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.3349-3458
• Main Authors: Marleau, S, de Laclos, BF, Sanchez, AB, Poubelle, P E, Borgeat, P
• Format: Article
• Language: English
• ISSN: 0022-1767

Studies were undertaken to define the role of 5-lipoxygenase (5-LO) products and, in particular, of leukotriene (LT) B sub(4) 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 super(51)Cr-labeled PMN accumulation in response to intradermally injected chemotactic agonists, including IL-8, FMLP, C5a, and LTB sub(4) itself. In addition, pretreatment of the labeled PMN with MK-0591 ex vivo before their injection in recipient animals was equally effective in reducing super(51)Cr-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 LTB sub(4) interferes with PMN extravasation inasmuch as a continuous i.v. infusion of LTB sub(4), in the range of 5-300 ng/min/kg, dose-dependently inhibited extravascular PMN accumulation to acute inflammatory skin sites elicited by the chemoattractants LTB sub(4), FMLP, C5a, and IL-8 and by TNF- alpha , IL-1 beta , 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 LTB sub(4) present in the extravascular compartment.