Inflammatory Aspects of Experimental Aneurysms. : Effect of Methylprednisolone and Cyclosporine

An experimental in vivo model of aortic aneurysm was established by perfusing an isolated segment of rat abdominal aorta with pancreatic elastase. Ten rats were used in each protocol. Saline-perfused aortas developed no aneurysmal dilations. Elastase-perfused aortas contained aneurysms in the perfused area and a total loss of elastic tissue. Control aortas contained no elastic tissue lesions. There was a quantitative relation between the amount of elastase perfused and aneurysm formation: 1-2 units induced neither macroscopic nor microscopic lesions; 3-6 units induced microscopic elastic tissue damage without macroscopic aneurysm; and more than 6 units produced aneurysmal dilation in all cases. In situ elastase secretion by macrophages was induced by perfusing rat aortas with thioglycollate-activated macrophages or with thioglycollate alone. There was aortitis without true aneurysm and a total loss of elastic tissue in the vicinity of activated macrophages within the aortic media. Perfusion of infra-aneurysmal amount of elastase (1 or 2 units) or thioglycollate plus plasmin (2 units) always induced a large aneurysm, whereas plasmin alone induced neither macroscopic nor microscopic lesions. These morphological results were supported by the significantly elevated elastolytic activity within the aortic wall of animals perfused with thioglycollate plus plasmin 9 days, after perfusion (207.6 +/- 54.8 micrograms elastin-rhodamine lysed/18 hr; control rats, 25.43 +/- 11.13). The results suggest that the presence of elastase within the aortic media leads to aneurysm formation. Activated macrophages within the aortic media may be responsible for elastase secretion and elastic tissue destruction. Plasmin may enhance elastase activity and aggravate the aneurysmal lesion.

Deficiencies of total collagen, type III collagen, and elastin have been proposed to explain aneurysm formation. Infrarenal aortas were collected from 19 patients (age 70 +/- 7 years) undergoing operative repair of abdominal aortic aneurysms (diameter 7 +/- 2 cm) and from 13 autopsies (age 63 +/- 17 years) of patients without aneurysm disease (controls). Wall thickness and collagen and elastin concentration were determined in full-thickness aorta. Collagen types I and III were measured after digestion with cyanogen bromide, which solubilized nearly 90% of total collagen for typing. Cyanogen bromide peptides were separated by sequential carboxymethylcellulose and agarose chromatography and quantified by peak area measurement with computerized image analysis. Histologic examination revealed prominent inflammatory cell infiltration and deficient, fragmented elastin in the aneurysms. Aortic wall thickness was similar in aneurysms and in control specimens. In the aneurysms, collagen was increased (37% +/- 16% vs 24% +/- 5%; p less than 0.05) and elastin was decreased (1% +/- 1% vs 12% +/- 7%; p less than 0.001), expressed as a percentage of delipidized, decalcified dry weight. Collagen type I accounted for 74% +/- 4% of aneurysm and 73% +/- 4% of control collagen solubilized for typing, and collagen type III accounted for 26% +/- 4% of aneurysm and 27% +/- 4% of control collagen solubilized for typing. Neither patients with a family history of aneurysms nor those without a history of aneurysms had collagen type III deficiency. Atherosclerotic abdominal aortic aneurysms are associated with an inflammatory process and may result from elastin degradation and not a deficiency of type III collagen.

The composition and mechanical properties of abdominal aortic aneurysms (AAAs) were studied. Stereologic study was used to measure volume fractions of the components of the aortic wall. Histochemical methods with picrosirus red and safranin O were developed to differentiate collagen from ground substance because they are difficult to distinguish from each other on histologic sections. Uniaxial tensile stress tests were carried out on a tensile-testing machine, and a stress-strain curve was plotted for each sample to study the mechanical properties of AAAs. The curves were fitted exponentially so sigma = aeb epsilon, where sigma is stress, epsilon is strain, and a and b are parameters. In aneurysms (n = 8) the volume fraction of elastin was decreased from 22.7% +/- 5.7% to 2.4% +/- 2.2%, and the volume fraction of smooth muscle cells was decreased from 22.6% +/- 5.5% to 2.2% +/- 2.0%, whereas the volume fraction of collagen and ground substance combined was increased from 54.8% +/- 4.5% to 95.6% +/- 2.5% compared with nonaneurysmal aortas (n = 8). There was no significant difference (p > 0.05) in the ratio of collagen to ground substance (2.1 +/- 0.5 vs 2.0 +/- 0.4) between AAAs and nonaneurysmal aortas. The elastic diagrams showed that AAAs (n = 7) are less distensible and stiffer than nonaneurysmal aortas (n = 5). Parameter a was unchanged (p > 0.5), but parameter b was significantly greater (p < 0.002) for aneurysmal aortas. Both the composition and mechanical properties of AAAs are different from those of nonaneurysmal aortas. The aneurysms were stiffer, and the volume fractions of collagen and ground substance were increased, whereas the volume fractions of elastin and muscle were decreased in aneurysms.