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Clinical trial of doxycycline for matrix metalloproteinase-9 inhibition in patients with an abdominal aneurysm doxycycline selectively depletes aortic wall neutrophils and cytotoxic t cells

Author: Lindeman, J.H.N. · Abdul-Hussien, H. · Bockel, J.H. van · Wolterbeek, R. · Kleemann, R.
Type:article
Date:2009
Institution: TNO Kwaliteit van Leven
Source:Circulation, 16, 119, 2209-2216
Identifier: 279993
doi: doi:10.1161/CIRCULATIONAHA.108.806505
Keywords: Health · Aneurysm · Immunology · Inflammation · Molecular biology · Trials · Doxycycline · Gelatinase B · Granulocyte colony stimulating factor receptor · Interleukin 13 · Interleukin 6 · Interleukin 8 · Antiinfective agent · CCAAT enhancer binding protein · Enzyme inhibitor · IL6 protein, human · Transcription factor AP 1 · Transcription factor RelA · Abdominal aorta aneurysm · Aged · Cytotoxic T lymphocyte · Drug effect · Drug megadose · Drug tolerability · Enzyme inhibition · Aortic Aneurysm, Abdominal · CCAAT-Enhancer-Binding Proteins · Doxycycline · Enzyme Inhibitors · Matrix Metalloproteinase 9 · Middle Aged · Neutrophils · T-Lymphocytes, Cytotoxic · Vasculitis

Abstract

Background-Doxycycline has been shown to effectively inhibit aneurysm formation in animal models of abdominal aortic aneurysm. Although this effect is ascribed to matrix metalloproteinase-9 inhibition, such an effect is unclear in human studies. We reevaluated the effect of doxycycline on aortic wall protease content in a inical trial and found that doxycycline selectively reduces neutrophil-derived proteases. We thus hypothesized that doxycycline acts through an effect on ascular nflammation. Methods and Results-Sixty patients scheduled for elective open aneurysmal repair were randomly assigned to 2 weeks of low-, medium-, or high-dose doxycycline (50, 100, or 300 mg/d, respectively) or no medication (control group). Aortic wall samples were collected at the time of operation, and the ffect of doxycycline treatment on vascular inflammation was evaluated. Independently of its dose, doxycycline treatment resulted in a profound but selective suppression of aortic wall inflammation as reflected by a selective 72% reduction of the aortic wall neutrophils and a 95% reduction of the aortic wall cytotoxic T-cell content (median values; P<0.00003). Evaluation of major inflammatory pathways suggested that doxycycline treatment specifically quenched AP-1 and C/EBP proinflammatory transcription pathways P<0.0158, NS) and reduced vascular interleukin-6 (P<0.00115), interleukin-8 (P<0.00246, NS), interleukin-13 (P<0.0184, NS), and granulocyte colony-stimulating factor (P<0.031, NS) protein levels. Doxycycline was well tolerated; there were no adverse effects. Conclusions-A brief period of doxycycline treatment has a profound but selective effect on vascular inflammation and reduces aortic wall neutrophil and cytotoxic T-cell content. Results of this study are relevant for pharmaceutical stabilization of the abdominal aneurysm and possibly for other inflammatory conditions that involve neutrophils and/or cytotoxic T cells. © 2009 American Heart Association, Inc.