Doxycycline inhibits elastin degradation and reduces metalloproteinase activity in a model of aneurysmal disease

被引:116
作者
Boyle, JR [1 ]
McDermott, E [1 ]
Crowther, M [1 ]
Wills, AD [1 ]
Bell, PRF [1 ]
Thompson, MM [1 ]
机构
[1] Univ Leicester, Dept Surg, Leicester LE1 7RH, Leics, England
关键词
D O I
10.1016/S0741-5214(98)70367-2
中图分类号
R61 [外科手术学];
学科分类号
摘要
Purpose: Abdominal aortic aneurysms are characterized by degradation of the extracellular matrix, with a reduction in the elastin concentration of the arterial media. These changes are mediated by increased levels of endogenous metalloproteinases (MMPs) within the aorta, which provide a potential therapeutic target for pharmacologic agents aimed at reducing the growth rate of small aneurysms. In this study, the ability of doxycycline-an MMP inhibitor-to reduce matrix degradation was assessed in a previously described model of aneurysmal disease that used a brief pulse of elastase to induce MMP production and elastin degradation in arterial organ cultures. Methods: Porcine aortic segments (n = 8) were preincubated in exogenous pancreatic elastase for 24 hours before culture in standard conditions for 13 days with both 1 and 10 mg/L doxycycline. Control segments were cultured both without doxycycline and without elastase. At the termination of culture, MMPs were extracted from the tissue and quantified by a combination of substrate gel enzymography and immunoblotting. The volume fractions of elastin and collagen were determined by stereologic analysis of sections stained with Miller's elastin and van Gieson's stain. Results: Stereologic analysis demonstrated a significant preservation of elastin in aorta treated with doxycycline 10 mg/L (p < 0.001) and demonstrated that this preservation was accompanied by a significant reduction in MMP-9 activity (p < 0.02). Immunoblotting for tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) showed no decreased production in the doxycycline-treated groups. Conclusions: Therapeutic ranges of doxycycline significantly inhibited elastin degradation and MMP-9 production within aortic organ cultures. These data suggest that doxycycline may have a potential application in reducing the growth rates of small abdominal aortic aneurysms.
引用
收藏
页码:354 / 361
页数:8
相关论文
共 51 条
[1]   ELASTASE-INDUCED EXPERIMENTAL ANEURYSMS IN RATS [J].
ANIDJAR, S ;
SALZMANN, JL ;
GENTRIC, D ;
LAGNEAU, P ;
CAMILLERI, JP ;
MICHEL, JB .
CIRCULATION, 1990, 82 (03) :973-981
[2]   CORRELATION OF INFLAMMATORY INFILTRATE WITH THE ENLARGEMENT OF EXPERIMENTAL AORTIC-ANEURYSMS [J].
ANIDJAR, S ;
DOBRIN, PB ;
EICHORST, M ;
GRAHAM, GP ;
CHEJFEC, G .
JOURNAL OF VASCULAR SURGERY, 1992, 16 (02) :139-147
[3]  
BANCROFT JD, 1984, MANUAL HISTOLOGICAL, P39
[4]   PROPRANOLOL DELAYS THE FORMATION OF ANEURYSMS IN THE MALE BLOTCHY MOUSE [J].
BROPHY, C ;
TILSON, JE ;
TILSON, MD .
JOURNAL OF SURGICAL RESEARCH, 1988, 44 (06) :687-689
[5]  
BROPHY CM, 1991, SURG RES COMMUN, V10, P315
[6]   SMOOTH-MUSCLE CELL ELASTASE, ATHEROSCLEROSIS, AND ABDOMINAL AORTIC-ANEURYSMS [J].
COHEN, JR ;
SARFATI, I ;
DANNA, D ;
WISE, L ;
HUNTER, G ;
MANNICK, JA ;
MACKENZIE, JW ;
DARLING, RC .
ANNALS OF SURGERY, 1992, 216 (03) :327-332
[7]  
COHEN JR, 1987, SURG GYNECOL OBSTET, V164, P355
[8]   The Oxford screening program for aortic aneurysm and screening first-order male siblings of probands with abdominal aortic aneurysm [J].
Collin, J .
ABDOMINAL AORTIC ANEURYSM: GENETICS, PATHOPHYSIOLOGY, AND MOLECULAR BIOLOGY, 1996, 800 :36-43
[9]   VARIABLES THAT AFFECT THE EXPANSION RATE AND OUTCOME OF SMALL ABDOMINAL AORTIC-ANEURYSMS [J].
CRONENWETT, JL ;
SARGENT, SK ;
WALL, MH ;
HAWKES, ML ;
FREEMAN, DH ;
DAIN, BJ ;
CURE, JK ;
WALSH, DB ;
ZWOLAK, RM ;
MCDANIEL, MD ;
SCHNEIDER, JR .
JOURNAL OF VASCULAR SURGERY, 1990, 11 (02) :260-269
[10]   Variables that affect the expansion rate and rupture of abdominal aortic aneurysms [J].
Cronenwett, JL .
ABDOMINAL AORTIC ANEURYSM: GENETICS, PATHOPHYSIOLOGY, AND MOLECULAR BIOLOGY, 1996, 800 :56-67