THE ACTIONS OF TETRACYCLINES ON CONNECTIVE TISSUE: TOWARD MEDICAL THERAPIES FOR AORTIC ANEURYSMS

I.J. Franklin, J.T. Powell
Imperial College School of Medicine at Charing Cross Department of Vascular Surgery Charing Cross Hospital
London, Kingdom

The extracellular matrix (ECM) was once considered to be a relatively inert structure, a stable scaffold in which the cells of the tissue were suspended. It is now clear that the ECM undergoes continuous synthesis and degradation. These processes are tightly regulated by complex interactions between the cell surfaces and the surrounding ECM, and abnormalities of connective tissue metabolism lead to a variety of diseases. As the intricacies of ECM biology are unraveled, potential new approaches to treating conditions resulting from disordered matrix turnover are being explored. The cause of abdominal aortic aneurysms is unknown though genetic make up, smoking, hypetension, serum lipids and atherosclerosis and have all been implicated. Destruction of elastin, the extensile component of the ECM in the aortic wall, appears to be an early event. This is followed by extensive remodelling of fibrillar collagen which is the EC M component providing the tensile strength of the aorta. This remodelling is associated with elevated activity of matrix metalloproteinases (MMPs), a family of tightly regulated enzymes responsible for connective tissue turnover. An important histological feature is a variable inflammatory infiltrate in the adventitial layer of the aneurysm wall. The number of inflammatory cells correlates with aneurysm diameter. Experimental aneurysms in rats and rabbits are also characterised by adventitial inflammation. The evidence that elevated MMP activity and inflammation are central processes in aneurysmal dilatation is mounting. Moreover, infectious agents, in particular Chlamydia pneumoniae, are being implicated in the causation of aneurysmal disease. These processes are therefore logical targets for drugs aimed at limiting expansion and rupture of AAAs. The tetracycline (TC) family of antibiotics has been found to modify collagen metabolism in ways quite unrelated to its original intended action. This review examines the role TC might play in the treatment of aortic aneurysms.

P. 139-147

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