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

Abstract

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 156Ϯ2% on day 14 after elastase perfusion, mice treated with cobra venom factor exhibited a mean aortic diameter of 90Ϯ4% (PϽ0.001). 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 105Ϯ4% in factor B-deficient mice, PϽ0.001 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.

Antibody directs properdin-dependent activation of the complement alternative pathway in a mouse model of abdominal aortic aneurysm

“…This aortic diameter (AD) remained relatively stable up to day 7, after which there was rapid and significant increase in AD in WT mice (12,18). AAA is typically defined on day 14 as an increase in AD of 100% or greater than the diameter measured before elastase perfusion (12,18). We have previously shown that fB −/− mice are largely resistant to the development of AAA (increase in AD of 105 ± 4%) (12).…”

“…AAA is typically defined on day 14 as an increase in AD of 100% or greater than the diameter measured before elastase perfusion (12,18). We have previously shown that fB −/− mice are largely resistant to the development of AAA (increase in AD of 105 ± 4%) (12). We now find that the absence of properdin protected mice from elastase-induced AAA to the same extent as fB deficiency (increase in AD of 0.50 ± 0.02 mm or 100 ± 3% in fP −/o mice compared with increase in AD of 0.75 ± 0.02 mm or 151 ± 5% in WT animals, P < 0.001) ( Fig.…”

“…We have previously presented evidence that complement activation occurs in human AAA (12). Whether complement activation in human AAA is a cause or consequence of aortic wall tissue injury and damage requires additional studies.…”

“…More recently, evidence has emerged that properdin may act as an initiator of the AP, binding directly to target cell surfaces and providing a platform for the AP C3 convertase assembly (15,16). We previously obtained compelling histochemical evidence for the presence of properdin on the luminal surface of human AAA specimens (12), and this finding led us to hypothesize that properdin may serve as a focal point for the initiation of the AP in AAA. Here, we show that properdin plays a critical role in the pathogenesis of elastaseinduced AAA, suggesting that properdin-targeting strategies merit additional investigation.…”

“…We have shown that the complement system is a critical mediator of elastase-induced AAA (12). Using mice deficient in factor B (fB; an essential component of the AP) and C4 (a component of both the LP and CP), we established that the AP plays a major role in AAA development, whereas the CP and LP seem dispensable.…”