Antigen-induced Microvascular Leakage Research Articles

Adrenomedullin inhibits ovalbumin-induced bronchoconstriction and airway microvascular leakage in guinea-pigs.

Human adrenomedullin is a potent vasodilator with bronchodilation properties. The effects of adrenomedullin on antigen-induced bronchoconstriction and airway microvascular leakage in guinea-pigs was investigated. The portion of the adrenomedullin molecule possessing these pulmonary active profiles was also examined, using two truncated adrenomedullin molecules: adrenomedullin (1-25) and adrenomedullin (22-52). Four weeks after sensitization with ovalbumin (0.1 mg x k(-1)), the guinea-pigs were anaesthetized and mechanically ventilated. Respiratory resistance, dynamic compliance and arterial blood pressure were monitored. Airway microvascular leakage was evaluated by extravasation of 20 mg x kg(-1) Evans blue into airway interstitial tissue. In order to enhance the pulmonary effects of adrenomedullin, the active production of endogenous nitric oxide was inhibited by coadministration of a nitric oxide synthase inhibitor, L-N(G)-nitroarginine methethyl ester (10 mg x kg(-1)). Intravenous pretreatment with adrenomedullin (10, 30 and 100 microg x mL(-1)) dose-dependently inhibited ovalbumin-induced bronchoconstriction and airway microvascular leakage in all airway segments. Inhaled adrenomedullin (100 microg.mL(-1), 1 min) also significantly inhibited pulmonary changes induced by ovalbumin inhalation (3 mg x mL (-1) , 3 min). These pulmonary profiles of adrenomedullin were enhanced by inhibiting the active production of endogenous nitric oxide. In conclusion, adrenomedullin has inhibitory effects on antigen-induced microvascular leakage and bronchoconstriction in guinea-pigs. These beneficial effects strongly related to its unique ring structure and N-terminal segment, making it a potential anti-asthma.

Effects of phosphodiesterase inhibitors and salbutamol on microvascular leakage in guinea-pig trachea.

The aim of this study was to investigate the effects of selective phosphodiesterase inhibitors and their combination with salbutamol on antigen-induced microvascular leakage in the trachea. In actively sensitized anaesthetized guinea-pigs, the non-selective phosphodiesterase inhibitor theophylline (100 mg/kg p.o.) and the selective phosphodiesterase type 4 inhibitor Ro 20-1724 (30 mg/kg p.o.) inhibited antigen-induced microvascular leakage (-73.8% and -44.1%, respectively) as demonstrated by a reduced extravasation of plasma proteins measured by the use of Evans blue dye. No significant reduction in microvascular leakage was seen with (a) the selective phosphodiesterase type 4 inhibitor rolipram (10 mg/kg p.o.), (b) the selective phosphodiesterase type 3 inhibitors milrinone (30 mg/kg p.o.) and SK and F 94-836 (30 mg/kg p.o.) or (c) the selective phosphodiesterase type 1/5 inhibitor zaprinast (30 mg/kg p.o.). Neither Ro 20-1724 nor rolipram and theophylline inhibited microvascular leakage induced by either substance P or histamine. Pretreatment with aerosolized salbutamol (10 microg/ml) potentiated the inhibitory effects of theophylline (-49.8% at 30 mg/kg p.o.) and Ro 20-1724 (-52.6% at 10 mg/kg p.o.) versus antigen-induced microvascular leakage. Furthermore, a significant inhibitory effect of rolipram (10 mg/kg, p.o.) was obtained following pretreatment with this concentration of aerosolized salbutamol. Even at higher concentrations (0.3-2 mg/ml) salbutamol did not augment the corresponding inhibitory effects of rolipram and Ro 20-1724 versus microvascular leakage induced by either histamine or substance P. Theophylline had no effect versus substance P-induced microvascular leakage, but did inhibit it significantly (P < 0.05) after pretreatment with aerosolized salbutamol (0.3 mg/ml). The potentiation by salbutamol of the inhibitory effects of both non-selective and selective phosphodiesterase type 4 inhibitors versus antigen-induced microvascular leakage probably results from a synergistic reduction in the release of anaphylactic mediators.

The effects of NK1 receptor antagonists (FK224 and FK888) on agonist- and antigen-induced nasal microvascular leakage in guinea pigs.

To study the inhibitory effects of two NK1 receptor antagonists on substance P (SP) and antigen-induced increase of nasal vascular permeability in ovalbumen (OA)-sensitized guinea pigs. Male Dunkin-Hartley guinea pigs. SP (100 mumol/l), FK224 (1-10 mumol/kg) and FK888 (0.2-2 mumol/kg). The in vivo model of nasal microvascular leakage was used for nasal allergic challenge in ovalbumin (OA)-sensitized guinea pigs, or nasal stimulation with substance P (SP) in non-sensitized animals. Nasal microvascular leakage was measured by the accumulation of Evans Blue dye after intravenous injection. Following nasal stimulation with SP 100 microM, the concentration of dye in the nasal lavage fluid rapidly increased. NK1 receptor antagonists FK224 (10 mumol/kg i.v.) and FK888 (2 mumol/kg i.v.) inhibited SP-induced microvascular leakage. In OA-sensitized guinea pigs, exudation of dye into nasal lavage fluid was observed soon after topical antigenic stimulation and continued for over 60 min. Both NK1 receptor antagonists inhibited the immediate phase of the antigen-induced microvascular leakage. We conclude that the immediate change of vascular permeability during the nasal allergic response is mediated by activation of the NK1 receptor in the guinea-pig.

Endogenous nitric oxide modifies antigen-induced microvascular leakage in sensitized guinea pig airways

To examine the role of endogenous nitric oxide in allergic airway inflammation, we investigated the effect of a nitric oxide synthase inhibitor, Nω-nitro- l-arginine methyl ester ( l-NAME), on antigen-induced airway microvascular leakage in actively sensitized guinea pigs by using Evans blue dye. Three weeks after sensitization with ovalbumin (10 μg), the tracheas were cannulated, and lungs were artificially ventilated. Animals were pretreated with atropine and propranolol (both 1 mg/kg, intravenously) to avoid neural modification. Ovalbumin inhalation (3 mg/ml, 1 minute) challenge caused significant microvascular leakage in all airway portions, which was significantly suppressed in a dose-dependent manner by pretreatment with intravenous injection of l--NAME (1 and 10 mg/kg) but not with the inactive enantiomer d-NAME (10 mg/kg). This inhibition by l-NAME was significantly reversed by co-administration of l-arginine (100 mg/kg, intravenously). Pretreatment with a vasoconstrictor, phenylephrine (20 μg/kg, intravenously), had no inhibitory effects on antigen-induced airway microvascular leakage despite increasing systemic blood pressure. Inhalation of representative mast cell–derived mediators, histamine (2 mg/ml, 1 minute) or leukotriene D 4 (5 μg/ml, 1 minute), produced significant microvascular leakage in all airways. l-NAME (10 mg/kg, intravenously) partially but significantly inhibited leukotriene D 4–induced leakage, whereas histamine-induced leakage was not affected. These results suggest that endogenous nitric oxide acts to increase airway microvascular leakage after airway allergic reaction. (J A LLERGY C LIN I MMUNOL 1996;98:144-51.)

Effect of a Paf antagonist, WEB 2086, on airway microvascular leakage in the guinea-pig and platelet aggregation in man.

1. The triazolodiazepine WEB 2086 has been evaluated as an antagonist of platelet-activating factor (Paf) by studying its effects on Paf-induced human platelet aggregation and microvascular leakage in guinea-pigs. 2. WEB 2086 inhibited Paf-induced platelet aggregation in platelet-rich plasma in vitro (IC50 = 117 +/- 35 nM, mean +/- s.d.) but had no effect on adenosine 3',5'-diphosphate-induced aggregation. 3. Paf-induced microvascular leakage, measured by the extravasation of intravenously-injected Evans blue dye, was inhibited in a dose-related fashion in the airways and other tissues by WEB 2086, achieving a maximal inhibitory effect at 10 micrograms kg-1, i.v. 4. However, WEB 2086 (10 micrograms kg-1, i.v.) did not inhibit a comparable increase in vascular permeability induced by ovalbumin in sensitized guinea-pigs. 5. We conclude that WEB 2086 is a potent antagonist of Paf and that Paf does not appear to be responsible for antigen-induced microvascular leakage.