Blocking TNF-alpha attenuates aneurysm formation in a murine model.
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.
Xiong
Wanfen
W
Department of Surgery, University of Nebraska Medical Center, Omaha,NE 68198, USA.
MacTaggart
Jason
J
Knispel
Rebecca
R
Worth
Jennifer
J
Persidsky
Yuri
Y
Baxter
B Timothy
BT
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D002461:Cell Line, Transformed; D002464:Cell Migration Inhibition / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004547:Elastic Tissue / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology
D018836:Inflammation Mediators; D061965:Matrix Metalloproteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D020778:Matrix Metalloproteinase 2