Blocking TNF-α attenuates aneurysm formation in a murine Model

Wanfen Xiong, Jason N Mactaggart, Rebecca Knispel, Jennifer Worth, Yuri Persidsky, Bernard Timothy Baxter

Research output: Contribution to journalArticle

102 Citations (Scopus)

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-α. Elevated levels of TNF-α were observed in patients with AAA, suggesting that TNF-α may play a role in the pathogenic mechanisms of AAA. In the present study, we investigated the role of TNF-α in AAA formation. By studying a murine aneurysm model, we found that both mRNA and protein levels of TNF-α were increased in aneurysm tissue compared with normal aortic tissues. Therefore, we tested the response of mice lacking expression of TNF-α. These mice were resistant to aneurysm formation. Our results show that TNF-α deficiency attenuates matrix metalloproteinase (MMP) 2 and MMP-9 expression and macrophage infiltration into the aortic tissue. These data suggest that TNF-α 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-α 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-α antagonism may be an important therapeutic strategy for treating AAA.

Original languageEnglish (US)
Pages (from-to)2741-2746
Number of pages6
JournalJournal of Immunology
Volume183
Issue number4
DOIs
StatePublished - Aug 15 2009

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Abdominal Aortic Aneurysm
Aneurysm
Macrophages
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Elastic Tissue
United States Food and Drug Administration
Pharmacology
Cytokines
Inflammation
T-Lymphocytes
Messenger RNA
Therapeutics
Growth
Proteins

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Blocking TNF-α attenuates aneurysm formation in a murine Model. / Xiong, Wanfen; Mactaggart, Jason N; Knispel, Rebecca; Worth, Jennifer; Persidsky, Yuri; Baxter, Bernard Timothy.

In: Journal of Immunology, Vol. 183, No. 4, 15.08.2009, p. 2741-2746.

Research output: Contribution to journalArticle

Xiong, Wanfen ; Mactaggart, Jason N ; Knispel, Rebecca ; Worth, Jennifer ; Persidsky, Yuri ; Baxter, Bernard Timothy. / Blocking TNF-α attenuates aneurysm formation in a murine Model. In: Journal of Immunology. 2009 ; Vol. 183, No. 4. pp. 2741-2746.
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