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J Immunol. 2009 Aug 15;183(4):2741-6. doi: 10.4049/jimmunol.0803164. Epub 2009 Jul 20.

Blocking TNF-alpha attenuates aneurysm formation in a murine model.

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  • 1Department of Surgery, University of Nebraska Medical Center, Omaha,NE 68198, USA.

Abstract

Abdominal aortic aneurysm (AAA) is one of a number of diseases associated with a prominent inflammatory cell infiltrate and local destruction of structural matrix macromolecules. This chronic infiltrate is predominately composed of macrophages and T lymphocytes. Activated macrophages produce a variety of cytokines, including TNF-alpha. Elevated levels of TNF-alpha were observed in patients with AAA, suggesting that TNF-alpha may play a role in the pathogenic mechanisms of AAA. In the present study, we investigated the role of TNF-alpha in AAA formation. By studying a murine aneurysm model, we found that both mRNA and protein levels of TNF-alpha were increased in aneurysm tissue compared with normal aortic tissues. Therefore, we tested the response of mice lacking expression of TNF-alpha. These mice were resistant to aneurysm formation. Our results show that TNF-alpha deficiency attenuates matrix metalloproteinase (MMP) 2 and MMP-9 expression and macrophage infiltration into the aortic tissue. These data suggest that TNF-alpha plays a central role in regulating matrix remodeling and inflammation in the aortic wall leading to AAA. In addition, we investigated the pharmacological inhibition of AAA. A Food and Drug Administration-approved TNF-alpha antagonist, infliximab, inhibited aneurysm growth. Our data also show that infliximab treatment attenuated elastic fiber disruption, macrophage infiltration, and MMP-2 and MMP-9 expression in aortic tissue. This study confirms that a strategy of TNF-alpha antagonism may be an important therapeutic strategy for treating AAA.

PMID:
19620291
[PubMed - indexed for MEDLINE]
PMCID:
PMC4028114
Free PMC Article

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