Unorthodox routes to prostanoid formation: new twists in cyclooxygenase-initiated pathways

Serhan, Charles N.; Oliw, Ernst H.

doi:10.1172/jci13375

Cited by 135 publications

(109 citation statements)

References 70 publications

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“…Expanding on this concept, we define thromboregulation as a process or group of processes by which circulating hematologic cells and cells of the vessel wall interact to regulate or inhibit thrombus formation. Essentially, all thromboregulatory reactions are biochemical in nature and result in formation of biologically active metabolites that could have only arisen through interactions between heterogeneous cell types in the vasculature (Marcus et al, 1980(Marcus et al, , 1982(Marcus et al, , 1988Valles et al, 1993Valles et al, , 2002Serhan and Oliw, 2001). Thromboregulation is accomplished by biological compounds that are either cellassociated or released from the cell into the fluid-phase microenvironment.…”

Section: Hemostasis and Thrombosis As Models Of Cell-cell Interactionsmentioning

confidence: 99%

Metabolic Control of Excessive Extracellular Nucleotide Accumulation by CD39/Ecto-Nucleotidase-1: Implications for Ischemic Vascular Diseases

Marcus

Broekman

Drosopoulos

et al. 2003

J Pharmacol Exp Ther

121

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Platelets are responsible for maintaining vascular integrity. In thrombocytopenic states, vascular permeability and fragility increase, presumably due to the absence of this platelet function. Chemical or physical injury to a blood vessel induces platelet activation and platelet recruitment. This is beneficial for the arrest of bleeding (hemostasis), but when an atherosclerotic plaque is ulcerated or fissured, it becomes an agonist for vascular occlusion (thrombosis). Experiments in the late 1980s cumulatively indicated that endothelial cell CD39 -an ecto-ADPase-reduced platelet reactivity to most agonists, even in the absence of prostacyclin or nitric oxide. As discussed herein, CD39 rapidly and preferentially metabolizes ATP and ADP released from activated platelets to AMP, thereby drastically reducing or even abolishing platelet aggregation and recruitment. Since ADP is the final common agonist for platelet recruitment and thrombus formation, this finding highlights the significance of CD39. A recombinant, soluble form of human CD39, solCD39, has enzymatic and biological properties identical to the full-length form of the molecule and strongly inhibits human platelet aggregation induced by ADP, collagen, arachidonate, or TRAP (thrombin receptor agonist peptide). In sympathetic nerve endings isolated from guinea pig hearts, where neuronal ATP enhances norepinephrine exocytosis, solCD39 markedly attenuated norepinephrine release. This suggests that NTPDase (nucleoside triphosphate diphosphohydrolase) could exert a cardioprotective action by reducing ATP-mediated norepinephrine release, thereby offering a novel therapeutic approach to myocardial ischemia and its consequences. In a murine model of stroke, driven by excessive platelet recruitment, solCD39 reduced the sequelae of stroke, without an increase in intracerebral hemorrhage. CD39 null mice, generated by deletion of apyrase-conserved regions 2 to 4, exhibited a decrease in postischemic perfusion and an increase in cerebral infarct volume when compared with controls. "Reconstitution" of CD39 null mice with solCD39 reversed these changes. We hypothesize that solCD39 has potential as a novel therapeutic agent for thrombotic diatheses. The Hemostatic MechanismThe hemostatic process consists of a series of physiologic and biochemical reactions that culminate in the arrest of bleeding from blood vessels that have been severed or traumatized physically or chemically. Hemostasis is accomplished via the interaction of three biological systems: 1) components of the vasculature per se, including endothelial cells; 2) blood platelets; and 3) plasma proteins comprising the intrinsic and extrinsic coagulation pathways (Marcus, 1999). Qualitative or quantitative deficiencies in any one of these systems result in a defect of hemostasis, coagulation, or both. These abnormalities can lead to a hemorrhagic diathesis that is clinically mild, moderate, or severe. -methyladenosine-3Ј,5Ј-diphosphate; NTPDase, nucleoside triphosphate diphosphohydrolase.

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Section: Hemostasis and Thrombosis As Models Of Cell-cell Interactionsmentioning

confidence: 99%

Metabolic Control of Excessive Extracellular Nucleotide Accumulation by CD39/Ecto-Nucleotidase-1: Implications for Ischemic Vascular Diseases

Marcus

Broekman

Drosopoulos

et al. 2003

J Pharmacol Exp Ther

121

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“…15R-HETE can also be converted by neutrophils and other cells to 15-epi-LXA 4 . LXA 4 and 15-epi LXA 4 are rapidly generated in response to specific signals, act locally, and then are quickly inactivated by conversion to 15-oxocontaining metabolites in monocytes (1)(2)(3). A series of metabolically resistant LXA 4 analogues (e.g., 15-epi-16-( p-fluoro)-phenoxy-LXA 4 -methyl ester or aspirin-triggered LXA 4 -stable analog (ATLa)) were designed and synthesized to prevent this rapid inactivation (4).…”

Section: Ipoxins Are Endogenous Anti-inflammatory Lipid Mediatorsmentioning

confidence: 99%

A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils

Ohira

Bannenberg

Arita

et al. 2004

The Journal of Immunology

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Lipoxins and their aspirin-triggered 15-epimers are endogenous anti-inflammatory agents that block neutrophil chemotaxis in vitro and inhibit neutrophil influx in several models of acute inflammation. In this study, we examined the effects of 15-epi-16-(p-fluoro)-phenoxy-lipoxin A4 methyl ester, an aspirin-triggered lipoxin A4-stable analog (ATLa), on the protein phosphorylation pattern of human neutrophils. Neutrophils stimulated with the chemoattractant fMLP were found to exhibit intense phosphorylation of a 55-kDa protein that was blocked by ATLa (10–50 nM). This 55-kDa protein was identified as leukocyte-specific protein 1, a downstream component of the p38-MAPK cascade in neutrophils, by mass spectrometry, Western blotting, and immunoprecipitation experiments. ATLa (50 nM) also reduced phosphorylation/activation of several components of the p38-MAPK pathway in these cells (MAPK kinase 3/MAPK kinase 6, p38-MAPK, MAPK-activated protein kinase-2). These results indicate that ATLa exerts its anti-inflammatory effects, at least in part, by blocking activation of the p38-MAPK cascade in neutrophils, which is known to promote chemotaxis and other proinflammatory responses by these cells.

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“…Some of these actions include inhibition of neutrophil (PMN) and eosinophil chemotaxis, inhibition of PMN transmigration across epithelial and endothelial cell layers, and of O 2 O and IL-1␤ production in neutrophils, as well as inhibition of TNF-␣-induced IL-8 secretion from colon epithelial cells (reviewed in Ref. 8). LX-stable analogs also reduce LTB 4 -induced infiltration of PMN into mouse ears (12) and TNF-␣-induced infiltration of PMN into murine dorsal air pouches (13).…”

mentioning

confidence: 99%

“…The physiological function of cyclooxygenase 2 is still not fully understood; however, its acetylation by aspirin modifies its activity to generate 15R-hydroxyeicosatetraenoic acid, which can be oxygenated to produce 15-epi-LXA 4 , termed aspirin-triggered LX (ATL; reviewed in Ref. 8). Also of interest, aspirin shares anti-inflammatory actions with 15-epi-LXA 4 , such as inhibition of IL-12 production from dendritic cells (11,17), but the 15-epi-LXA 4 analog acts at much lower concentrations (100 -1000ϫ) than aspirin when blocking PMN infiltration to the ears of mice during inflammation (13).…”

mentioning

confidence: 99%

Aspirin-Triggered Lipoxin A4 and B4 Analogs Block Extracellular Signal-Regulated Kinase-Dependent TNF-α Secretion from Human T Cells

Ariel

Chiang

Arita

et al. 2003

The Journal of Immunology

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170

117

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Lipoxins (LX) and their aspirin-triggered 15-epimer endogenous isoforms are endogenous anti-inflammatory and pro-resolution eicosanoids. In this study, we examined the impact of LX and aspirin-triggered LXA4-stable analogs (ATLa) on human T cell functions. 15-epi-16-(p-fluoro)phenoxy-LXA4 (ATLa1) blocked the secretion of TNF-α from human PBMC after stimulation by anti-CD3 Abs, with the IC50 value of ≈0.05 nM. A similar action was also exerted by the native aspirin-triggered 15-epi-LXA4, a new 15-epi-16-(p-trifluoro)phenoxy-LXA4 analog (ATLa2), as well as LXB4, and its analog 5-(R/S)-methyl-LXB4. The LXA4 receptor (ALX) is expressed in peripheral blood T cells and mediates the inhibition of TNF-α secretion from activated T cells by ATLa1. This action was accomplished by inhibition of the anti-CD3-induced activation of extracellular signal-regulated kinase, which is essential for TNF-α secretion from anti-CD3-activated T cells. These results demonstrate novel roles for LX and aspirin-triggered LX in the regulation of T cell-mediated responses relevant in inflammation and its resolution. Moreover, they provide potential counterregulatory signals in communication(s) between the innate and acquired immune systems.

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Unorthodox routes to prostanoid formation: new twists in cyclooxygenase-initiated pathways

Cited by 135 publications

References 70 publications

Metabolic Control of Excessive Extracellular Nucleotide Accumulation by CD39/Ecto-Nucleotidase-1: Implications for Ischemic Vascular Diseases

Metabolic Control of Excessive Extracellular Nucleotide Accumulation by CD39/Ecto-Nucleotidase-1: Implications for Ischemic Vascular Diseases

A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils

Aspirin-Triggered Lipoxin A4 and B4 Analogs Block Extracellular Signal-Regulated Kinase-Dependent TNF-α Secretion from Human T Cells

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