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INFLAMMATION AND IMMUNOPHARMACOLOGY

Angiopoietin-2 Causes Inflammation in Vivo by Promoting Vascular Leakage

Department of Experimental Pharmacology, Faculty of Pharmacy, University of Naples-Federico II, Naples, Italy (F.R., M.B., V.B., G.C.); "George P. Livanos-Marianthi Simou" Laboratories, Department of Critical Care and Pulmonary Services, Evangelismos Hospital, University of Athens, Athens, Greece (S.T., A.K., A.P.); and Laboratory for Molecular Pharmacology, School of Pharmacy, University of Patras, Patras, Greece (A.P.)

Angiopoietins (Angs) are endothelium-selective ligands that exert most of their actions through the Tie-2 receptor. It is widely accepted that Ang-1 promotes the structural integrity of blood vessels and exhibits anti-inflammatory properties. In contrast, the role of Ang-2 remains less clear because it has been shown to behave as a Tie-2 agonist or antagonist under different experimental conditions. To define the role of Ang-2 in acute inflammation, we studied the effects of recombinant Ang-2 administration in vivo. We show herein that Ang-2, but not Ang-1, induces edema formation in the mouse paw in a dose-dependent manner; the edema seems to be fast-peaking (maximum at 30 min) and resolves within 4 h. The effect of Ang-2 is blocked by the coadministration with a soluble form of the Tie-2 receptor or Ang-1. NO and prostaglandin E₂ levels in mouse paw following the injection of Ang-2 remained unaltered, suggesting that the action of Ang-2 does not involve these mediators. In addition, Ang-2 exerted a weak stimulatory effect on leukocyte migration in the mouse paw. Similarly, Ang-2 injected into the mouse air pouch produced only a modest effect on cell extravasation that peaked at 30 min. However, when cell migration was elicited using zymosan, Ang-2 significantly inhibited leukocyte migration. We conclude that Ang-2 by itself stimulates the extravasation of cell-poor fluid, but in the presence of ongoing inflammation it reduces cellular infiltration in tissues.

Address correspondence to: Dr. Andreas Papapetropoulos, Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece 26504. E-mail: apapapet{at}upatras.gr

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