Doxycycline therapy for abdominal aneurysm: Improved proteolytic balance through reduced neutrophil content

BackgroundMatrix metalloproteinase-9 (MMP-9) is thought to play a central role in abdominal aortic aneurysm (AAA) initiation. Doxycycline, a tetracycline analogue, has direct MMP-9-inhibiting properties in vitro, and it effectively suppresses AAA development in rodents. Observed inhibition of AAA progression, and contradictory findings in human studies evaluating the effect of doxycycline therapy on aortic wall MMP-9, suggest that the effects of doxycycline extend beyond MMP-9 inhibition and that the effect may be dose-dependent.MethodsThis clinical trial evaluated the effect of 2 weeks of low- (50 mg/d), medium- (100 mg/d), or high-dose (300 mg/d) doxycycline vs no medication in four groups of 15 patients undergoing elective AAA repair. The effect of doxycycline treatment on MMP and cysteine proteases, and their respective inhibitors, was evaluated by quantitative polymerase chain reaction, Western blot analysis, immunocapture protease activity assays, and immunohistochemistry.ResultsDoxycycline was well tolerated and no participants dropped out. Doxycycline treatment reduced aortic wall MMP-3 and MMP-25 messenger RNA expression (P < .045 and P < .014, respectively), selectively suppressed neutrophil collagenase and gelatinase (MMP-8 and MMP-9) protein levels (P < .013 and <.004, respectively), and increased protein levels of the protease inhibitors tissue inhibitor of metalloproteinase 1 and cystatin C (P < .029). As for the apparent selective effect on neutrophil-associated proteases, we sought for a reducing effect on aortic wall neutrophil content that was indeed confirmed by immunohistochemical analysis that revealed a 75% reduction in aneurysm wall neutrophil content (P < .001).ConclusionsIndependent of its dose, short-term preoperative doxycycline therapy improves the proteolytic balance in AAA, presumably through an effect on aortic wall neutrophil content. This study provides a rationale for doxycycline treatment in patients with an AAA as well as in other (vascular) conditions involving neutrophil influx such as Kawasaki disease and Behçet disease.

Clinical RelevanceThe concept of pharmaceutical stabilization of abdominal aneurysms is promising. Doxycycline, a tetracycline analogue, is considered a lead candidate, but its mode of action is still unclear. This clinical trial showed that doxycycline treatment, through a profound effect on the number aortic wall neutrophils, has a pronounced but selective effect on the proteolytic balance in the abdominal aneurysm, as indicated by reduced matrix metalloproteinase (MMP)-8 and -9 levels and concentrations of tissue inhibitor of metalloproteinase-1 and cystatin C. The observation that doxycycline has a selective effect on neutrophil-derived proteases is remarkable and novel, and suggests that doxycycline may also be effective in other vascular conditions involving neutrophils, such as Kawasaki disease and Behçet disease, and nonvascular conditions such as chronic obstructive pulmonary disease.