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

• DOI: 10.1161/circulationaha.108.806505
• Publication Date: 2009-04-14T00:44:51Z
• Authors: Jan H.N. Lindeman; Hazem Abdul-Hussien; J. Hajo van Bockel; Ron Wolterbeek; Robert Kleemann
• Keywords: Aged, 80 and over; Male; Interleukin-6; Neutrophils; Interleukin-8; Transcription Factor RelA; Matrix Metalloproteinase Inhibitors; Middle Aged; Anti-Bacterial Agents; 3. Good health; Transcription Factor AP-1; 03 medical and health sciences; 0302 clinical medicine; Matrix Metalloproteinase 9; Doxycycline; CCAAT-Enhancer-Binding Proteins; Humans; Female; Enzyme Inhibitors; Aorta; Aged; Aortic Aneurysm, Abdominal; T-Lymphocytes, Cytotoxic

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; 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.