Matrix 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.
This 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.
Doxycycline 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).
Independent 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.