase of methanol-water (65:35 v/v) and 1 mM trifluoroacetic acid was found to be +1.14 V versus an Ag/AgCl reference electrode. The use of trifluoroacetic acid instead of sulphuric acid and lithium perchlorate led to a background current of 6-8 nA at +1.20 V. The detection limits for both lipoxins, based on a signal-to-noise ratio of 3:1 were found to be 5-10 pg (15-30 fmol). The new method was applied to an extract of human polymorphonuclear granulocytes, preincubated with 15-hydroxyeicosatetraenoic acid and stimulated with Ca2+ ionophore A23187.

Chemical Phenomena↗

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↗

PubMed1999

Lipoxin and aspirin-triggered 15-epi-lipoxin cellular interactions anti-inflammatory lipid mediators.

Eicosanoids are known to play important roles in inflammation. Recent findings have given rise to several new concepts regulating the generation of eicosanoids, illustrated in Figure 1. Lipoxins (LX) are trihydroxytetraene-containing eicosanoids that are generated within vascular lumen by platelet-leukocyte interactions and at mucosal surfaces by leukocyte-epithelial cell interactions. During these cell-cell interactions, transcellular biosynthetic pathways are used as major routes, and thus, in humans, LX are formed in vivo during multicellular responses such as inflammation, atherosclerosis, and thrombosis. This branch of the eicosanoid cascade generates specific tetraene-containing products that appear to function as stop signals, since they inhibit key steps in leukocyte-mediated inflammation. Of special interest, it appears that aspirin also functions in part via production of novel epimers of lipoxins or 15-epi-lipoxins (Figure 1). Here, we review recent developments on the cellular interactions of these novel anti-inflammatory mediators.

Amino Acid Sequence↗