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Angiopoietin-1 Protects against Airway Inflammation and Hyperreactivity in Asthma

¹ "G. P. Livanos and M. Simou" Laboratories, Department of Critical Care and Pulmonary Services, Evangelismos Hospital, University of Athens School of Medicine, Athens, Greece; and ² Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece

Correspondence and requests for reprints should be addressed to Andreas Papapetropoulos, Ph.D., "G. P. Livanos and M. Simou" Laboratories, Evangelismos Hospital, Department of Critical Care and Pulmonary Services, University of Athens School of Medicine, Athens, Greece 10675. E-mail: apapapet{at}upatras.gr

Rationale: The angiopoietins (Ang) comprise a family of growth factors mainly known for their role in blood vessel formation and remodeling. The best-studied member, Ang-1, exhibits antiapoptotic and antiinflammatory effects. Although the involvement of Ang-1 in angiogenesis is well recognized, little information exists about its role in respiratory physiology and disease. On the basis of its ability to inhibit vascular permeability, adhesion molecule expression, and cytokine production, we hypothesized that Ang-1 administration might exert a protective role in asthma.

Objectives: To determine changes in the expression of Ang and to assess the ability of Ang-1 to prevent the histologic, biochemical, and functional changes observed in an animal model of asthma.

Methods: To test our hypothesis, a model of allergic airway disease that develops after ovalbumin (OVA) sensitization and challenge was used.

Measurements and Main Results: Ang-1 expression was reduced at the mRNA and protein levels in lung tissue of mice sensitized and challenged with OVA, leading to reduced Tie2 phosphorylation. Intranasal Ang-1 treatment prevented the OVA-induced eosinophilic lung infiltration, attenuated the increase in IL-5 and IL-13, and reduced eotaxin and vascular cell adhesion molecule 1 expression. These antiinflammatory actions of Ang-1 coincided with higher levels of IB and decreased nuclear factor-B binding activity. More importantly, Ang-1 reversed the OVA-induced increase in tissue resistance and elastance, improving lung function.

Conclusions: We conclude that Ang-1 levels are decreased in asthma and that administration of Ang-1 might be of therapeutic value because it prevents the increased responsiveness of the airways to constrictors and ameliorates inflammation.

Key Words: airway resistance • interleukin 5 • eotaxin • VCAM-1 • nuclear factor-B

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Angiopoietin (Ang)-1 exhibits antiinflammatory properties by inhibiting leukocyte transendothelial migration, cytokine production, and vascular permeability. Ang-1 administration ameliorates endotoxin-induced lung injury and improves survival. What This Study Adds to the Field Ang-1 levels are reduced in the lungs of animals with experimental asthma. Local Ang-1 administration prevents the biochemical and functional changes observed in asthma, suggesting that Tie2 agonists might have therapeutic potential in this disease.