Inhibition of platelet function in thrombosis.

Marcus, Aaron J.; Safier, Lenore B.; Ullman, H L; Broekman, M. Johan; Islam, Naziba; Oglesby, Thomas D.; Gorman, Robert R.; Ward, J W

doi:10.1161/01.cir.72.4.698

Cited by 23 publications

(24 citation statements)

References 8 publications

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“…In contrast, a transcellular origin for LTB4 and a need for such an origin can be established exclusively in terms of cellular, enzymatic, and chemical attributes of erythrocyte and neutrophil LTA4 hydrolase. The biological significance of transcellular metabolism remains to be established, but our results support Marcus' advocacy for cell-cell interactions as an important but novel form of icosanoid biosynthesis (3,16). Since cell combinations encountered in disease may differ from those encountered in normal circumstances the study of transcellular metabolism assumes some significance (20).…”

Section: Discussionsupporting

confidence: 67%

Erythrocyte-neutrophil interactions: formation of leukotriene B4 by transcellular biosynthesis.

McGee¹,

Fitzpatrick²

1986

Proc. Natl. Acad. Sci. U.S.A.

129

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Studies on the mechanism of leukotriene B4 biosynthesis in suspensions composed of neutrophils plus erythrocytes indicate that human erythrocytes convert neutrophil-derived leukotriene A4 into leukotriene B4. Leukotriene B4 formation by neutrophils in the presence of erythrocytes exceeded that from corresponding suspensions of neutrophils alone. The increase was proportional to the erythrocyte content of the suspension. The erythrocyte-dependent increase in leukotriene B4 biosynthesis did not equal the arithmetic sum of calcium ionophore-dependent biosynthesis by neutrophils plus calcium ionophore-dependent biosynthesis by erythrocytes, since erythrocytes produced no leukotriene B4 upon incubation with ionophore A23187. Erythrocytes did not stimulate 5-lipoxygenase activity within neutrophils, since the erythrocyte effect was confined to enzymatic hydration: leukotriene B4 increased coincident with decreased formation of 5,12-dihydroxyicosatetraenoic acids derived from nonenzymatic hydration. Biosynthesis of leukotriene B4 within the erythrocyte, from neutrophil-derived leukotriene A4, was established by comparing the effect of normal erythrocytes with erythrocytes containing a leukotriene A4 hydrolase that was inactivated by the substrate. In the latter case, leukotriene B4 formation increased by only 30-40%; in the former case, it increased by 100-200%. Transcellular biosynthesis of leukotriene B4 from erythrocyte-neutrophil interactions (i) explains the paradoxical presence of leukotriene A4 hydrolase within erythrocytes, a cell incapable of synthesizing leukotriene A4; (u) affords a mechanism to overcome rate limitations or "suicide inactivation" of leukotriene A4 hydrolase in neutrophils; (iii) exploits a cryptic capacity within erythrocytes, provisionally dormant cells in terms of icosanoid biosynthesis; (iv) indicates that the biosynthetic capacity of cell combinations is not necessarily equivalent to the sum of their separate capacities.Enzymatic cooperation between separate cell types may be a significant, but neglected, mechanism for the biosynthesis of certain prostaglandins or leukotrienes. This concept originated from studies on platelet-endothelial cell interactions, which showed that prostaglandin I2 (PGI2), an antithrombotic icosanoid, was produced by endothelial cells from plateletderived prostaglandin endoperoxide H2 (1-5). Analogous transcellular biosynthetic processes are conceivable for other cell combinations and for other arachidonic acid metabolites; however, few biologically relevant examples exist. Requirements for this process include "acceptor" cells with a constitutive enzymatic capacity for the formation of a biologically active icosanoid product but a deficient, or disabled, capacity for substrate generation, plus auxiliary "donor" cells that can fulfill that corresponding substrate requirement. In this context, neutrophil-erythrocyte interactions attracted our attention as potential sources for transcellular biosynthesis of leukotrienes (6).Ordinarily, biosynthesis of leu...

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Section: Discussionsupporting

confidence: 67%

Erythrocyte-neutrophil interactions: formation of leukotriene B4 by transcellular biosynthesis.

McGee¹,

Fitzpatrick²

1986

Proc. Natl. Acad. Sci. U.S.A.

129

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“…S2D). Six carbon-carbon double bonds hydrogenated 14S,21R-diHDHA (H 12 -14S,21R-diHDHA) was generated by bubbling hydrogen gas through a methanol solution of 14S,21R-diHDHA, in which Adam's catalyst PtO 2 (ϳ1 mg) was suspended (20 min, room temperature) (41)(42)(43).…”

Section: Sample Preparation and Lc-uv-ms/ms Analysis Of Lipid Mediatomentioning

confidence: 99%

14S,21R-Dihydroxydocosahexaenoic Acid Remedies Impaired Healing and Mesenchymal Stem Cell Functions in Diabetic Wounds

Tian

Lü

Shah

et al. 2011

Journal of Biological Chemistry

104

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Treatment of diabetes-impaired wound healing remains a major unresolved medical challenge. Here, we identified suppressed formation of a novel reparative lipid mediator 14S,21R-dihydroxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (14S,21R-diHDHA) in cutaneous wounds of diabetic db/db mice. These results indicate that diabetes impedes the biosynthetic pathways of 14S,21R-diHDHA in skin wounds. Administration of exogenous 14S,21R-diHDHA to wounds in diabetic animals rescued healing and angiogenesis. When db/db mesenchymal stem cells (MSCs) were administered together with 14S,21R-diHDHA to wounds in diabetic animals, they coacted to accelerate wound re-epithelialization, granulation tissue formation, and synergistically improved vascularization. In the pivotal cellular processes of angiogenesis, 14S,21R-diHDHA enhanced VEGF release, vasculature formation, and migration of db/db dermal microvascular endothelial cells (DMVECs), as well as remedied paracrine angiogenic functions of db/db MSCs, including VEGF secretion and the promotion of DMVEC migration and vasculature formation. Our results show that 14S,21R-diHDHA activates the p38 MAPK pathway in wounds, db/db MSCs, and DMVECs. Overall, the impeded formation of 14S,21R-diHDHA described in this study suggests that diabetes could affect the generation of pro-healing lipid mediators in wound healing. By restoring wound healing and MSC functions, 14S,21R-diHDHA is a new lead for the development of better therapeutics used in treating wounds of diabetics.

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“…Accordingly, endothelial cells will respond to eicosanoids, synthesized primarily by other ceils, such as platelets (TXA2) or leukocytes (leukotrienes). It is another unique feature of the eicosanoid system that these cell-to-cell interactions are partially mediated by precursor exchange, generating a product that either cannot be formed by the single cell type alone (44) or has a biological profile that is completely different from that of the precursor, such as PGI2 made from platelet-derived PG-endoperoxides (45). Clearly, there is still much to be learned before details of these interactions are sufficiently understood.…”

Section: A Bbrevia Tionsmentioning

confidence: 99%

Prostaglandins, other eicosanoids and endothelial cells

Schrör

1985

Basic Res Cardiol

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Endothelial cells are an important source of eicosanoid formation in the cardiovascular systems. All major pathways of eicosanoid production have been demonstrated in endothelial cells, yielding significant amounts of prostacyclin (PGI2), PGE2, PGF2 alpha, thromboxane A2, leukotrienes and a number of hydroxy fatty acids. The regulation of eicosanoid formation by endothelial cells is poorly understood. There is evidence that precursors, such as arachidonic acid or prostaglandin endoperoxides, may also be provided by other cell types. Endothelial cell-derived eicosanoids are involved in the regulation of local vessel tone, intravascular platelet activation, cell locomotion and, eventually, cell proliferation. Most of the available information considers PGI2. This compound is the quantitatively dominating eicosanoid in endothelial cells. Major actions of PGI2 include inhibition of platelet activation and aggregation, relaxation of arterial vessels and inhibition of growth-factor release. There is probably a tight interaction with other biologically active mediators which needs further evaluation. This also applies to the clinical significance of eicosanoid-related pathways for the mechanism of action of cardiovascular drugs, such as organic nitrates or acetylsalicylic acid. The unique property of the eicosanoid system to become activated only in response to stimulation, the local nature of this reaction, the multiplicity of products formed and the short half-time of most of them are currently the most significant obstacles to define the role of endothelial cell-derived eicosanoids in clinical practice.

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Inhibition of platelet function in thrombosis.

Cited by 23 publications

References 8 publications

Erythrocyte-neutrophil interactions: formation of leukotriene B4 by transcellular biosynthesis.

Erythrocyte-neutrophil interactions: formation of leukotriene B4 by transcellular biosynthesis.

14S,21R-Dihydroxydocosahexaenoic Acid Remedies Impaired Healing and Mesenchymal Stem Cell Functions in Diabetic Wounds

Prostaglandins, other eicosanoids and endothelial cells

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