Role of 5-Lipoxygenase Products in the Local Accumulation of Neutrophils in Dermal Inflammation in the Rabbit

• Published in: The Journal of immunology (1950) 1999-09, Vol.163 (6), p.3449-3458
• Main Authors: Marleau, Sylvie, Fruteau de Laclos, Bernard, Sanchez, Ana B, Poubelle, Patrice E, Borgeat, Pierre
• Format: Article
• Language: English
• Subjects: Animals; Arachidonate 5-Lipoxygenase - metabolism; Arachidonate 5-Lipoxygenase - physiology; Cell Movement - drug effects; Cell Movement - immunology; Chemotactic Factors - administration & dosage; Chromium Radioisotopes - metabolism; Complement C5a - administration & dosage; Dermatitis - enzymology; Dermatitis - immunology; Dermatitis - metabolism; Dermatitis - pathology; Indoles - administration & dosage; Inflammation Mediators - pharmacology; Infusions, Intravenous; Injections, Intravenous; Leukotriene B4 - administration & dosage; Leukotriene B4 - biosynthesis; Lipoxygenase Inhibitors - administration & dosage; Male; N-Formylmethionine Leucyl-Phenylalanine - administration & dosage; Neutrophils - drug effects; Neutrophils - enzymology; Neutrophils - immunology; Neutrophils - metabolism; Quinolines - administration & dosage; Rabbits; Skin - immunology; Skin - metabolism; Skin - pathology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.163.6.3449

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.