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.
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.


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.
Lindeman
Jan H N
JH
Department of Vascular Surgery, K6R, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands. Lindeman@LUMC.nl
Abdul-Hussien
Hazem
H
van Bockel
J Hajo
JH
Wolterbeek
Ron
R
Kleemann
Robert
R
D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D001011:Aorta / Q000166:cytology / Q000276:immunology; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000276:immunology / Q000601:surgery; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D004318:Doxycycline / Q000008:administration & dosage*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014657:Vasculitis / Q000188:drug therapy / Q000276:immunology
D000900:Anti-Bacterial Agents; D022762:CCAAT-Enhancer-Binding Proteins; D004791:Enzyme Inhibitors; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D061965:Matrix Metalloproteinase Inhibitors; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline