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Uptake of tetracycline by aortic aneurysm wall and its effect on inflammation and proteolysis
I J Franklin1, S L Harley, R M Greenhalgh
1Department of Vascular Surgery, Imperial College School of Medicine at Charing Cross, Charing Cross Hospital, London, UK.
Background:
Proteolytic degradation of the aortic wall by matrix metalloproteinases (MMPs) is considered important in the pathogenesis of abdominal aortic aneurysms (AAAs). Many of these MMPs are inhibited by tetracycline derivatives, which may have the potential to retard aneurysm growth.
Methods:
Patients undergoing elective repair of an AAA (n = 5) received an intravenous bolus of tetracycline (500 mg) on induction of anaesthesia and levels of tetracycline in serum, aneurysm wall and mural thrombus were assessed by microbiological assay. In a separate series of patients (n = 7) aneurysm biopsies were placed into explant culture (with and without tetracyline) and the accumulation of protein, hydroxyproline, MMP-9, interleukin (IL) 6 and monocyte chemoattractant protein (MCP) 1 in the medium was assessed by colorimetric assay or immunoassay.
Results:
At aortic cross-clamping the median concentration of tetracycline was 8.3 microg/ml in serum, 2.9 microg per g tissue in aortic wall and zero in mural thrombus. Tetracycline inhibited, in a concentration-dependent manner, both MMP-9 and MCP-1 secretion (P = 0.022 and P = 0.018 respectively), but did not alter hydroxyproline or IL-6 secretion. At the highest concentration of tetracycline (100 microg/ml) median MMP-9 secretion was reduced from 27 to 5 ng/ml (P = 0.007) and median MCP-1 secretion was reduced from 50 to 10 ng/ml (P = 0.008).
Conclusion:
Tetracycline rapidly penetrates the aortic wall, but the concentration achieved may be insufficient to alter collagen turnover through limitation of MMP production or activity.
Insights
Tetracycline effectively penetrates the aortic wall, reducing matrix metalloproteinase-9 (MMP-9) and monocyte chemoattractant protein-1 (MCP-1) in abdominal aortic aneurysm (AAA) patients. However, concentrations may not be sufficient to impact collagen turnover.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Biochemistry
Background:
- Matrix metalloproteinases (MMPs) drive proteolytic degradation of the aortic wall, a key factor in abdominal aortic aneurysm (AAA) pathogenesis.
- Tetracycline derivatives are known inhibitors of MMPs and show potential for retarding aneurysm growth.
Purpose of the Study:
- To assess tetracycline penetration into the aortic wall and its effect on MMPs and inflammatory mediators in AAA patients.
- To determine if therapeutic tetracycline concentrations can inhibit key enzymes involved in AAA progression.
Main Methods:
- Intravenous tetracycline administration to AAA patients undergoing elective repair.
- Measurement of tetracycline levels in serum, aortic wall, and mural thrombus.
- Explant culture of aneurysm biopsies to assess the impact of tetracycline on MMP-9, MCP-1, IL-6, and hydroxyproline secretion.
Main Results:
- Tetracycline achieved measurable concentrations in serum and aortic wall tissue.
- Tetracycline demonstrated a concentration-dependent inhibition of MMP-9 and MCP-1 secretion.
- No significant alteration in hydroxyproline or IL-6 secretion was observed.
Conclusions:
- Tetracycline rapidly penetrates the aortic wall in AAA patients.
- Achieved concentrations may be insufficient to significantly alter collagen turnover by limiting MMP production or activity.
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