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

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Author: Abdul-Hussien, H. · Hanemaaijer, R. · Verheijen, J.H. · Bockel, J.H. van · Geelkerken, R.H. · Lindeman, J.H.N.
Type:article
Date:2009
Institution: TNO Kwaliteit van Leven
Source:Journal of Vascular Surgery, 3, 49, 741-749
Identifier: 241427
doi: doi:10.1016/j.jvs.2008.09.055
Keywords: Biology · Biomedical Research · antihypertensive agent · antithrombocytic agent · cystatin C · cysteine proteinase · doxycycline · gelatinase B · hydroxymethylglutaryl coenzyme A reductase inhibitor · messenger RNA · neutrophil collagenase · stromelysin · tissue inhibitor of metalloproteinase 1 · abdominal aorta aneurysm · adult · aged · aorta wall · article · clinical article · clinical trial · controlled clinical trial · controlled study · dose response · drug effect · drug megadose · drug tolerability · enzyme activity · enzyme assay · female · gene expression · human · human tissue · immunohistochemistry · low drug dose · male · neutrophil · polymerase chain reaction · priority journal · protein degradation · quantitative analysis · randomized controlled trial · treatment duration · Western blotting · Aged · Aged, 80 and over · Aorta, Abdominal · Aortic Aneurysm, Abdominal · Cardiovascular Agents · Cystatin C · Cysteine Endopeptidases · Dose-Response Relationship, Drug · Doxycycline · Female · Gene Expression Regulation, Enzymologic · Humans · Male · Matrix Metalloproteinases · Middle Aged · Neutrophil Infiltration · Neutrophils · Prospective Studies · Protease Inhibitors · RNA, Messenger · Time Factors · Tissue Inhibitor of Metalloproteinase-1 · Treatment Outcome · Vascular Surgical Procedures

Abstract

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. © 2009 The Society for Vascular Surgery.