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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

Characterization of Human Neutrophil and Endothelial Cell Ligand-Operated Extracellular Acidification Rate by Microphysiometry: Impact of Reoxygenation

Karsten Gronert, Sean P. Colgan and Charles N. Serhan
Journal of Pharmacology and Experimental Therapeutics April 1998, 285 (1) 252-261;
Karsten Gronert
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Sean P. Colgan
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Charles N. Serhan
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Abstract

Neutrophil (PMN) activation and recruitment are coordinated by ligand-operated surface receptors. These responses are involved in the tissue injury that follows hypoxia/reoxygenation. Here, we report that inflammatory mediators each evoke distinct and characteristic extracellular acidification rates (EAR) in both PMN and endothelial cells (EC) as measured by a Cytosensor microphysiometer. Leukotriene B4 (LTB4) and the peptide N-formylmethionyl-leucyl-phenylalanine were the most potent activators of EAR, whereas other potent stimuli including interleukin-8 and platelet-activating factor only weakly stimulated EAR in PMN. In contrast, other lipid-derived PMN mediators such as prostaglandin E2 and lipoxin A4 (LXA4) did not evoke EAR. Ligand-operated EAR exhibited desensitization as well as ligand specificity and sensitivity to pertussis toxin. Human endothelial cell agonists including histamine, prostacyclin stable analog and LXA4 each gave sharply different EAR responses, with only histamine evoking an EAR in these cells. Hypoxia/reoxygenation did not alter ligand-operated EAR from PMN, and similarly LTB4-stimulated PMN transendothelial migration, a functional response, was not influenced by either PMN or EC exposure to intervals of hypoxia/reoxygenation. LXA4 stable analogs inhibited PMN transendothelial migration (1 nM–1 μM), and this PMN-EC responsiveness to inhibition by a lipoxin stable analog (e.g., 16-phenoxy-LXA4) was enhanced ∼2 log orders of magnitude after hypoxia/reoxygenation. Results demonstrate that ligand-receptor interactions evoke characteristic profiles of EAR and that some well-characterized ligand-receptor pairs (including interleukin-8, platelet-activating factor, prostaglandin E2 or LXA4) on these cell types either weakly activate the EAR pathway or are silent. Furthermore, hypoxia/reoxygenation did not alter LTB4 PMN responses but did heighten responsiveness to 16-phenoxy-LXA4, which suggests a potential protective role in leukocyte-mediated injury.

Footnotes

  • Send reprint requests to: Dr. Charles N. Serhan, Director, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115.

  • ↵1 This work was supported in part by grants from the National Institutes of Health GM38765, P01-DK50305 (to C.N.S.) and DK50189 (to S.P.C.), and a discovery research grant from Ono Pharmaceutical Co., Japan (to C.N.S.).

  • ↵2 Recipient of a postdoctoral fellowship from the National Arthritis Foundation.

  • Abbreviations:
    DPBS
    Dulbecco’s phosphate-buffered saline
    EAR
    extracellular acidification rate
    EC
    endothelial cells
    fMLP
    N-formylmethionyl-leucyl-phenylalanine
    GM-CSF
    granulocyte-macrophage colony-stimulating factor
    HUVEC
    human umbilical vein endothelial cells
    IL-8
    interleukin 8
    LTB4
    leukotriene B4
    LXA4
    5(S),6(R),15(S)-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid
    15 (R/S)-methyl-LXA4
    5(S),6(R), 15(R/S)-trihydroxy-15-methyl-7,9,13-trans-11-cis-eicosatetraenoic acid
    16-phenoxy-LXA4
    16-phenoxy-17,18,19,20-tetranor-LXA4
    MD
    modified
    ME
    carboxy methyl ester
    MPO
    myeloperoxidase
    O2−
    superoxide anion
    PAF
    platelet-activating factor
    PGE2
    prostaglandin E2
    pHi
    intracellular pH
    PMN
    polymorphonuclear leukocytes
    PTX
    pertussis toxin
    • Received June 5, 1997.
    • Accepted December 24, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 1
1 Apr 1998
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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

Characterization of Human Neutrophil and Endothelial Cell Ligand-Operated Extracellular Acidification Rate by Microphysiometry: Impact of Reoxygenation

Karsten Gronert, Sean P. Colgan and Charles N. Serhan
Journal of Pharmacology and Experimental Therapeutics April 1, 1998, 285 (1) 252-261;

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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

Characterization of Human Neutrophil and Endothelial Cell Ligand-Operated Extracellular Acidification Rate by Microphysiometry: Impact of Reoxygenation

Karsten Gronert, Sean P. Colgan and Charles N. Serhan
Journal of Pharmacology and Experimental Therapeutics April 1, 1998, 285 (1) 252-261;
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