Clinical Trial of Doxycycline for Matrix Metalloproteinase-9 Inhibition in Patients With an Abdominal Aneurysm

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 clinical trial and found that doxycycline selectively reduces neutrophil-derived proteases. We thus hypothesized that doxycycline acts through an effect on vascular inflammation. 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 effect 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; PϽ0.00003). Evaluation of major inflammatory pathways suggested that doxycycline treatment specifically quenched AP-1 and C/EBP proinflammatory transcription pathways (PϽ0.0158, NS) and reduced vascular interleukin-6 (PϽ0.00115), interleukin-8 (PϽ0.00246, NS), interleukin-13 (PϽ0.0184, NS), and granulocyte colony-stimulating factor (PϽ0.031, 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.

Matrix metalloproteinase 9 expression: new regulatory elements

“…MMP-9 is considered one of the pharmacological targets in the treatment of glaucoma [15] and other diseases [19][20][21][22]. Thus, the knowledge of the mechanisms regulating MMP-9 is important for the understanding of the neuron survivaldeath pathways and for deciphering the glaucomatous alterations in the retina and optic nerve.…”

Activation of the vitamin D receptor selectively interferes with calcineurin-mediated inflammation: a clinical evaluation in the abdominal aortic aneurysm

“…In two previous studies, we have shown that brief 2-4-week pre-operative interventions with doxycycline and the ACE inhibitor ramipril profoundly reduced aortic wall inflammation through, respectively, the effects on the AP-1 (doxycycline) 26 and NFκB 27 proinflammatory pathways. Similarly, it was found that statins dose dependently reduce NFκB-driven inflammation in the aneurysm wall.…”

“…Yet, if such effects exist, they presumably compare weakly with the effect exerted on the NFAT pathways, and with pleiotropic effects on NFκB and AP-1 signaling exerted by, respectively, statins 28 and ACE inhibitors, 27 and doxycycline. 26 A further limitation of the study is that evaluation of baseline vitamin D status was not included in the study protocol. We therefore assessed vitamin D levels in plasma from AAA patients participating PHAST study who were included in same center as the patients in this study.…”

Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

“…Furthermore, this compound enhances Cystatin C and TIMP-1, important MMP inhibitors [81]. Beyond regulating the major extracellular matrix modulators, doxycycline also produced a significant and selective suppression of aortic wall inflammation by reducing neutrophil infiltration, as well as cytotoxic T-cell and vascular cytokines [82].…”