The matrix metalloproteinase inhibitor BB-94 limits expansion of experimental abdominal aortic aneurysms

Purpose: Matrix metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix of the aortic wall and lead to the formati on of abdominal aortic aneurysms (AAAs). MMP inhibitors are a class of drug s that were developed to inhibit the activity of these proteolytic enzymes and are currently being studied as a way to control inflammatory diseases a nd cancer metastases. In this project, BB-94 (also known as batimastat), a specific inhibitor of MMPs, was evaluated for its ability to control aneury smal growth in an experimental AAA model. Methods: Experimental AAAs were created in a standard rat model by perfusin g elastase into an isolated segment of aorta. The rats then were randomized to postoperatively undergo treatment daily with the MMP inhibitor BB-94 or the carrier control solution. Measurements of the aortic diameter were mad e at the time of initial surgery and at the time of death on postoperative day 7. Aortic tissue was obtained for histologic examination, elastin evalu ation, and MAC 1-alpha antibody staining to evaluate the inflammatory respo nse. Results: The rats that underwent treatment with BB-94 had significantly les s aneurysmal dilatation and a 113% increase in aortic size, as compared wit h the control rats that. had a 157% increase (P =.026). Histologic examinat ion of the harvested aortas and grading of the elastin content showed a sig nificantly greater elastin preservation in these rats that were treated wit h BB-94 as compared with the control rats (P =.036). MAC I-alpha antibody s taining showed an attenuation of the inflammatory response in the group of rats that underwent treatment with BB-94. Morphologic examination also reve aled that the control of the inflammatory response correlated with the area s of elastin preservation. Conclusion: MMP inhibition with BB-94 limited the expansion of AAAs in this rat model. BB-94 appears to work not only as a direct pharmacologic inhibi tor of MMPs but also as an interference with the inflammatory response seen in AAAs. Control of the inflammatory response was an unexpected result and may be related to the alterations in feedback mechanisms that are related to extracellular matrix degradation. Because this class of drugs is present ly being developed to control the MMP inflammatory response seen with arthr itis, these drugs also may ultimately serve as a pharmacologic treatment fo r patients with AAAs.