Print Email Facebook Twitter Doxycycline therapy for abdominal aneurysm: Improved proteolytic balance through reduced neutrophil content Title Doxycycline therapy for abdominal aneurysm: Improved proteolytic balance through reduced neutrophil content Author Abdul-Hussien, H. Hanemaaijer, R. Verheijen, J.H. van Bockel, J.H. Geelkerken, R.H. Lindeman, J.H.N. TNO Kwaliteit van Leven Publication year 2009 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. Subject BiologyBiomedical Researchantihypertensive agentantithrombocytic agentcystatin Ccysteine proteinasedoxycyclinegelatinase Bhydroxymethylglutaryl coenzyme A reductase inhibitormessenger RNAneutrophil collagenasestromelysintissue inhibitor of metalloproteinase 1abdominal aorta aneurysmadultagedaorta wallarticleclinical articleclinical trialcontrolled clinical trialcontrolled studydose responsedrug effectdrug megadosedrug tolerabilityenzyme activityenzyme assayfemalegene expressionhumanhuman tissueimmunohistochemistrylow drug dosemaleneutrophilpolymerase chain reactionpriority journalprotein degradationquantitative analysisrandomized controlled trialtreatment durationWestern blottingAgedAged, 80 and overAorta, AbdominalAortic Aneurysm, AbdominalCardiovascular AgentsCystatin CCysteine EndopeptidasesDose-Response Relationship, DrugDoxycyclineFemaleGene Expression Regulation, EnzymologicHumansMaleMatrix MetalloproteinasesMiddle AgedNeutrophil InfiltrationNeutrophilsProspective StudiesProtease InhibitorsRNA, MessengerTime FactorsTissue Inhibitor of Metalloproteinase-1Treatment OutcomeVascular Surgical Procedures To reference this document use: http://resolver.tudelft.nl/uuid:8acc3dc4-4f33-4f74-b4ad-97ec0547c802 DOI https://doi.org/10.1016/j.jvs.2008.09.055 TNO identifier 241427 ISSN 0741-5214 Source Journal of Vascular Surgery, 49 (3), 741-749 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.