Abstract |
Studies were undertaken to define the role of 5-lipoxygenase (5-LO) products and, in particular, of leukotriene (LT) B4 in the polymorphonuclear leukocyte (PMN) emigration process using a rabbit model of dermal inflammation. Our results show that i.v. administration to rabbits of MK-0591, a compound that inhibits LT biosynthesis in blood and tissues when administered in vivo, significantly reduced 51Cr-labeled PMN accumulation in response to intradermally injected chemotactic agonists, including IL-8, FMLP, C5a, and LTB4 itself. In addition, pretreatment of the labeled PMN with MK-0591 ex vivo before their injection in recipient animals was equally effective in reducing 51Cr-labeled PMN emigration to dermal inflammatory sites. These results support a role for de novo synthesis of 5-LO metabolites by PMN for their chemotactic response to inflammatory mediators. Other studies demonstrated that elevated intravascular concentration of LTB4 interferes with PMN extravasation inasmuch as a continuous i.v. infusion of LTB4, in the range of 5-300 ng/min/kg, dose-dependently inhibited extravascular PMN accumulation to acute inflammatory skin sites elicited by the chemoattractants LTB4, FMLP, C5a, and IL-8 and by TNF-alpha, IL-1beta, and LPS; such phenomena may constitute a natural protective mechanism from massive tissue invasion by activated PMN in specific pathologic conditions such as ischemia (and reperfusion). These studies demonstrate additional functions of 5-LO products in the regulation of PMN trafficking, distinct from the well-characterized chemotactic activity of LTB4 present in the extravascular compartment.
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Authors | S Marleau, B Fruteau de Laclos, A B Sanchez, P E Poubelle, P Borgeat |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 163
Issue 6
Pg. 3449-58
(Sep 15 1999)
ISSN: 0022-1767 [Print] United States |
PMID | 10477617
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Chemotactic Factors
- Chromium Radioisotopes
- Indoles
- Inflammation Mediators
- Lipoxygenase Inhibitors
- Quinolines
- MK 0591
- Leukotriene B4
- N-Formylmethionine Leucyl-Phenylalanine
- Complement C5a
- Arachidonate 5-Lipoxygenase
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Topics |
- Animals
- Arachidonate 5-Lipoxygenase
(metabolism, physiology)
- Cell Movement
(drug effects, immunology)
- Chemotactic Factors
(administration & dosage)
- Chromium Radioisotopes
(metabolism)
- Complement C5a
(administration & dosage)
- Dermatitis
(enzymology, immunology, metabolism, pathology)
- Indoles
(administration & dosage)
- Inflammation Mediators
(pharmacology)
- Infusions, Intravenous
- Injections, Intravenous
- Leukotriene B4
(administration & dosage, biosynthesis)
- Lipoxygenase Inhibitors
(administration & dosage)
- Male
- N-Formylmethionine Leucyl-Phenylalanine
(administration & dosage)
- Neutrophils
(drug effects, enzymology, immunology, metabolism)
- Quinolines
(administration & dosage)
- Rabbits
- Skin
(immunology, metabolism, pathology)
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