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Role of 5-Lipoxygenase Products in the Local Accumulation of Neutrophils in Dermal Inflammation in the Rabbit¹

Sylvie Marleau^2,3,*, Bernard Fruteau de Laclos, Ana B. Sanchez^*, Patrice E. Poubelle^* and Pierre Borgeat^*

^* Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du Centre Hospitalier Universitaire de Québec (Pavillon Centre Hospitalier de l’Université Laval) et Faculté de Médecine, Université Laval, Ste-Foy, Québec, Canada; and Hôpital du Saint-Sacrement, Québec, Canada

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-, IL-1ß, 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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