4.6 Article

Selectivity of recombinant human leukotriene D-4, leukotriene B-4, and lipoxin A(4) receptors with aspirin-triggered 15-epi-LXA(4) and regulation of vascular and inflammatory responses

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AMERICAN JOURNAL OF PATHOLOGY
卷 158, 期 1, 页码 3-9

出版社

AMER SOC INVESTIGATIVE PATHOLOGY, INC
DOI: 10.1016/S0002-9440(10)63937-5

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资金

  1. NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [F32AI010389] Funding Source: NIH RePORTER
  2. NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCH [P01DE013499] Funding Source: NIH RePORTER
  3. NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM038765, R29GM038765, R37GM038765] Funding Source: NIH RePORTER
  4. NIAID NIH HHS [F32-AI10389, F32 AI010389] Funding Source: Medline
  5. NIDCR NIH HHS [P01 DE013499, DE13499] Funding Source: Medline
  6. NIGMS NIH HHS [R01 GM038765, R37 GM038765, GM38765] Funding Source: Medline

向作者/读者索取更多资源

Aspirin-triggered Lipoxin A(4) (ATL, 15-epi-LXA(4)) and leukotriene D-4 (LTD4) possess opposing vascular actions mediated via receptors distinct from the LXA(4) receptor (ALX) that is involved in leukocyte trafficking. Here, we identified these receptors by nucleotide sequencing and demonstrate that LTD4 receptor (CysLT(1)) is induced in human vascular endothelia by interkukin-1 beta. Recombinant CysLT(1) receptor gave stereospecific binding with both [H-3]-LTD4 and a novel labeled mimetic of ATL ([H-3]-ATLa) that was displaced with LTD4 and ATLa (similar to IC50 0.2 to 0.9 nmol/ L), but not with a bioinactive ATL isomer. The clinically used CysLT(1) receptor antagonist, Singulair, showed a lower rank order for competition with [H-3]-ATLa (IC50 approximate to 8.3 nmol/L). In contrast, LTD4 was an ineffective competitive ligand for recombinant ALX receptor with [H-3]-ATLa, and ATLa did not compete for [H-3]-LTB4 binding with recombinant LTB4 receptor. Endogenous murine CysLT(1) receptors also gave specific [H-3]-ATLa binding that was displaced with essentially equal affinity by LTD, or ATLa, Systemic ATLa proved to be a potent inhibitor (>50%) of CysLT(1)-mediated vascular leakage in murine skin (200 mug/kg) in addition to its ability to block polymorphonuclear leukocyte recruitment to dorsal air pouch (4 mug/kg). These results indicate that ATL and LTD, bind and compete with equal affinity at CysLT(1), providing a molecular basis for aspirin-triggered LXs serving as a local damper of both vascular CysLT(1) signals as well as ALX receptor-regulated polymorphonuclear leukocyte traffic.

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