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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0803164v1 183/4/2741    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Xiong, W. Articles by Baxter, B. T. PubMed PubMed Citation Articles by Xiong, W. Articles by Baxter, B. T. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Aortic Aneurysm

Blocking TNF- Attenuates Aneurysm Formation in a Murine Model¹

Wanfen Xiong^*, Jason MacTaggart^*, Rebecca Knispel^*, Jennifer Worth^*, Yuri Persidsky and B. Timothy Baxter^2,*,

^* Department of Surgery, Department of Pathology and Microbiology, and Department of Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198

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

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by National Institute Health Grants 5R01HL62400-02 (to B.T.B.) and R01AA015913(to Y.P.).

² Address correspondence and reprint requests to Dr. B. Timothy Baxter, Department of Surgery, 987690 University of Nebraska Medical Center, Omaha, NE 68198-7690. E-mail address: btbaxter{at}unmc.edu

³ Abbreviations used in this paper: AAA, abdominal aortic aneurysm; MMP, matrix metalloproteinase; TNF-BP, TNF-binding protein; SMC, smooth muscle cell; WT, wild type.