Synergistic actions of blocking angiopoietin-2 and tumor necrosis factor-α in suppressing remodeling of blood vessels and lymphatics in airway inflammation.

Abstract

Remodeling of blood vessels and lymphatics are prominent features of sustained inflammation. Angiopoietin-2 (Ang2)/Tie2 receptor signaling and tumor necrosis factor-α (TNF)/TNF receptor signaling are known to contribute to these changes in airway inflammation after Mycoplasma pulmonis infection in mice. We determined whether Ang2 and TNF are both essential for the remodeling on blood vessels and lymphatics, and thereby influence the actions of one another. Their respective contributions to the initial stage of vascular remodeling and sprouting lymphangiogenesis were examined by comparing the effects of function-blocking antibodies to Ang2 or TNF, given individually or together during the first week after infection. As indices of efficacy, vascular enlargement, endothelial leakiness, venular marker expression, pericyte changes, and lymphatic vessel sprouting were assessed. Inhibition of Ang2 or TNF alone reduced the remodeling of blood vessels and lymphatics, but inhibition of both together completely prevented these changes. Genome-wide analysis of changes in gene expression revealed synergistic actions of the antibody combination over a broad range of genes and signaling pathways involved in inflammatory responses. These findings demonstrate that Ang2 and TNF are essential and synergistic drivers of remodeling of blood vessels and lymphatics during the initial stage of inflammation after infection. Inhibition of Ang2 and TNF together results in widespread suppression of the inflammatory response.

• Authors: Catherine T K Le, Grace Laidlaw, Christopher A Morehouse, Brian Naiman, Philip Brohawn, Tomas Mustelin, Jane R Connor, Donald M McDonald
• Journal: The American journal of pathology (Am J Pathol) Vol. 185 Issue 11 Pg. 2949-68 (Nov 2015) ISSN: 1525-2191 [Electronic] United States
• PMID: 26348576 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Tumor Necrosis Factor-alpha
• Ang2 protein, mouse
• Ribonuclease, Pancreatic

Topics

• Animals
• Female
• Inflammation
• Lymphangiogenesis
• Lymphatic System (metabolism, pathology)
• Lymphatic Vessels (pathology)
• Mice
• Mice, Inbred C57BL
• Mycoplasma Infections (immunology, pathology)
• Mycoplasma pulmonis (physiology)
• Oligonucleotide Array Sequence Analysis
• Pericytes (pathology)
• Respiratory System (metabolism, pathology)
• Ribonuclease, Pancreatic (antagonists & inhibitors, metabolism)
• Signal Transduction
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)