Doxycycline therapy for abdominal aneurysm: Improved proteolytic balance through reduced neutrophil content Hazem Abdul-Hussien, MD, Roeland Hanemaaijer,

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Doxycycline therapy for abdominal aneurysm: Improved proteolytic balance through reduced neutrophil content Hazem Abdul-Hussien, MD, Roeland Hanemaaijer, PhD, Jan H. Verheijen, PhD, J. Hajo van Bockel, MD, PhD, Robert H. Geelkerken, MD, PhD, Jan H.N. Lindeman, MD, PhD Journal of Vascular Surgery Volume 49, Issue 3, Pages 741-749 (March 2009) DOI: 10.1016/j.jvs.2008.09.055 Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 1 Left, Matrix metalloproteinase (MMP)-3 and (right) MMP-25 transcript levels relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Independent of its dose, doxycycline reduces aortic wall MMP-3 and MMP-25 messenger RNA expression. Maximum level of suppression was already found in the low-dose doxycycline group. Results for the higher doses are more variable. Results are presented in box plots depicting median value (horizontal line), interquartile range (box borders), and range (bars). *P < .045 and P < .014 respectively (t test). Journal of Vascular Surgery 2009 49, 741-749DOI: (10.1016/j.jvs.2008.09.055) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 2 The effect of doxycycline on (left) matrix metalloproteinase (MMP)-2, (center) MMP-8, and (right) MMP-9 proenzyme levels in untreated abdominal aortic aneurysm controls and doxycycline-treated patients as measured in the protease activity assays. Maximum level of suppression was already found in the low-dose doxycycline group. Results for the higher doses are more variable. *P < .015 for MMP-2, P < .013 for MMP-8, and P < .004 for MMP-9 by Wilcoxon-Mann-Whitney U test. Results are presented in box plots depicting median value (horizontal line), interquartile range (box borders), and range (bars). Journal of Vascular Surgery 2009 49, 741-749DOI: (10.1016/j.jvs.2008.09.055) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 3 The effect of doxycycline on pro (gray bars) and activated (white bars) (left) matrix metalloproteinase (MMP)-8 and (right) MMP-9 levels (relative protein levels, mean control, 100%) in untreated abdominal aortic aneurysm controls (n = 5) and doxycycline-treated patients (n = 4 per dose) measured by Western blot analysis. Results are presented with the standard error (range bars). *P < .020 by Wilcoxon-Mann-Whitney U test. Journal of Vascular Surgery 2009 49, 741-749DOI: (10.1016/j.jvs.2008.09.055) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 4 Doxycycline treatment increases protein levels of (left) cystatin C, the principle extracellular inhibitor of cysteine proteases, as well as (right) tissue inhibitor of metalloproteinase 1 (TIMP1) protein levels (100 and 300 mg only). Results are presented in box plots depicting median value (horizontal line), interquartile range (box borders), and range (bars). *P < .029 by Wilcoxon-Mann-Whitney U test. Journal of Vascular Surgery 2009 49, 741-749DOI: (10.1016/j.jvs.2008.09.055) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 5 A, Doxycycline reduces neutrophil content in the aneurysmal wall. Results are presented in box plots depicting median value (horizontal line), interquartile range (box borders), and range (bars). *P < .001 by Wilcoxon-Mann-Whitney U test. B, Aneurysm wall neutrophil infiltration (myeloperoxidase staining) in the medial-adventitial border zone in untreated and (C) doxycycline-treated individuals. Bar represents 100 μm. Journal of Vascular Surgery 2009 49, 741-749DOI: (10.1016/j.jvs.2008.09.055) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions