Abstract
Cysteinyl leukotrienes are bioactive lipid mediators known to possess potent proinflammatory actions. Included in these are effects on vascular endothelium to promote surface expression of the adhesion molecule P-selectin. In the present study we were interested in investigating the receptor mechanism(s) involved in cysteinyl leukotriene-induced endothelial P-selectin expression. As such we examined the effect of several potent and selective cysteinyl leukotriene receptor antagonists on this response. Incubation of cultured human umbilical vein endothelial cells (HUVEC) with the cysteinyl leukotrienes leukotriene C4 (LTC4) or leukotriene D4 (LTD4) induced surface expression of P-selectin which was concentration dependent and rapid in onset. Expression of endothelial P-selectin induced by either LTC4 or LTD4 was not blocked however by pretreatment of HUVEC with the selective cysteinyl leukotriene-1 (CysLT1) receptor antagonists SKF 104353, pranlukast or zafirlukast before agonist exposure. In contrast, SKF 104353 effectively antagonized the LTC4-induced contractions in isolated human bronchial smooth muscle preparations, shifting the agonist dose-response curve to the right by some 3 log-fold in this tissue. The present results suggest that cysteinyl leukotrienes induce surface expression of endothelial P-selectinvia a mechanism independent of theCysLT1 receptor.
Footnotes
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Send reprint requests to: Dr. Bradley J. Undem, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224.
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↵1 This study was supported by Grants HL-38095 and HL-49545 from the National Heart, Lung and Blood Institute.
- Abbreviations:
- HUVEC
- human umbilical vein endothelial cells
- LTC4
- leukotriene C4
- LTD4
- leukotriene D4
- LTE4
- leukotriene E4
- LTB4
- leukotriene B4
- CysLT1
- cysteinyl leukotriene-1
- M199
- medium 199
- mAb
- monoclonal antibody
- DPBS
- Dulbecco’s phosphate buffered saline
- HSA
- human serum albumin
- SKF 104353
- 2(S)-hydroxy-3(R)-(2-carboxyethylthio)-3-[2-(8-phenyl)]-propanoic acid
- Received October 15, 1996.
- Accepted January 23, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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