Accelerated enlargement of experimental abdominal aortic aneurysms in a mouse model of chronic cigarette smoke exposure.

BACKGROUND: Cigarette smoking and pulmonary emphysema are strongly associated with abdominal aortic aneurysms (AAAs), but the biologic mechanisms linking these conditions are undefined. STUDY DESIGN: To determine if exposure to cigarette smoke influences formation and growth of experimental AAAs, 129/SvEv mice were acclimated to daily cigarette smoke exposure for 2 weeks followed by transient elastase perfusion of the abdominal aorta to induce aneurysmal degeneration. Smoking was continued for intervals of either 2 or 12 weeks (8 mice per group). Nonsmoking 129/SvEv controls (n = 29) underwent elastase perfusion and followup evaluation at the same time intervals. In all animals, abdominal aortic diameter (AD) was measured to determine interval increases in AD (Delta AD), with AAAs defined as a Delta AD > 100%. RESULTS: Preperfusion and immediate postperfusion ADs were not significantly different between experimental groups. Aneurysmal dilatation was present 2 weeks after elastase perfusion in both smoking mice and nonsmoking controls, with no significant difference in final AD (mean +/- SEM: smoking, 1.23 +/- 0.11 mm versus nonsmoking, 1.22 +/- 0.05 mm). There were also no differences in the overall extent of aortic dilatation (Delta AD smoking, 136 +/- 24% versus nonsmoking, 138 +/- 10%), or the incidence of AAAs (smoking, 75% versus nonsmoking, 79%). Although all animals had developed AAAs by 12 weeks after elastase perfusion, the overall extent of aortic dilatation was 50% greater in smoking mice compared with nonsmoking controls (Delta AD smoking, 204 +/- 23% versus nonsmoking, 135 +/- 17%; p < 0.05). CONCLUSIONS: Short-term exposure to cigarette smoke did not alter initial development of experimental AAAs, but chronic smoke exposure was associated with a substantial increase in the late progression of aneurysmal dilatation. This novel combination of in vivo experimental models offers a new approach to investigate mechanisms by which cigarette smoking promotes aneurysmal degeneration.

Transient exposure to elastase induces mouse aortic wall smooth muscle cell production of MCP-1 and RANTES during development of experimental aortic aneurysm.

PURPOSE: Abdominal aortic aneurysm (AAA) is associated with chronic transmural inflammation and destruction of the elastic media. The purpose of this study was to elucidate molecular mechanisms that might orchestrate leukocyte recruitment into the outer aortic wall by determining whether CC chemokines contribute to development of aneurysm degeneration in an elastase-induced mouse model of AAA. METHODS: Adult male C57BL/6J mice underwent transient elastase perfusion of the abdominal aorta to induce development of AAA. At various intervals after elastase perfusion (0, 4, 7, 14 days), real-time reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assays were used to measure aortic wall expression of the CC (beta) chemokines, monocyte chemoattractant protein-1 (MCP-1) and regulated on activation, normal T-cell expressed and secreted (RANTES). Expression of these chemokines by cultured mouse aortic smooth muscle cells (AoSMC) was similarly assessed after transient (5 minutes) exposure to elastase solutions in vitro. RESULTS: Mouse aortic diameter (mean +/- SEM) increased to aneurysmal proportions by 14 days after elastase perfusion (from 0.51 +/- 0.03 mm to 1.34 +/- 0.32 mm; 163% increase; P <.05), with macrophage infiltration of the outer aortic wall beginning within 7 to 10 days. Increased aortic wall messenger RNA expression for MCP-1 (28-fold) and RANTES (11-fold) was observed on day 4, with maximal production of chemokine protein on day 7 (MCP-1, from 7.07 +/- 0.06 ng/mL to 19.60 +/- 0.19 ng/mL; P <.001; RANTES, from 0.23 +/- 0.006 ng/mL to 2.03 +/- 0.057 ng/mL; P <.001). Neither MCP-1 nor RANTES was detected in normal mouse aorta with immunohistochemistry, but both chemokines were abundant in AAA. Within 48 hours of transient exposure to elastase, cultured mouse AoSMC exhibited pronounced induction (>90-fold) of MCP-1 and RANTES, despite concomitant decrease in cell numbers. CONCLUSIONS: Increased mouse aortic wall expression of MCP-1 and RANTES occurs early in development of elastase-induced AAA and before onset of the chronic inflammatory response. Moreover, elastase directly stimulates AoSMC chemokine production in vitro. Elastase-induced medial SMC production of CC chemokines may therefore provide an important link between enzymatic injury, leukocyte recruitment, and aneurysmal degeneration of the aortic wall.