Role of 5-lipoxygenase products in the local accumulation of neutrophils in dermal inflammation in the rabbit.
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.
Marleau
S
S
Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Ste-Foy, Canada. sylvie.marleau@umontreal.ca
Fruteau de Laclos
B
B
Sanchez
A B
AB
Poubelle
P E
PE
Borgeat
P
P
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D002630:Chemotactic Factors / Q000008:administration & dosage; D002860:Chromium Radioisotopes / Q000378:metabolism; D015936:Complement C5a / Q000008:administration & dosage; D003872:Dermatitis / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007211:Indoles / Q000008:administration & dosage; D018836:Inflammation Mediators / Q000494:pharmacology; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007975:Leukotriene B4 / Q000008:administration & dosage / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000008:administration & dosage; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage; D011817:Rabbits; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D002630:Chemotactic Factors; D002860:Chromium Radioisotopes; D007211:Indoles; D018836:Inflammation Mediators; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; C078266:MK 0591; D007975:Leukotriene B4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015936:Complement C5a; D001094:Arachidonate 5-Lipoxygenase