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(Circulation. 2009;119:1805-1813.)
© 2009 American Heart Association, Inc.

Vascular Medicine

Complement-Dependent Neutrophil Recruitment Is Critical for the Development of Elastase-Induced Abdominal Aortic Aneurysm

Monica B. Pagano, MD^*; Hui-fang Zhou, PhD^*; Terri L. Ennis, BS^*; Xiaobo Wu, MD; John D. Lambris, PhD; John P. Atkinson, MD; Robert W. Thompson, MD; Dennis E. Hourcade, PhD; Christine T.N. Pham, MD

From the Department of Surgery (M.B.P., T.L.E., R.W.T.), Section of Vascular Surgery, and Department of Medicine (H.-f.Z., X.W., J.P.A., D.E.H., C.T.N.P.), Division of Rheumatology, Washington University School of Medicine, St Louis, Mo; and Department of Pathology and Laboratory Medicine (J.D.L.), University of Pennsylvania School of Medicine, Philadelphia.

Correspondence to Christine T.N. Pham, 660 S Euclid Ave, Box 8045, St Louis, MO 63110. E-mail cpham{at}im.wustl.edu

Received October 31, 2008; accepted January 30, 2009.

Background— We previously established that neutrophils play a critical role in the development of experimental abdominal aortic aneurysm (AAA). The signal that initiates the influx of neutrophils to the aortic wall, however, remains unknown. In this study, we tested the hypothesis that complement participates in the development of AAA by providing the necessary chemotactic signal that recruits neutrophils to the aortic wall.

Methods and Results— Using an elastase-induced model of AAA, we showed that pretreatment of C57BL/6 mice with cobra venom factor, which depleted serum of complement activity, protected mice from AAA development. Whereas control mice exhibited a mean aortic diameter of 156±2% on day 14 after elastase perfusion, mice treated with cobra venom factor exhibited a mean aortic diameter of 90±4% (P<0.001). Examination of mice deficient in factor B further indicated that the alternative pathway of complement played a major role in this process (mean aortic diameter of 105±4% in factor B–deficient mice, P<0.001 compared with controls). Activation of the alternative pathway led to generation of the anaphylatoxins C3a and C5a, which recruited neutrophils to the aortic wall. Moreover, antagonism of both C3a and C5a activity was required to block AAA, which suggests that each can independently promote the aneurysmal phenotype. In addition, we demonstrated that complement alternative-pathway involvement was not restricted to this experimental model but was also evident in human AAAs.

Conclusions— The identification of involvement of the complement system in the pathophysiology of AAA provides a new target for therapeutic intervention in this common disease.

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Clinical Summaries
Circulation 2009 119: 1691-1693. [Extract] [Full Text]