Articoli di riviste: "Lipoxine A4"

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Busija, D. W., W. Armstead, C. W. Leffler e R. Mirro. "Lipoxins A4 and B4 dilate cerebral arterioles of newborn pigs". American Journal of Physiology-Heart and Circulatory Physiology 256, n. 2 (1 febbraio 1989): H468—H471. http://dx.doi.org/10.1152/ajpheart.1989.256.2.h468.

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We determined the effects of lipoxins A4 and B4 on the cerebral microcirculation of neonatal pigs and whether vascular responses were modulated by prostanoids. Pial arteriolar diameters were determined using a closed cranial window and intravital microscopy. Before lipoxin A4 application, arteriolar diameter was 143 +/- 6 microns (means +/- SE). Topical application of lipoxin A4 increased the diameter to 160 +/- 7 microns at 0.1 ng/ml, 167 +/- 7 microns at 1 ng/ml, and 173 +/- 7 microns at 10 ng/ml (n = 9). Before application of lipoxin B4, arteriolar diameter was 146 +/- 7 microns. Topical application of lipoxin B4 increased the diameter to 165 +/- 7, 169 +/- 6, and 175 +/- 6 microns at 0.1, 1, and 10 ng/ml (n = 9), respectively. Intravenous injection of indomethacin (5 mg/kg) or vehicle did not affect these responses. Levels of prostaglandins E2 and F2 alpha in cerebrospinal fluid (measured by radioimmunoassay) did not increase in response to lipoxins. We conclude that lipoxins are dilator stimuli in the cerebral circulation and that prostanoids do not mediate these responses.

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Chandrasekharan, Jayashree A., Xiao M. Huang, Alexander C. Hwang e Neelam Sharma-Walia. "Altering the Anti-inflammatory Lipoxin Microenvironment: a New Insight into Kaposi's Sarcoma-Associated Herpesvirus Pathogenesis". Journal of Virology 90, n. 24 (28 settembre 2016): 11020–31. http://dx.doi.org/10.1128/jvi.01491-16.

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ABSTRACTLipoxins are host anti-inflammatory molecules that play a vital role in restoring tissue homeostasis. The efficacy of lipoxins and their analog epilipoxins in treating inflammation and its associated diseases has been well documented. Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL) are two well-known inflammation related diseases caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Controlling inflammation is one of the strategies adopted to treat KS and PEL, a primary motivation for exploring and evaluating the therapeutic potential of using lipoxins. This study documents how KSHV manipulates and downregulates the secretion of the anti-inflammatory lipoxin A4 in host cells and the viral factors involved in this process usingin vitroKS and PEL cells as models. The presence of the lipoxin A4 receptor/formyl peptidyl receptor (ALX/FPR) in KS patient tissue sections andin vitroKS and PEL cell models offers a novel possibility for treating KS and PEL with lipoxins. Treatingde novoKSHV-infected endothelial cells with lipoxin and epilipoxin creates an anti-inflammatory environment by decreasing the levels of NF-κB, AKT, ERK1/2, COX-2, and 5-lipoxygenase. Lipoxin treatment on CRISPR/CAS9 technology-mediated ALX/FPR gene deletion revealed the importance of the lipoxin receptor ALX for effective lipoxin signaling. A viral microRNA (miRNA) cluster was identified as the primary factor contributing to the downregulation of lipoxin A4 secretion in host cells. The KSHV miRNA cluster probably targets enzyme 15-lipoxygenase, which is involved in lipoxin A4 synthesis. This study provides a new insight into the potential treatment of KS and PEL using nature's own anti-inflammatory molecule, lipoxin.IMPORTANCEKSHV infection has been shown to upregulate several host proinflammatory factors, which aid in its survival and pathogenesis. The influence of KSHV infection on anti-inflammatory molecules is not well studied. Since current treatment methods for KS and PEL are fraught with unwanted side effects and low efficiency, the search for new therapeutics is therefore imperative. The use of nature's own molecule lipoxin as a drug is promising. This study opens up new domains in KSHV research focusing on how the virus modulates lipoxin secretion and warrants further investigation of the therapeutic potential of lipoxin usingin vitrocell models for KS and PEL.

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Tułowiecka, Nikola, Dariusz Kotlęga, Andrzej Bohatyrewicz e Małgorzata Szczuko. "Could Lipoxins Represent a New Standard in Ischemic Stroke Treatment?" International Journal of Molecular Sciences 22, n. 8 (19 aprile 2021): 4207. http://dx.doi.org/10.3390/ijms22084207.

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Introduction: Cardiovascular diseases including stroke are one of the most common causes of death. Their main cause is atherosclerosis and chronic inflammation in the body. An ischemic stroke may occur as a result of the rupture of unstable atherosclerotic plaque. Cardiovascular diseases are associated with uncontrolled inflammation. The inflammatory reaction produces chemical mediators that stimulate the resolution of inflammation. One of these mediators is lipoxins—pro-resolving mediators that are derived from the omega-6 fatty acid family, promoting inflammation relief and supporting tissue regeneration. Aim: The aim of the study was to review the available literature on the therapeutic potential of lipoxins in the context of ischemic stroke. Material and Methods: Articles published up to 31 January 2021 were included in the review. The literature was searched on the basis of PubMed and Embase in terms of the entries: ‘stroke and lipoxin’ and ‘stroke and atherosclerosis’, resulting in over 110 articles in total. Studies that were not in full-text English, letters to the editor, and conference abstracts were excluded. Results: In animal studies, the injection/administration of lipoxin A4 improved the integrity of the blood–brain barrier (BBB), decreased the volume of damage caused by ischemic stroke, and decreased brain edema. In addition, lipoxin A4 inhibited the infiltration of neutrophils and the production of cytokines and pro-inflammatory chemokines, such as interleukin (Il-1β, Il-6, Il-8) and tumor necrosis factor-α (TNF-α). The beneficial effects were also observed after introducing the administration of lipoxin A4 analog—BML-111. BML-111 significantly reduces the size of a stroke and protects the cerebral cortex, possibly by reducing the permeability of the blood–brain barrier. Moreover, more potent than lipoxin A4, it has an anti-inflammatory effect by inhibiting the production of pro-inflammatory cytokines and increasing the amount of anti-inflammatory cytokines. Conclusions: Lipoxins and their analogues may find application in reducing damage caused by stroke and improving the prognosis of patients after ischemic stroke.

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Chiron, R., Y. Grumbach, Nga Vuthi Quynh, V. Verriere e V. Urbach. "116 Influence de l’antibiothérapie sur le taux d’IL-8 et de Lipoxine A4 dans les expectorations des patients atteints de mucoviscidose". Revue des Maladies Respiratoires 23, n. 5 (novembre 2006): 573. http://dx.doi.org/10.1016/s0761-8425(06)71944-1.

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Svensson, Camilla I., Michela Zattoni e Charles N. Serhan. "Lipoxins and aspirin-triggered lipoxin inhibit inflammatory pain processing". Journal of Experimental Medicine 204, n. 2 (22 gennaio 2007): 245–52. http://dx.doi.org/10.1084/jem.20061826.

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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.

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Grumbach, Y., N. Vu Thi Quynh e V. Urbach. "095 Effet de la lipoxine A4 sur l’expression de la zonula-occludens-1 et la formation des jonctions serrées dans l’épithelium bronchique". Revue des Maladies Respiratoires 23, n. 5 (novembre 2006): 562. http://dx.doi.org/10.1016/s0761-8425(06)71923-4.

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Romano, M., X. S. Chen, Y. Takahashi, S. Yamamoto, C. D. Funk e C. N. Serhan. "Lipoxin synthase activity of human platelet 12-lipoxygenase". Biochemical Journal 296, n. 1 (15 novembre 1993): 127–33. http://dx.doi.org/10.1042/bj2960127.

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Human platelets and megacaryocytes generate lipoxins from exogenous leukotriene A4 (LTA4). We examined the role of human 12-lipoxygenase (12-LO) in lipoxin generation with recombinant histidine-tagged human platelet enzyme (6His-12-LO), partially purified 12-LO from human platelets (HPL 12-LO) and, for the purposes of direct comparison, permeabilized platelets. Recombinant and HPL 12-LO catalysed the conversion of intact LTA4 into both lipoxin A4 (LXA4) and lipoxin B4 (LXB4). In contrast, only negligible quantities of LXA4 were generated when recombinant 12-LO was incubated with the non-enzymic hydrolysis products of LTA4.6His-12-LO also converted a non-allylic epoxide, 5(6)-epoxy-(8Z,11Z,14Z)-eicosatrienoic acid. The apparent Km and Vmax. for lipoxin synthase activity of 6His-12-LO were estimated to be 7.9 +/- 0.8 microM and 24.5 +/- 2.5 nmol/min per mg respectively, and the LXB4 synthase activity of this enzyme was selectively regulated by suicide inactivation. Aspirin gave a 2-fold increase in lipoxin formation by platelets but did not enhance the conversion of LTA4 by the recombinant 12-LO. These results provide direct evidence for LXA4 and LXB4 synthase activity of human platelet 12-LO. Moreover, they suggest that 12-LO is a dual-function enzyme that carries both oxygenase and lipoxin synthase activity.

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Tarannum, Fouzia, e Mohamed Faizuddin. "Effect of Alox-15 Polymorphism on GCF Levels of Lipoxin-A4 in Chronic Periodontitis: A Preliminary Study". Brazilian Dental Journal 28, n. 2 (aprile 2017): 140–47. http://dx.doi.org/10.1590/0103-6440201701094.

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Lipoxins play an important role in periodontal resolution, hence, investigation of genetic polymorphism of lipoxin gene may provide important information on the role of lipoxins in periodontal disease pathogenesis. The aim of this study was to investigate a polymorphism of C-to-T substitution at position c.-292 in ALOX15 (reticulocyte-type 15 lipoxygenase 1) gene in patients with chronic periodontitis and to associate the polymorphism with gingival crevicular fluid (GCF) lipoxin A4 (LXA4) levels. Forty-five chronic periodontitis and 45 periodontally healthy patients were included in this case-control study. Plaque index, calculus index, sulcus bleeding index, full mouth probing depth (PD) and clinical attachment loss (CAL) were recorded. GCF and blood samples were collected. GCF was analyzed for LXA4 levels by enzyme linked immunosorbant assay. Genotyping of ALOX15 polymorphism was studied using PCR. Mean LXA4 was lower in periodontitis group compared to the periodontally healthy group. There was a negative correlation between CAL and LXA4. The CC genotype was higher in the study group than in the control group. In the study group, mean CAL was significantly lower among individuals with the CT genotype. Mean LXA4 was significantly lower in CC genotype (45.0±7.11 ng/mL) compared to CT genotype (50.81±5.81 ng/mL) among the patients with periodontitis. The results suggest that LXA4 and c.-292T allele are associated with periodontal health. Polymorphisms in the ALOX15 gene may influence periodontal disease pathogenesis. Hence, investigation of such polymorphisms could benefit the evaluation of lipoxins role in periodontal disease.

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Yu, Suhui, Jianming Xie, Yukai Xiang, Shengjie Dai, Dinglai Yu, Hongwei Sun, Bicheng Chen e Mengtao Zhou. "Downregulation of TNF-α/TNF-R1 Signals by AT-Lipoxin A4 May Be a Significant Mechanism of Attenuation in SAP-Associated Lung Injury". Mediators of Inflammation 2019 (11 aprile 2019): 1–13. http://dx.doi.org/10.1155/2019/9019404.

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Our previous studies verified the potent anti-inflammatory effects against severe acute pancreatitis (SAP) of AT-Lipoxin A4 and their analogues. However, the anti-inflammatory effects of AT-Lipoxin A4 on SAP-associated lung injury are not thoroughly known. We used western blot, polymerase chain reaction (PCR), and immunofluorescence to investigate the downregulation of TNF-α signals in cellular and animal models of SAP-associated lung injury following AT-Lipoxin A4 intervention. In vitro, we found that AT-Lipoxin A4 markedly suppressed protein expression in TNF-α signals in human pulmonary microvascular endothelial cell, such as tumor necrosis factor receptor-associated factor 2 (TRAF2), TNF-R1-associated death domain (TRADD), receptor-interacting protein (RIP), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Moreover, AT-Lipoxin A4 inhibited downstream signals activated by TNF-α, including NF-κB/p65, JNK/MAPK, and ERK/MAPK. In vivo, AT-Lipoxin A4 significantly decreased pathological scores of the pancreas and lungs and the serum levels of IL-6 and TNF-α. Immunofluorescence, western blotting, and real-time PCR assay showed that AT-Lipoxin A4 significantly attenuated the expression of TNF-R1, TRADD, TRAF2, and RIP in the lungs of SAP rats. In addition, the activation of NF-κB was also downregulated by AT-Lipoxin A4 administration as compared with SAP rats. AT-Lipoxin A4 could inhibit the production of proinflammatory mediators and activation of TNF-α downstream signals such as NF-κB and MAPK. Downregulation of TNF-α signals by AT-Lipoxin A4 may be a significant mechanism in the attenuation of SAP-associated lung injury.

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Katoh, T., K. Takahashi, D. K. DeBoer, C. N. Serhan e K. F. Badr. "Renal hemodynamic actions of lipoxins in rats: a comparative physiological study". American Journal of Physiology-Renal Physiology 263, n. 3 (1 settembre 1992): F436—F442. http://dx.doi.org/10.1152/ajprenal.1992.263.3.f436.

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Interactions between either the arachidonate 5-lipoxygenase (5-LO) and 15-LO or 5-LO and 12-LO can lead to the formation of lipoxins. Although the functional significance of lipoxygenase products of arachidonic acid has been recognized increasingly in glomerular inflammation, less is known regarding the specific effects of lipoxins on renal hemodynamics. Here, we examine the renal actions of lipoxin (LX) A4, LXB4, and, the recently identified 7-cis-11-trans-LXA4, which were administered into the renal artery of the euvolemic male Munich-Wistar rat. LXA4 caused increases in renal plasma flow (RPF) and glomerular filtration rate (GFR) in a dose-dependent manner. These effects were reversed during cyclooxygenase inhibition. LXB4 decreased both RPF and GFR, and its mode of action was independent of cyclooxygenase activity. 7-cis-11-trans-LXA4 decreased RPF and GFR, which effects were abolished during systemic infusion of the leukotriene D4 receptor antagonist SKF 104353. Results indicate that each of these lipoxins displays distinct hemodynamic effects via a specific mode of action on the renal vasculature of rats. Moreover, they suggest mechanisms whereby lipoxins may participate in the changes of renal hemodynamics that occur during glomerular inflammatory processes.

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Prescott, David, e Derek M. McKay. "Aspirin-triggered lipoxin enhances macrophage phagocytosis of bacteria while inhibiting inflammatory cytokine production". American Journal of Physiology-Gastrointestinal and Liver Physiology 301, n. 3 (settembre 2011): G487—G497. http://dx.doi.org/10.1152/ajpgi.00042.2011.

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The macrophage plays a major role in the induction and resolution phases of inflammation; however, how lipid mediator-derived signals may modulate macrophage function in the resolution of inflammation driven by microbes (e.g., in inflammatory bowel disease) is not well understood. We examined the effects of aspirin-triggered lipoxin (ATL), a stable analog of lipoxin A4, on the antimicrobial responses of human peripheral blood mononuclear cell-derived macrophages and the monocytic THP-1 cell line. Additionally, we assessed the expression and localization of the lipoxin receptor, formyl peptide receptor 2 (FPR2), in colonic mucosal biopsies from patients with Crohn's disease to determine whether the capacity for lipoxin signaling is altered in inflammatory bowel disease. We found that THP-1 cells treated with ATL (100 nM) displayed increased phagocytosis of inert fluorescent beads and Escherichia coli in a scavenger receptor- and PI3K-dependent, opsonization-independent manner. This ATL-induced increase in phagocytosis was also observed in primary human macrophages, where it was associated with an inhibition of E. coli -induced IL-1β and IL-8 production. Finally, we found that FPR2 gene expression was increased approximately sixfold in the colon of patients with Crohn's disease, a finding reproduced in vitro by the treatment of THP-1 cells with interferon-γ or lipopolysaccharide. These results suggest that lipoxin signaling is upregulated in inflammatory environments, and, in addition to their known role in tissue resolution following injury, lipoxins can enhance macrophage clearance of invading microbes.

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Nascimento-Silva, V., M. A. Arruda, C. Barja-Fidalgo, C. G. Villela e I. M. Fierro. "Novel lipid mediator aspirin-triggered lipoxin A4 induces heme oxygenase-1 in endothelial cells". American Journal of Physiology-Cell Physiology 289, n. 3 (settembre 2005): C557—C563. http://dx.doi.org/10.1152/ajpcell.00045.2005.

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Lipoxins (LX) and aspirin-triggered LX (ATL) are eicosanoids generated during inflammation via transcellular biosynthetic routes that elicit distinct anti-inflammatory and proresolution bioactions, including inhibition of leukocyte-mediated injury, stimulation of macrophage clearance of apoptotic neutrophils, repression of proinflammatory cytokine production, and inhibition of cell proliferation and migration. Recently, it was reported that aspirin induces heme oxygenase-1 (HO-1) expression on endothelial cells (EC) in a COX-independent manner, what confers protection against prooxidant insults. However, the underlying mechanisms remain unclear. In this study, we investigated whether an aspirin-triggered lipoxin A4 stable analog, 15-epi-16-( para-fluoro)-phenoxy-lipoxin A4 (ATL-1) was able to induce endothelial HO-1. Western blot analysis showed that ATL-1 increased HO-1 protein expression associated with increased mRNA levels on EC in a time- and concentration-dependent fashion. This phenomenon appears to be mediated by the activation of the G protein-coupled LXA4 receptor because pertussis toxin and Boc-2, a receptor antagonist, significantly inhibited ATL-1-induced HO-1 expression. We demonstrate that treatment of EC with ATL-1 inhibited VCAM and E-selectin expression induced by TNF-α or IL-1β. This inhibitory effect of the analog is modulated by HO-1 because it was blocked by SnPPIX, a competitive inhibitor that blocks HO-1 activity. Our results establish that ATL-1 induces HO-1 in human EC, revealing an undescribed mechanism for the anti-inflammatory activity of these lipid mediators.

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Shanmugalingam, Renuka, XiaoSuo Wang, Penelope Motum, Ian Fulcher, Gaksoo Lee, Roshika Kumar, Annemarie Hennessy e Angela Makris. "The 15-Epilipoxin-A4 Pathway with Prophylactic Aspirin in Preventing Preeclampsia: A Longitudinal Cohort Study". Journal of Clinical Endocrinology & Metabolism 105, n. 12 (15 settembre 2020): e4811-e4822. http://dx.doi.org/10.1210/clinem/dgaa642.

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Abstract Introduction The benefit of aspirin in preventing preeclampsia is increasingly recognized; however, its mechanism of action remains unclear. Nonobstetric studies have described an anti-inflammatory effect of aspirin through the 15-epilipoxin-A4 pathway (aspirin-triggered lipoxin [ATL]). However, the anti-inflammatory mechanism of aspirin in the prevention of preeclampsia remains unknown. Objective/Hypothesis To examine (1) the difference in longitudinal endogenous lipoxin-A4 (En-Lipoxin-A4) concentration in low-risk (LR) and high-risk (HR) pregnancies, and (2) the effect of aspirin on endogenous ATL concentration and the associated effect on cytokine profile of HR women. Methods Plasma from 220 HR women was collected at 12, 16, 20, 24, 28, 32, and 36 weeks of gestation. Adherence to aspirin was biochemically verified. Plasma En-Lipoxin-A4 and ATL concentrations were analyzed using liquid chromatography mass spectrometry, and cytokines, interleukin (IL)-10, tumor necrosis factor-α, interferon-γ, IL-8, and IL-1β, with the high-sensitivity multibead Luminex® assay. Results HR women have up to 70% lower plasma concentration of En-Lipoxin-A4 (P < 0.001) than LR women. HR women with adequate aspirin adherence (HR-AA) (n = 82) had higher plasma concentration of ATL (P < .001), lower concentration of IL-8 from 16 to 36 weeks of gestation (P < .001), and increased IL-10 concentration from 16 to 28 weeks of gestation (P = .03) compared with high-risk women who were not on aspirin (HR-NA). HR-AA who did not develop preeclampsia had higher plasma En-lipoxin-A4 (P < .001), ATL (P = .02), and IL-10 concentrations (P < .001) with lower IL-8 concentration (P = .004) than HR women who developed preeclampsia. Discussion Plasma concentration of En-Lipoxin-A4 is lower in HR women than in LR controls. Adequate adherence with aspirin results in an increase in ATL and IL-10 with reduced IL-8 plasma concentration. This study suggests a potential anti-inflammatory role of aspirin through the ATL pathway with prophylactic aspirin in HR pregnant women.

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Simchowitz, L., S. Fiore e C. N. Serhan. "Carrier-mediated transport of lipoxin A4 in human neutrophils". American Journal of Physiology-Cell Physiology 267, n. 6 (1 dicembre 1994): C1525—C1534. http://dx.doi.org/10.1152/ajpcell.1994.267.6.c1525.

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Lipoxins and other eicosanoids display potent and selective biological effects on leukocytes. In this study, we utilized radiolabeled lipoxin A4 ([3H]LXA4) to investigate whether carrier-mediated transport of LXA4 might occur in human neutrophils. At a concentration of 5 nM, uptake of [3H]LXA4, above that due to specific binding to receptors, amounted to approximately 0.6 fmol.10(6) cells-1.min-1. This influx was sensitive to a number of anionic inhibitors, including 3,5-diiodosalicylic acid (K0.5 12 microM), pentachlorophenol (K0.5 25 microM), alpha-cyano-beta-(1-phenylindol-3-yl) acrylic acid, and the organomercurial agents mersalyl (K0.5 110 microM) and p-hydroxy-mercuribenzoate. Influx, which was Na+ and membrane voltage independent, exhibited a striking dependence on pH (negative log of dissociation 5.9), results compatible with an H+ + LXA4 anion cotransport system. The LXA4 carrier did not appear to interact with arachidonic acid, prostaglandin E2, 15(S)-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid, or the leukotrienes B4, C4, and D4. Moreover, transport activity was not observed in human erythrocytes, lymphocytes, or platelets, but it was inducible in HL-60 cells on differentiation by exposure to retinoic acid. These findings represent the identification and initial characterization of a novel carrier-mediated pathway in human neutrophils that facilitates transport of LXA4 into cells.

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Wang, Qi, Guang-xiao Xu, Qi-hang Tai e Yan Wang. "Lipoxin A4 Reduces Ventilator-Induced Lung Injury in Rats with Large-Volume Mechanical Ventilation". Mediators of Inflammation 2020 (22 novembre 2020): 1–8. http://dx.doi.org/10.1155/2020/6705985.

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Ventilator-induced lung injury (VILI) is a severe and inevitable complication in patients who require mechanical ventilation (MV) for respiratory support. Lipoxin A4 is an endogenous anti-inflammatory and antioxidant mediator. The present study determined the effects of lipoxin A4 on VILI. Twenty-four rats were randomized to the sham, VILI, and lipoxin A4 (LX4) groups. The rats in the VILI and LX4 groups received large-volume MV for 4 hours to simulate VILI. Capillary permeability was evaluated using the PaO2/FiO2 ratio, lung wet/dry weight ratio, and protein level in the lung. VILI-induced inflammation was assessed by measuring cytokines in serum and lung tissue, the expression and activity of NF-κB, and phosphorylated myosin light chain. The oxidative stress response, lung tissue injury, and apoptosis in lung tissue were also estimated, and the expression of apoptotic proteins was examined. MV worsened all of the indices compared to the sham group. Compared to the VILI group, the LX4 group showed significantly improved alveolar-capillary permeability (increased PaO2/FiO2 and decreased wet/dry weight ratios and protein levels), ameliorated histological injury, and reduced local and systemic inflammation (downregulated proinflammatory factors and NF-κB expression and activity). Lipoxin A4 notably inhibited the oxidative stress response and apoptosis and balanced apoptotic protein levels in lung tissue. Lipoxin A4 protects against VILI via anti-inflammatory, antioxidant, and antiapoptotic effects.

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Levy, Bruce D., Sherry Bertram, H. H. Tai, Elliot Israel, Andrew Fischer, Jeffrey M. Drazen e Charles N. Serhan. "Agonist-induced lipoxin A4 generation: Detection by a novel lipoxin A4-ELISA". Lipids 28, n. 12 (dicembre 1993): 1047–53. http://dx.doi.org/10.1007/bf02537069.

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Decker, Yann, Gethin McBean e Catherine Godson. "Lipoxin A4 inhibits IL-1β-induced IL-8 and ICAM-1 expression in 1321N1 human astrocytoma cells". American Journal of Physiology-Cell Physiology 296, n. 6 (giugno 2009): C1420—C1427. http://dx.doi.org/10.1152/ajpcell.00380.2008.

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There is a growing appreciation that endogenously produced mediators may actively promote the resolution of inflammation. Lipoxins (LX) are a group of recently discovered lipid mediators that have been shown to exert anti-inflammatory and proresolution effects on cells of myeloid and nonmyeloid origin. LXs mediate a number of processes, including regression of pro-inflammatory cytokine production, inhibition of cell proliferation, and stimulation of phagocytosis of apoptotic leukocytes by macrophages. Lipoxin A4 (LXA4) is one of the principal LXs formed by mammalian cells. Recently, a G protein-coupled receptor that binds LXA4, the lipoxin A4 receptor, was identified in astrocytes and microglia, suggesting that these cells may be a target for LX action in the brain. In this study, we have investigated the potential of LXA4 to modify inflammatory responses of astrocytes, using the 1321N1 human astrocytoma cell line as a model system. As shown by quantitative RT-PCR, LXA4 (10 nM) significantly inhibited ( P < 0.05) the IL-1β-induced stimulation of IL-8 and ICAM-1 expression in these cells. Furthermore, LXA4 (10 nM) decreased the expression of IL-1β-induced IL-8 protein levels ( P < 0.05). LXA4 (10 nM) was found to inhibit IL-1β-induced degradation of IκBα ( P < 0.05), and the activation of an NFκB regulated reporter gene construct ( P < 0.05). Overall, these data suggest that LXA4 exerts anti-inflammatory effects in 1321N1 astrocytoma cells at least in part via an NFκB-dependent mechanism. It is concluded that LXA4 may represent a potentially novel therapeutic approach to acute or chronic inflammation in the brain.

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Romano, Mario, Graziella Luciotti, Sebastiano Gangemi, Francesca Marinucci, Cesaria Prontera, Etrusca D'Urbano e Giovanni Davì. "Urinary Excretion of Lipoxin A4 and Related Compounds: Development of New Extraction Techniques for Lipoxins". Laboratory Investigation 82, n. 9 (settembre 2002): 1253–54. http://dx.doi.org/10.1097/01.lab.0000028823.53486.4a.

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Souza, Marcellus H. L. P., Octavio Menezes de Lima, Stella R. Zamuner, Stefano Fiorucci e John L. Wallace. "Gastritis increases resistance to aspirin-induced mucosal injury via COX-2-mediated lipoxin synthesis". American Journal of Physiology-Gastrointestinal and Liver Physiology 285, n. 1 (luglio 2003): G54—G61. http://dx.doi.org/10.1152/ajpgi.00525.2002.

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Products of cyclooxygenase (COX)-2 contribute to mucosal defense. Acetylation of COX-2 by aspirin has been shown to result in the generation of 15(R)-epi-lipoxin A4, which exerts protective effects in the stomach. In gastritis, it is possible that lipoxin A4 makes a greater contribution to mucosal defense. We tested this hypothesis in the rat, by using the iodoacetamide-induced gastritis model. Iodoacetamide was added to the drinking water for 5 days. Rats were then given aspirin, and the extent of gastric damage was blindly assessed 3 h later. Gastric 15(R)-epi-lipoxin A4 and PGE2 levels were determined. The effects of pretreatment with a selective COX-2 inhibitor, rofecoxib, and of a lipoxin receptor antagonist were assessed. Effects of aspirin and the other test drugs on leukocyte adherence within mesenteric venules were assessed by intravital microscopy. Aspirin elicited greater lipoxin synthesis in the inflamed than in the normal stomach, and there was reduced gastric damage. Rofecoxib inhibited lipoxin synthesis and exacerbated aspirin-induced damage. The lipoxin antagonist also exacerbated aspirin-induced damage. In rats with gastritis, aspirin reduced leukocyte adherence (in contrast to an increase in normal rats), and this effect was reversed by rofecoxib or by the lipoxin antagonist. These results support the notion that aspirin-triggered lipoxin synthesis via COX-2 makes an important contribution to mucosal defense in both the normal and inflamed stomach.

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Hashimoto, Atsushi, Yousuke Murakami, Hidero Kitasato, Izumi Hayashi e Hirahito Endo. "Glucocorticoids co-interact with lipoxin A4 via lipoxin A4 receptor (ALX) up-regulation". Biomedicine & Pharmacotherapy 61, n. 1 (gennaio 2007): 81–85. http://dx.doi.org/10.1016/j.biopha.2006.06.023.

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Paul-Clark, Mark J., Thong van Cao, Niloufar Moradi-Bidhendi, Dianne Cooper e Derek W. Gilroy. "15-epi-lipoxin A4–mediated Induction of Nitric Oxide Explains How Aspirin Inhibits Acute Inflammation". Journal of Experimental Medicine 200, n. 1 (5 luglio 2004): 69–78. http://dx.doi.org/10.1084/jem.20040566.

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Abstract (sommario):

The established model for the mechanism of action of aspirin is the inhibition of prostaglandin synthesis. However, this has never fully explained aspirin's repertoire of antiinflammatory properties. We found in acute pleuritis that aspirin, but not salicylate, indomethacin, or piroxicam, increased plasma nitric oxide (NO), which correlated with a reduction in inflammation. Inhibiting aspirin-elicited NO pharmacologically in this model nullified the antiinflammatory effects of aspirin. Moreover, aspirin was not antiinflammatory in either constitutive (eNOS) or inducible NO synthase (iNOS) knockout mice with IL-1β–induced peritonitis. It transpires that aspirin generates NO through its unique ability to trigger the synthesis of 15-epi-lipoxin A4. Aspirin and 15-epi-lipoxin A4 were shown to inhibit leukocyte trafficking in an NO-dependent manner using intravital microscopy on IL-1β–stimulated mouse mesentery. Not only did aspirin inhibit leukocyte–endothelial interaction in a manner similar to NO in wild-type mice but both aspirin and 15-epi-lipoxin A4 had markedly reduced effects on leukocyte–endothelial cell adherence in eNOS- and iNOS-deficient mice compared with wild type. Collectively, these data suggest that aspirin triggers the synthesis of 15-epi-lipoxin A4, which increases NO synthesis through eNOS and iNOS. This aspirin-elicited NO exerts antiinflammatory effects in the microcirculation by inhibiting leukocyte–endothelium interactions.

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22

Dias, Irundika H. K., e Helen R. Griffiths. "Current and Future Directions for Targeting Lipoxin A4 in Alzheimer’s Disease". Journal of Alzheimer's Disease 81, n. 1 (4 maggio 2021): 87–90. http://dx.doi.org/10.3233/jad-210121.

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Abstract (sommario):

Neuroinflammation has been implicated in Alzheimer’s disease onset and progression. Chronic neuroinflammation is initiated by amyloid-β-activated microglial cells that secrete immuno-modulatory molecules within the brain and into the vasculature. Inflammation is normally self-limiting and actively resolves by “switching off” the generation of pro-inflammatory mediators and by non-phlogistic clearance of spent cells and their debris to restore tissue homeostasis. Deficits in these anti-inflammatory/pro-resolution pathways may predispose to the development of chronic inflammation. The synthesis of endogenous lipid mediators from arachidonic acid, lipoxins via cyclooxygenase 2 and lipoxygenases, and conversion of exogenous polyunsaturated fatty acids, namely docosahexaenoic acid and eicosapentaenoic acid, to resolvins contributes to effective, timely resolution of acute inflammation. Work by Xiuzhe et al., 2020 in the Journal of Alzheimer’s Disease reported that plasma level of LXA4 is related to cognitive status in ischemic stroke patients suggesting that decreased LXA4 may be a potential risk factor for post post-stroke cognitive impairment. As evident by recent clinical trials and development of drug analogues, there is recent drive to search for lipoxin analogues as therapeutics for inflammatory diseases. Understanding how bioactive lipid signaling is involved in resolution will increase our understanding of controlling inflammation and may facilitate the discovery of new classes of therapeutic pro-resolution agents for evaluation in AD prevention studies.

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23

Fischer, Carrie D., Stephanie C. Duquette, Bernard S. Renaux, Troy D. Feener, Douglas W. Morck, Morley D. Hollenberg, Merlyn J. Lucas e Andre G. Buret. "Tulathromycin Exerts Proresolving Effects in Bovine Neutrophils by Inhibiting Phospholipases and Altering Leukotriene B4, Prostaglandin E2, and Lipoxin A4Production". Antimicrobial Agents and Chemotherapy 58, n. 8 (12 maggio 2014): 4298–307. http://dx.doi.org/10.1128/aac.02813-14.

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Abstract (sommario):

ABSTRACTThe accumulation of neutrophils and proinflammatory mediators, such as leukotriene B4(LTB4), is a classic marker of inflammatory disease. The clearance of apoptotic neutrophils, inhibition of proinflammatory signaling, and production of proresolving lipids (including lipoxins, such as lipoxin A4[LXA4]) are imperative for resolving inflammation. Tulathromycin (TUL), a macrolide used to treat bovine respiratory disease, confers immunomodulatory benefits via mechanisms that remain unclear. We recently reported the anti-inflammatory properties of TUL in bovine phagocytesin vitroand inMannheimia haemolytica-challenged calves. The findings demonstrated that this system offers a powerful model for investigating novel mechanisms of pharmacological immunomodulation. In the present study, we examined the effects of TUL in a nonbacterial model of pulmonary inflammationin vivoand characterized its effects on lipid signaling. In bronchoalveolar lavage (BAL) fluid samples from calves challenged with zymosan particles (50 mg), treatment with TUL (2.5 mg/kg of body weight) significantly reduced pulmonary levels of LTB4and prostaglandin E2(PGE2). In calcium ionophore (A23187)-stimulated bovine neutrophils, TUL inhibited phospholipase D (PLD), cytosolic phospholipase A2(PLA2) activity, and the release of LTB4. In contrast, TUL promoted the secretion of LXA4in resting and A23187-stimulated neutrophils, while levels of its precursor, 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE], were significantly lower. These findings indicate that TUL directly modulates lipid signaling by inhibiting the production of proinflammatory eicosanoids and promoting the production of proresolving lipoxins.

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24

Wu, B., J. A. Walker, D. Temmermand, K. Mian, B. Spur, A. Rodriguez, T. P. Stein, P. Banerjee e K. Yin. "Lipoxin A4 promotes more complete inflammation resolution in sepsis compared to stable lipoxin A4 analog". Prostaglandins, Leukotrienes and Essential Fatty Acids 89, n. 1 (luglio 2013): 47–53. http://dx.doi.org/10.1016/j.plefa.2013.04.005.

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25

Maddox, J. F., e C. N. Serhan. "Lipoxin A4 and B4 are potent stimuli for human monocyte migration and adhesion: selective inactivation by dehydrogenation and reduction." Journal of Experimental Medicine 183, n. 1 (1 gennaio 1996): 137–46. http://dx.doi.org/10.1084/jem.183.1.137.

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Abstract (sommario):

Monocyte recruitment and adherence are important events in inflammatory and vascular diseases. Here, we evaluated the actions of lipoxin A4 (LXA4) and LXB4, a series of lipoxygenase products from arachidonic acid generated by cell-cell interactions, on human monocytes. LXA4 and LXB4 (10(-7) M) each increased monocyte migration in chamber chemotaxis assays and, in migration under agarose, exhibited chemotactic indices similar to those of the chemotactic peptide formyl-methionyl-leucyl-phenylalanine at 10(-10)-10(-8) M and to the chemokine macrophage inflammatory protein-1 alpha (MIP-1 alpha) at 10(-8)-10(-7) M with a rank order of potency: Monocyte chemotactic protein-1 alpha > LXA4 approximately LXB4 approximately MIP-1 alpha. Lipoxins also stimulated monocyte adherence to laminin. In addition, human monocytes rapidly transformed LXA4 and LXB4 to several metabolites. LXB4 (> 80%) was converted within 30 s to new products, in a trend similar to that of LXA4. The novel monocyte-derived LXB4 products were identified as 5-oxo-6,7-dihydro-LXB4 and 6,7-dihydro-LXB4, indicating a role for site-selective dehydrogenation and reduction. Unlike monocytes, intact polymorphonuclear leukocytes (PMN) did not metabolize LXA4 in significant quantities, and only approximately 12% of exogenous LXB4 was omega-oxidized to 20-OH-LXB4 and 20-COOH-LXB4 by PMN. To determine if lipoxin conversion altered bioactivity, we evaluated the actions of these metabolites on monocytes. Each of the novel products of LXA4 and LXB4 from monocytes, namely oxo- and dihydrolipoxins, were essentially inactive in stimulating monocyte adherence. In contrast, the omega-oxidation products of LXB4 isolated from PMN were equipotent with LXB4 for monocyte adherence. Dehydrogenation of LXA4 in monocytes appears to be carried out by a 15-hydroxyprostaglandin dehydrogenase, which is present in human monocytes as determined by reverse transcription PCR and Western blots. Together, these results provide the first evidence that LXA4 and LXB4 are both potent stimulants for migration and adherence of human monocytes. Moreover, they underscore the importance of the major route of lipoxin metabolism in leukocytes, namely, the rapid dehydrogenation and inactivation carried out by monocytes.

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26

Hachicha, Mohamed, Marc Pouliot, Nicos A. Petasis e Charles N. Serhan. "Lipoxin (LX)A4 and Aspirin-triggered 15-epi-LXA4 Inhibit Tumor Necrosis Factor 1α–initiated Neutrophil Responses and Trafficking: Regulators of a Cytokine–Chemokine Axis". Journal of Experimental Medicine 189, n. 12 (21 giugno 1999): 1923–30. http://dx.doi.org/10.1084/jem.189.12.1923.

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Abstract (sommario):

The impact of lipoxin A4 (LXA4) and aspirin-triggered lipoxins (ATLs) was investigated in tumor necrosis factor (TNF)-α–initiated neutrophil (polymorphonuclear leukocyte) responses in vitro and in vivo using metabolically stable LX analogues. At concentrations as low as 1–10 nM, the LXA4 and ATL analogues each inhibited TNF-α–stimulated superoxide anion generation and IL-1β release by human polymorphonuclear leukocytes. These LXA4-ATL actions were time and concentration dependent and proved selective for TNF-α, as these responses were not altered with either GM-CSF– or zymosan-stimulated cells. TNF-α–induced IL-1β gene expression was also regulated by both anti-LXA4 receptor antibodies and LXA4-ATL analogues. In murine air pouches, 15R/S-methyl-LXA4 dramatically inhibited TNF-α–stimulated leukocyte trafficking, as well as the appearance of both macrophage inflammatory peptide 2 and IL-1β, while concomitantly stimulating IL-4 in pouch exudates. Together, these results indicate that both LXA4 and ATL regulate TNF-α–directed neutrophil actions in vitro and in vivo and stimulate IL-4 in exudates, playing a pivotal role in immune responses.

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27

Balode, Līga, Gunta Strazda, Normunds Jurka, Uldis Kopeika, Agnese Kislina, Māris Bukovskis, Marina Beinare, Valentīna Gardjušina e Immanuels Taivāns. "Lipoxygenase-Derived Arachidonic Acid Metabolites in Chronic Obstructive Pulmonary Disease". Medicina 48, n. 6 (5 novembre 2011): 43. http://dx.doi.org/10.3390/medicina48060043.

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Abstract (sommario):

Background and Objective. Chronic obstructive pulmonary disease (COPD) is characterized by a persistence of inflammation in large and small airways. We hypothesized that this could be caused by the inability of an inflammatory process to resolve. In the resolution of inflammation, a switching of arachidonic acid metabolism from the production of proinflammatory leukotriene B4 (LtB4) to the synthesis of anti-inflammatory lipoxins plays an important role. The aim of our study was to determine the content of lipoxin A4 (LXA4) and LtB4 in induced sputum of patients with exacerbated COPD and to compare it to healthy controls, as well as to analyze the relationship between proinflammatory and anti-inflammatory mediators and an inflammatory cell spectrum in induced sputum. Material and Methods. Induced sputum from 17 COPD patients and 7 healthy controls were analyzed for LXA4 and LtB4 content and inflammatory cell spectrum. Results. COPD patients had a significantly lower sputum LXA4 concentration and LtB4/LXA4 ratio compared with healthy controls. A significant negative correlation was found between the LXA4 concentration and the relative neutrophil count and between the LtB4/LXA4 ratio and the relative macrophage count. Conclusions. COPD patients during the late phase of exacerbation had a suppressed production of LXA4 and an elevated LtB4/LXA4 ratio in induced sputum demonstrating a proinflammatory imbalance. The correction of a balance between proinflammatory and anti-inflammatory eicosanoids by the administration of stable analogues of lipoxins could improve the treatment of chronic obstructive pulmonary disease in the future.

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28

Wenzel, Alexander, e Ger Van Zandbergen. "Lipoxin A4 receptor dependent leishmania infection". Autoimmunity 42, n. 4 (gennaio 2009): 331–33. http://dx.doi.org/10.1080/08916930902828239.

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29

Barja-Fidalgo, Christina, Vany Nascimento-Silva, Maria Arruda e Iolanda Fierro. "Aspirin-triggered lipoxin A4 blocks reactive oxygen species generation in endothelial cells: A novel antioxidative mechanism". Thrombosis and Haemostasis 97, n. 01 (2007): 88–98. http://dx.doi.org/10.1160/th06-06-0315.

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Abstract (sommario):

SummaryLipoxins 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 A4 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 p47phox 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-κB, 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.

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30

Rodrı́guez, A., M. Nomen, B. W. Spur, J. J. Godfroid e T. H. Lee. "Total synthesis of lipoxin A4 and lipoxin B4 from butadiene". Tetrahedron Letters 41, n. 6 (febbraio 2000): 823–26. http://dx.doi.org/10.1016/s0040-4039(99)02201-7.

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31

Titos, Esther, Nan Chiang, Charles N. Serhan, Mario Romano, Joan Gaya, Gloria Pueyo e Joan Clària. "Hepatocytes are a rich source of novel aspirin-triggered 15-epi-lipoxin A4". American Journal of Physiology-Cell Physiology 277, n. 5 (1 novembre 1999): C870—C877. http://dx.doi.org/10.1152/ajpcell.1999.277.5.c870.

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Abstract (sommario):

Novel aspirin (ASA)-triggered 15-epi-lipoxins (ATL) comprise new potent bioactive eicosanoids that may contribute to the therapeutic effect of this drug. ATL biosynthesis is initiated by ASA acetylation of cyclooxygenase (COX)-2 and was originally identified during the interaction of leukocytes with either endothelial or epithelial cells. Here, we examined ATL biosynthesis in rat hepatocytes either alone or in coincubation with nonparenchymal liver cells (NPC) and in liver homogenates from ASA-treated rats. Rat hepatocytes and CC-1 cells, a rat hepatocyte cell line, displayed COX-1 but not COX-2 mRNA expression and predominantly produced thromboxane A2(TXA2) and 15-hydroxyeicosatetraenoic acid (15-HETE). In these cells, ASA shifted the arachidonic acid metabolism from TXA2 to 15-HETE in a concentration-dependent manner. In contrast, neither indomethacin, ibuprofen, valeryl salicylate, nor nimesulide was able to trigger 15-HETE biosynthesis. SKF-525A, a cytochrome P-450 inhibitor, significantly reduced the effect of ASA on 15-HETE biosynthesis. Furthermore, phenobarbital, a potent inducer of cytochrome P-450 activity, further increased ASA-induced 15-HETE production. ASA treatment of hepatocyte-NPC coincubations resulted in the generation of significant amounts of ATL. In addition, in vivo experiments demonstrated augmented hepatic levels of 15-epi-lipoxin A4 in ASA-treated rats. Taken together and considering that ASA is hydrolyzed on its first pass through the portal circulation, these data indicate that, during ASA's consumption, liver tissue generates biologically relevant amounts of ATL by COX-2-independent mechanisms.

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32

Mitchell, S., K. Harvey, C. Godson e H. R. Brady. "Lipoxin A4-stimulated phagocytosis of apoptotic neutrophils (PMN) by macrophages: A novel anti-inflammatory bioaction of the lipoxins". Prostaglandins & Other Lipid Mediators 59, n. 1-6 (dicembre 1999): 25. http://dx.doi.org/10.1016/s0090-6980(99)90260-5.

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33

Chiang, Nan, Iolanda M. Fierro, Karsten Gronert e Charles N. Serhan. "Activation of Lipoxin a4 Receptors by Aspirin-Triggered Lipoxins and Select Peptides Evokes Ligand-Specific Responses in Inflammation". Journal of Experimental Medicine 191, n. 7 (3 aprile 2000): 1197–208. http://dx.doi.org/10.1084/jem.191.7.1197.

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Abstract (sommario):

Lipoxin (LX) A4 and aspirin-triggered LX (ATL) are endogenous lipids that regulate leukocyte trafficking via specific LXA4 receptors (ALXRs) and mediate antiinflammation and resolution. ATL analogues dramatically inhibited human neutrophil (polymorphonuclear leukocyte [PMN]) responses evoked by a potent necrotactic peptide derived from mitochondria as well as a rogue synthetic chemotactic peptide. These bioactive lipid analogues and small peptides each selectively competed for specific 3H-LXA4 binding with recombinant human ALXR, and its N-glycosylation proved essential for peptide but not LXA4 recognition. Chimeric receptors constructed from receptors with opposing functions, namely ALXR and leukotriene B4 receptors (BLTs), revealed that the seventh transmembrane segment and adjacent regions of ALXR are essential for LXA4 recognition, and additional regions of ALXR are required for high affinity binding of the peptide ligands. Together, these findings are the first to indicate that a single seven-transmembrane receptor can switch recognition as well as function with certain chemotactic peptides to inhibitory with ATL and LX (lipid ligands). Moreover, they suggest that ALXR activation by LX or ATL can protect the host from potentially deleterious PMN responses associated with innate immunity as well as direct effector responses in tissue injury by recognition of peptide fragments.

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34

Macdonald, Linsay J., Sheila C. Boddy, Fiona C. Denison, Kurt J. Sales e Henry N. Jabbour. "A role for lipoxin A4 as an anti-inflammatory mediator in the human endometrium". REPRODUCTION 142, n. 2 (agosto 2011): 345–52. http://dx.doi.org/10.1530/rep-11-0021.

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Abstract (sommario):

Lipoxin A4is 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 A4and 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 A4by ELISA revealed no difference in its levels across the menstrual cycle but an elevation in early pregnancy (P<0.001). We found that lipoxin A4was regulated by human chorionic gonadotrophin (hCG) during early pregnancy, because treatment of human decidua tissue with hCG increased lipoxin A4release (P<0.01). Finally, we have shown that lipoxin A4can 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 A4and its receptor FPR2/ALX can regulate inflammatory events in the human endometrium and decidua of early pregnancy.

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35

Brancaleone, Vincenzo, Thomas Gobbetti, Nicolas Cenac, Pauline le Faouder, Bartomeu Colom, Roderick J. Flower, Nathalie Vergnolle, Sussan Nourshargh e Mauro Perretti. "A vasculo-protective circuit centered on lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 operative in murine microcirculation". Blood 122, n. 4 (25 luglio 2013): 608–17. http://dx.doi.org/10.1182/blood-2013-04-496661.

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Abstract (sommario):

Key Points Fpr2/3 activation controls platelet/neutrophil aggregates to afford LXA4 synthesis, thus inhibiting vascular inflammation on reperfusion. Aspirin can jumpstart this circuit by triggering 15-epi-lipoxin synthesis.

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36

Kong, Xia, Sheng-Hua Wu, Li Zhang e Xiao-Qing Chen. "Pilot application of lipoxin A4 analog and lipoxin A4 receptor agonist in asthmatic children with acute episodes". Experimental and Therapeutic Medicine 14, n. 3 (12 luglio 2017): 2284–90. http://dx.doi.org/10.3892/etm.2017.4787.

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37

Fiore, Stefano, e Charles N. Serhan. "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". Biochemistry 34, n. 51 (dicembre 1995): 16678–86. http://dx.doi.org/10.1021/bi00051a016.

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38

Lee, Tak H., Claire E. Horton, U. Kyan-Aung, Dorian Haskard, Atttlio E. G. Crea e Bernd W. Spur. "Lipoxin A4 and Lipoxin B4 Inhibit Chemotactic Responses of Human Neutrophils Stimulated by Leukotriene B4 and N-Formyl-l-Methionyl-l-Leucyl-l-Phenylalanine". Clinical Science 77, n. 2 (1 agosto 1989): 195–203. http://dx.doi.org/10.1042/cs0770195.

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Abstract (sommario):

1. Lipoxin A4 (LXA4) and lipoxin B4 (LXB4) have been evaluated for their capacities to modulate neutrophil (PMN) migration and endothelial cell adherence using compounds prepared by total chemical synthesis. 2. Increased PMN migration was seen with concentrations of LXA4 from 10−9 mol/l to 10−7 mol/l. LXA4 was 100-fold less potent than leukotriene B4 (LTB4) and it elicited only one-half of the maximal response of LTB4. 3. The (5S,6S,15S)-isomer of LXA4 induced only a weak migratory response and LXB4 was inactive, suggesting that the activity of LXA4 was stereospecific. 4. Modified chequerboard analysis indicated that LXA4 was a chemokinetic agent. 5. Preincubation of PMN with increasing concentrations of LXA4 induced a very similar dose- and time-dependent inhibition of the subsequent response to 10−7 mol/l LTB4 or 10−7 mol/l N-formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP). The inhibition was observed at 10−10 mol/l LXA4; the concentration which produced 50% inhibition was 10−8 mol/l and 100% inhibition of PMN locomotion occurred at 10−6 mol/l LXA4. 6. The (5S,6S,15S)-isomers of LXA4 and LXB4 were 5- and 100-fold less potent than LXA4, respectively, in suppressing LTB4- or FMLP-induced PMN migration. 7. Preincubation of PMN with LXA4 led to a suppression of calcium mobilization, as assessed by Quin2-AM fluorescence, when the cells were subsequently stimulated under optimal conditions by LTB4 or FMLP. 8. These results suggest that the inhibitory activity of lipoxins may be related to the capacity of these molecules to regulate calcium ion mobilization. 9. LXA4 and LXB4 did not promote PMN adherence to human endothelial cell monolayers and they did not modulate FMLP-stimulated PMN-endothelial cell adhesion.

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39

Lee, T. H. "Lipoxin A4: a novel anti-inflammatory molecule?" Thorax 50, n. 2 (1 febbraio 1995): 111–12. http://dx.doi.org/10.1136/thx.50.2.111.

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40

Maderna, Paola, Catherine Godson, Gary Hannify, Madeline Murphy e Hugh R. Brady. "Influence of lipoxin A4 and other lipoxygenase-derived eicosanoids on tissue factor expression". American Journal of Physiology-Cell Physiology 279, n. 4 (1 ottobre 2000): C945—C953. http://dx.doi.org/10.1152/ajpcell.2000.279.4.c945.

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Abstract (sommario):

Lipoxins (LX) are eicosanoids generated via transcellular biosynthetic routes during inflammation, hypersensitivity reaction, and after angioplasty. LXs are modulators of leukocyte trafficking and vascular tone. Their influence on the coagulation cascade has not been determined. In this study, we evaluated the influence of LXs on the expression of tissue factor (TF), a key regulator of coagulation. TF activity was measured in lysates of monocytes, human umbilical vein endothelial cells, and ECV304 cells using a one-stage clotting assay. LXA4 stimulated TF activity in each cell type. The influence of LXA4 on TF activity by ECV304 cells was studied further to explore the mechanism of induction of TF expression. LXA4-induced TF activity was dose dependent, cycloheximide sensitive, and associated with increased TF mRNA levels. Induction of TF activity was specific for LXA4 and was not observed with LXB4, the other major lipoxin generated by mammalian cells. Furthermore, ECV304 cell TF expression was not influenced by 15( R/S)-methyl-LXA4 or 16-phenoxy-LXA4, synthetic analogs of LXA4 that activate the myeloid LXA4 receptor, and was not modulated by SKF-104353, which blocks LXA4 bioactivities transduced through the putative shared LXA4/LTD4 receptor. LXA4-stimulated TF expression was blunted by pertussis toxin and by GF-109203X, an inhibitor of protein kinase C, and was not associated with degradation of IκBα. Our results establish that LXA4 induces TF activity via cell signaling pathways with different structural and receptor requirements from those described for inhibition of leukocyte-endothelial cell interactions. They suggest a role for LXA4 as a modulator of TF-related vascular events during inflammation and thrombosis.

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Fierro, Iolanda M., Jeffery L. Kutok e Charles N. Serhan. "Novel Lipid Mediator Regulators of Endothelial Cell Proliferation and Migration: Aspirin-Triggered-15R-Lipoxin A4 and Lipoxin A4". Journal of Pharmacology and Experimental Therapeutics 300, n. 2 (1 febbraio 2002): 385–92. http://dx.doi.org/10.1124/jpet.300.2.385.

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42

Gronert, Karsten, Andrew Gewirtz, James L. Madara e Charles N. Serhan. "Identification of a Human Enterocyte Lipoxin A4 Receptor That Is Regulated by Interleukin (IL)-13 and Interferon γ and Inhibits Tumor Necrosis Factor α–induced IL-8 Release". Journal of Experimental Medicine 187, n. 8 (20 aprile 1998): 1285–94. http://dx.doi.org/10.1084/jem.187.8.1285.

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Abstract (sommario):

Epithelial cells of the alimentary tract play a central role in mucosal immunophysiology. Pathogens and/or agonists that interact with mucosal surfaces often elicit epithelial responses that upregulate inflammation. Therefore, it was of interest to explore potential epithelial targeted antiinflammatory signals. Here we identified and sequenced a human enterocyte lipoxin (LX) A4 [5(S),6(R),15(S)-trihydroxy-7,9,13-trans-11-cis eicosatetraenoic acid] receptor, and demonstrate that transcription of this receptor was controlled by cytokines, of which lymphocyte-derived interleukin (IL)-13 and interferon γ were the most potent. When lipoxins and LXA4 stable analogs were evaluated for enterocyte functional as well as immune responses, lipoxins sharply inhibited TNF-α–induced IL-8 release but did not alter either barrier function or agonist-stimulated chloride secretion. 15R/S-methyl-LXA4 and 16-phenoxy-LXA4 each attenuated (IC50 ∼10 nM) IL-8 release. Cyclooxygenase (COX) II is emerging as an important component in wound healing and proliferation in intestinal epithelia and when acetylated by acetylsalicylic acid (aspirin) initiates the biosynthesis of a LXA4 receptor ligand. We therefore determined whether colonic cell lines (HT-29 Cl.19A, Caco-2, or T84) express the COX II isozyme. Results for RT-PCR and Western blot analysis showed that COX I as well as an IL-1β– and TNF-α–inducible COX II are expressed in HT-29 Cl.19A. In addition, aspirin-treated enterocytes generated 15R-HETE, a precursor of 15-epi-LXA4 biosynthesis, whose potent bioactions were mimicked by the stable analog 15R/S-methyl-LXA4. Taken together, these results identify an endogenous pathway for downregulating mucosal inflammatory events and suggest a potential therapeutic benefit for LXA4 stable analogs.

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43

Martini, Alessandra Cadete, Stefânia Forner, Allisson Freire Bento e Giles Alexander Rae. "Neuroprotective Effects of Lipoxin A4 in Central Nervous System Pathologies". BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/316204.

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Abstract (sommario):

Many diseases of the central nervous system are characterized and sometimes worsened by an intense inflammatory response in the affected tissue. It is now accepted that resolution of inflammation is an active process mediated by a group of mediators that can act in synchrony to switch the phenotype of cells, from a proinflammatory one to another that favors the return to homeostasis. This new genus of proresolving mediators includes resolvins, protectins, maresins, and lipoxins, the first to be discovered. In this short review we provide an overview of current knowledge into the cellular and molecular interactions of lipoxins in diseases of the central nervous system in which they appear to facilitate the resolution of inflammation, thus exerting a neuroprotective action.

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44

Fiore, S., S. W. Ryeom, P. F. Weller e C. N. Serhan. "Lipoxin recognition sites. Specific binding of labeled lipoxin A4 with human neutrophils." Journal of Biological Chemistry 267, n. 23 (agosto 1992): 16168–76. http://dx.doi.org/10.1016/s0021-9258(18)41982-5.

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Nicolaou, K. C., B. E. Marron, C. A. Veale, S. E. Webber e C. N. Serhan. "Total synthesis of novel geometric isomers of lipoxin A4 and lipoxin B4". Journal of Organic Chemistry 54, n. 23 (novembre 1989): 5527–35. http://dx.doi.org/10.1021/jo00284a026.

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46

Rodriguez, A., M. Nomen, B. W. Spur, J. J. Godfroid e T. H. Lee. "ChemInform Abstract: Total Synthesis of Lipoxin A4 and Lipoxin B4 from Butadiene." ChemInform 31, n. 16 (9 giugno 2010): no. http://dx.doi.org/10.1002/chin.200016251.

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Szczuko, Małgorzata, Joanna Palma, Justyna Kikut, Natalia Komorniak e Maciej Ziętek. "Changes of lipoxin levels during pregnancy and the monthly-cycle, condition the normal course of pregnancy or pathology". Inflammation Research 69, n. 9 (2 giugno 2020): 869–81. http://dx.doi.org/10.1007/s00011-020-01358-6.

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Abstract Objective and Design The purpose of the review was to gather information on the role and possibilities of using lipoxin in the treatment of infertility and maintaining a normal pregnancy. Ovulation, menstruation, embryo implantation, and childbirth are reactions representing short-term inflammatory events involving lipoxin activities. Lipoxin A4 (LXA4) is an arachidonic acid metabolite, and in cooperation with its positional isomer lipoxin B4 (LXB4), it is a major lipoxin in mammals. Biosynthesis process occurs in two stages: in the first step, the donor cell releases the eicosanoid intermediate; secondarily, the acceptor cell gets and converts the intermediate product into LXA4 (leukocyte/platelet interaction). Results Generating lipoxin synthesis may also be triggered by salicylic acid, which acetylates cyclooxygenase-2. Lipoxin A4 and its analogues are considered as specialized pro-resolving mediators. LXA4 is an important component for a proper menstrual cycle, embryo implantation, pregnancy, and delivery. Its level in the luteal phase is high, while in the follicular phase, it decreases, which coincides with an increase in estradiol concentration with which it competes for the receptor. LXA4 inhibits the progression of endometriosis. However, during the peri-implantation period, before pregnancy is confirmed clinically, high levels of LXA4 can contribute to early pregnancy loss and may cause miscarriage. After implantation, insufficient LXA4 levels contribute to incorrect maternal vessel remodeling; decreased, shallow trophoblastic invasion; and the immuno-energetic abnormality of the placenta, which negatively affects fetal growth and the maintenance of pregnancy. Moreover, the level of LXA4 increases in the final stages of pregnancy, allowing vessel remodeling and placental separation. Methods The review evaluates the literature published in the PubMed and Embase database up to 31 December 2019. The passwords were checked on terms: lipoxin and pregnancy with combined endometriosis, menstrual cycle, implantation, pre-eclampsia, fetal growth restriction, and preterm labor. Conclusions Although no human studies have been performed so far, the cell and animal model study results suggest that LXA4 will be used in obstetrics and gynecology soon.

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Köhnke, Thomas, Beate Gomolka, Süleyman Bilal, Xiangzhi Zhou, Yanping Sun, Michael Rothe, Daniel C. Baumgart e Karsten H. Weylandt. "Acetylsalicylic Acid Reduces the Severity of Dextran Sodium Sulfate-Induced Colitis and Increases the Formation of Anti-Inflammatory Lipid Mediators". BioMed Research International 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/748160.

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The role of non-steroidal anti-inflammatory drugs in inflammatory bowel disease is controversial, as they have been implicated in disease aggravation. Different from other cyclooxygenase inhibitors, acetylsalicylic acid (ASA) enhances the formation of anti-inflammatory and proresolution lipoxins derived from arachidonic acid as well as resolvins from omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA). In this study, we examined the effect of ASA on murine dextran sodium sulfate colitis. A mouse magnetic resonance imaging (MRI) protocol and post mortem assessment were used to assess disease severity, and lipid metabolites were measured using liquid chromatography-coupled tandem mass spectrometry. Decreased colitis activity was demonstrated by phenotype and MRI assessment in mice treated with ASA, and confirmed in postmortem analysis. Analysis of lipid mediators showed sustained formation of lipoxin A4 and an increase of DHA-derived 17-hydroxydocosahexaenoic acid (17-HDHA) after treatment with ASA. Furthermore,in vitroexperiments in RAW264.7 murine macrophages demonstrated significantly increased phagocytosis activity after incubation with 17-HDHA, supporting its proresolution effect. These results show a protective effect of ASA in a murine colitis model and could give a rationale for a careful reassessment of ASA therapy in patients with inflammatory bowel disease and particularly ulcerative colitis, possibly combined with DHA supplementation.

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Han, Xue, Weifeng Yao, Zipeng Liu, Haobo Li, Zhong-jun Zhang, Ziqing Hei e Zhengyuan Xia. "Lipoxin A4 Preconditioning Attenuates Intestinal Ischemia Reperfusion Injury through Keap1/Nrf2 Pathway in a Lipoxin A4 Receptor Independent Manner". Oxidative Medicine and Cellular Longevity 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/9303606.

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Oxidative stress plays a critical role in the pathogenesis of intestinal ischemia reperfusion (IIR) injury. Enhancement in endogenous Lipoxin A4 (LXA4), a potent antioxidant and mediator, is associated with attenuation of IIR. However, the effects of LXA4 on IIR injury and the potential mechanisms are unknown. In a rat IIR (ischemia 45 minutes and subsequent reperfusion 6 hours) model, IIR caused intestinal injury, evidenced by increased serum diamine oxidase, D-lactic acid, intestinal-type fatty acid-binding protein, and the oxidative stress marker 15-F2t-Isoprostane. LXA4 treatment significantly attenuated IIR injury by reducing mucosal 15-F2t-Isoprostane and elevating endogenous antioxidant superoxide dismutase activity, accompanied with Keap1/Nrf2 pathway activation. Meanwhile, LXA4 receptor antagonist Boc-2 reversed the protective effects of LXA4 on intestinal injury but failed to affect the oxidative stress and the related Nrf2 pathway. Furthermore, Nrf2 antagonist brusatol reversed the antioxidant effects conferred by LXA4 and led to exacerbation of intestinal epithelium cells oxidative stress and apoptosis, finally resulting in a decrease of survival rate of rat. Meanwhile, LXA4 pretreatment upregulated nuclear Nrf2 level and reduced hypoxia/reoxygenation-induced IEC-6 cell damage and Nrf2 siRNA reversed this protective effect of LXA4in vitro. In conclusion, these findings suggest that LXA4 ameliorates IIR injury by activating Keap1/Nrf2 pathway in a LXA4 receptor independent manner.

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Chinthamani, Sreedevi, Olutayo Odusanwo, Nandini Mondal, Joel Nelson, Sriram Neelamegham e Olga J. Baker. "Lipoxin A4inhibits immune cell binding to salivary epithelium and vascular endothelium". American Journal of Physiology-Cell Physiology 302, n. 7 (1 aprile 2012): C968—C978. http://dx.doi.org/10.1152/ajpcell.00259.2011.

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Lipoxins are formed by leukocytes during cell-cell interactions with epithelial or endothelial cells. Native lipoxin A4(LXA4) binds to the G protein-coupled lipoxin receptors formyl peptide receptor 2 (FPR2)/ALX and CysLT1. Furthermore, LXA4inhibits recruitment of neutrophils, by attenuating chemotaxis, adhesion, and transmigration across vascular endothelial cells. LXA4thus appears to serve as an endogenous “stop signal” for immune cell-mediated tissue injury (Serhan CN; Annu Rev Immunol 25: 101–137, 2007). The role of LXA4has not been addressed in salivary epithelium, and little is known about its effects on vascular endothelium. Here, we determined that interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) receptor activation in vascular endothelium and salivary epithelium upregulated the expression of adhesion molecules that facilitates the binding of immune cells. We hypothesize that the activation of the ALX/FPR2 and/or CysLT1 receptors by LXA4decreases this cytokine-mediated upregulation of cell adhesion molecules that enhance lymphocyte binding to both the vascular endothelium and salivary epithelium. In agreement with this hypothesis, we observed that nanomolar concentrations of LXA4blocked IL-1β- and TNF-α-mediated upregulation of E-selectin and intercellular cell adhesion molecule-1 (ICAM-1) on human umbilical vein endothelial cells (HUVECs). Binding of Jurkat cells to stimulated HUVECs was abrogated by LXA4. Furthermore, LXA4preincubation with human submandibular gland cell line (HSG) also blocked TNF-α-mediated upregulation of vascular cell adhesion molecule-1 (VCAM-1) in these cells, and it reduced lymphocyte adhesion. These findings suggest that ALX/FPR2 and/or CysLT1 receptor activation in endothelial and epithelial cells blocks cytokine-induced adhesion molecule expression and consequent binding of lymphocytes, a critical event in the pathogenesis of Sjögren's syndrome (SS).

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