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Role of 5-lipoxygenase products in the local accumulation of neutrophils in dermal inflammation in the rabbit.

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.
AuthorsS Marleau, B Fruteau de Laclos, A B Sanchez, P E Poubelle, P Borgeat
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 163 Issue 6 Pg. 3449-58 (Sep 15 1999) ISSN: 0022-1767 [Print] United States
PMID10477617 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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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