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Am J Pathol. 2015 Nov;185(11):2949-68. doi: 10.1016/j.ajpath.2015.07.010. Epub 2015 Sep 5.

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

Author information

1
Department of Anatomy, Cardiovascular Research Institute, University of California San Francisco, San Francisco, California; University of California San Francisco Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
2
MedImmune LLC, Gaithersburg, Maryland.
3
University of California San Francisco Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California; MedImmune LLC, Gaithersburg, Maryland.
4
Department of Anatomy, Cardiovascular Research Institute, University of California San Francisco, San Francisco, California; University of California San Francisco Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California. Electronic address: donald.mcdonald@ucsf.edu.

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.

PMID:
26348576
PMCID:
PMC4630170
DOI:
10.1016/j.ajpath.2015.07.010
[Indexed for MEDLINE]
Free PMC Article

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