Complement-dependent neutrophil recruitment is critical for the development of elastase-induced abdominal aortic aneurysm.
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.


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.
Pagano
Monica B
MB
Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, St Louis, Mo., USA.
Zhou
Hui-fang
HF
Ennis
Terri L
TL
Wu
Xiaobo
X
Lambris
John D
JD
Atkinson
John P
JP
Thompson
Robert W
RW
Hourcade
Dennis E
DE
Pham
Christine T N
CT
D000818:Animals; D001011:Aorta / Q000276:immunology / Q000378:metabolism; D017544:Aortic Aneurysm, Abdominal / Q000276:immunology* / Q000378:metabolism*; D015926:Complement C3a / Q000276:immunology / Q000378:metabolism; D003181:Complement C4 / Q000276:immunology / Q000378:metabolism; D015936:Complement C5a / Q000276:immunology / Q000378:metabolism; D011415:Complement Factor B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003165:Complement System Proteins / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism*
D003181:Complement C4; D015926:Complement C3a; D015936:Complement C5a; D003165:Complement System Proteins; D010196:Pancreatic Elastase; D011415:Complement Factor B