title: Role of platelet activating factor, leukotrienes and polymorphs in the FMLP induced increase in microvascular leakage in rabbit trachea.
abstract: This study was designed to determine the time course of N-formyl-methionyl-leucyl-phenylalanine (FMLP) induced microvascular leakage in the airways of anaesthetized, tracheostomized New Zealand white rabbits. We have previously shown that FMLP increases microvascular leakage in the rabbit trachea at 30 min post challenge. A further aim was to determine the mechanisms underlying this response. Microvascular leakage was assessed using the albumin binding dye, Evans blue which was injected intravenously (50 mg/kg) immediately prior to FMLP challenge (10 mg nebulised for 2 min) or the control (dimethylsulphoxide/saline). Microvascular leakage was assessed in the trachea and bronchi at 15 min, 22.5 min, 45 min and 120 minutes with n = 6 for each group. The only significant difference between control and FMLP challenged groups was at 45 min in the bronchi (FMLP 77.6 +/- 12.2, control 33.4 +/- 5.7, P < 0.05). To determine the mechanism underlying FMLP-induced increases in microvascular leakage rabbits were treated with one of the following: (i) nitrogen mustard (1.75 mg/kg intravenously), which depletes circulating polymorphs (n = 6); (ii) the platelet activating factor (PAF) receptor antagonist WEB 2086 (10 mg/kg; n = 5); (iii) the Cys-LTR1 receptor antagonist ICI198615 (nebulised 10(-4) mol/L), or challenged with the thromboxane agonist U46619. Tracheal Evans blue concentration was assessed at 30 min after FMLP challenge and compared with the appropriate control. Treatment with WEB 2086 significantly (P < 0.05) reduced tracheal microvascular leakage (FMLP 76.3 +/- 13.1 WEB 2086/FMLP 31.4 +/- 3.7 micrograms/g trachea) as did ICI198615 (FMLP 69.8 +/- 11.5 ICI198615/FMLP 30.0 +/- 5.7). In conclusion FMLP induced an increase in tracheal microvascular leakage which was significant in the bronchi at 45 min and this increase was mediated by platelet activating factor and the sulphidopeptide leukotrienes C4 and D4.
authors.affiliation: Department of Thoracic Medicine, Royal North Shore Hospital, Sydney, New South Wales, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Matheson
authors.forename: A C
authors.initials: AC
authors.lastname: Rynell
authors.forename: M A
authors.initials: MA
authors.lastname: McClean
authors.forename: N
authors.initials: N
authors.lastname: Berend
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001991:Bronchitis / Q000139:chemically induced / Q000503:physiopathology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D004396:Coloring Agents; D004195:Disease Models, Animal; D004347:Drug Interactions; D005070:Evans Blue; D007191:Indazoles / Q000494:pharmacology; D015289:Leukotrienes / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D008466:Mechlorethamine / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine; D010972:Platelet Activating Factor / Q000494:pharmacology / Q000502:physiology*; D011817:Rabbits; D012016:Reference Values; D014132:Trachea / Q000187:drug effects / Q000502:physiology*; D014230:Triazoles / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D000477:Alkylating Agents; D001381:Azepines; D004396:Coloring Agents; D007191:Indazoles; D015289:Leukotrienes; D010972:Platelet Activating Factor; D014230:Triazoles; D014662:Vasoconstrictor Agents; C054217:ICI 198615; C052518:WEB 2086; D005070:Evans Blue; D008466:Mechlorethamine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid