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


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Abdul-Hussien
Hazem
H
Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
Hanemaaijer
Roeland
R
Verheijen
Jan H
JH
van Bockel
J Hajo
JH
Geelkerken
Robert H
RH
Lindeman
Jan H N
JH
D000368:Aged; D000369:Aged, 80 and over; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000601:surgery; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D055316:Cystatin C / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000627:therapeutic use*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D011446:Prospective Studies; D011480:Protease Inhibitors / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016896:Treatment Outcome; D014656:Vascular Surgical Procedures
C525030:CST3 protein, human; D002317:Cardiovascular Agents; D055316:Cystatin C; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D003546:Cysteine Endopeptidases; D020782:Matrix Metalloproteinases; D004318:Doxycycline