腹主动脉瘤动物模型 z-bo 2020-12-28 1712

　　Abdominal aortic aneurysm (AAA) is a disease related to sudden death caused by aneurysm rupture. So far, there has not been any drug treatment, including monitoring and the option of opening or endovascular repair. Both positive interventions are expensive and dangerous for patients. If medical treatment is available, surgical costs and risks can be reduced. To identify potential medical treatment, one must understand the formation and development of AAA. Animal models can be used as useful tools to study the formation and development of AAAS. Some animal models replicate inflammation, fibrous extracellular matrix (ECM) destruction, and aortic dilation, all of which can affect the development of aortic aneurysms in humans. In addition to the advantages of experimental AAA models, there are limitations, including that they do not replicate the exact pathological conditions of human AAA. Therefore, it is difficult to translate the results of experimental research into the clinical application of human AAA. The various injuries used to obtain experimental aortic dilatation reflect the many ways in which an aneurysm may be triggered or damaged. The purpose of the systematic review is to identify different types of animal models for studying the development, progression and treatment of AAA, and to emphasize their advantages and limitations. Rodents

　　 Elastase model: The elastase model is an anesthetized animal through a midline abdominal incision. The aorta is dissected, and noninvasive forceps are positioned below the renal artery and at the bifurcation. Through the catheter, the separated part of the aorta is perfused with porcine pancreatic elastase. After the perfusion, the catheter was removed and blood flow was restored before the abdomen was closed. The pathological findings of this AAA model have multiple similarities with human findings, including degradation of inner elastin and infiltration of outer membrane macrophages. Anidal and others successfully developed a rat AAA elastase animal model. Perfusion for 2 hours, AAA lasted more than 3 weeks. Significant expansion can be seen after inferior renal artery perfusion, but the early expansion of blood vessels is the result of mechanical stress. , The AAA generation rate was 91% after 5 minutes of elastase infusion. After 7 days, the aortic diameter did not increase after self-perfusion. After 14 days, the aorta increased by 134±8%. The observation period is now 2 to 4 weeks, but the most common is 14 days. Bhamidipati et al. reported aneurysm formation in a mouse model around the outer membrane of elastase. An increase of 82±15% after 14 days indicates that the elastase model is feasible and less traumatic. The elastase model was used to test the sex difference of AAA. Ailawadi et al. reported that 14 days after elastase infusion, the average aortic diameter of male and female mice increased by 200±37.6% and 69.4±26.5%, respectively. The incidence of AAA is 100% in males and 29% in female mice. These findings are consistent with those of human AAAS. Macrophage infiltration and matrix metalloproteinase (MMP) 9 are more obvious in the outer membrane and outer membrane of male mice. Wu et al. also found that female mice had a significant protective effect on AAA formation. They reported that estrogen treatment in male rats significantly reduced AAA formation and inhibited inflammatory cell infiltration and the expression of MMP-2 and MMP-9. , Indicating the protective effect of estrogen on AAA.

　　Calcium chloride model: Calcium chloride (CaCl2) is applied around the aorta to induce AAAS in the inferior renal artery. Qiu et al. reported the first reproducible animal model in mice, covering the dissected subrenal aorta with cotton gauze soaked in calcium chloride for 10 minutes. A 110% increase in diameter was reported at the end of the third week after CACl2 exposure. After CaCl2 exposure, the application of phosphate to the inferior renal artery to improve the CaCl2 model resulted in increased calcification. In mice and rats, various CaCl2 concentrations, different exposure times and follow-up times seem to be used; mice exposed to 0.25-0.5M for 15 minutes, followed up for 6-10 weeks, the incidence rate is 50- 100%. Aortic dilation is mainly reported immediately after exposure. For rats, 0.5-0.75M CaCl2 treatment lasted 15-30 minutes, increasing by 42% at 28 days postoperatively. CaCl2 exposure around the aorta resulted in a decrease in elastin content and loss of elastin integrity in the aorta of rats and mice. The presence of inflammatory cells, such as macrophages, neutrophils and white blood cells. There was no significant increase in the diameter of the aorta 1 week after surgery. The results of Longo et al. showed that 3 days after CaCl2 induced AAA, the infiltrating inflammation of the intima and middle layer of the aorta of mice changed. Aortic elastin degradation was reported 7 days after surgery. Many attempts have been reported to prevent the formation or expansion of AAA by blocking and stimulating different biochemical pathways. Yoshimura et al. reported that inhibition of CaCl2-induced c-Jun N-terminal kinase (JNK) in mouse AAAs resulted in the inhibition of AAA formation and growth. JNK helps to promote ECM synthesis and MMP production. In established AAAs, inhibition of JNK resulted in a significant reduction in the diameter of the aorta and less damage to the elastic layer. The results of Isenburg et al. showed that prior to the application of CaCl2, topical treatment of healthy rat aorta with five-alloy glucose (PGG) would hinder the formation of AAA. The histological changes caused by CACl2 treatment were not obvious when the aorta was treated with PGG. The rat aorta treated with PGG has complete elasticity. In addition, compared with the control group, after 56 days of treatment around the PGG aorta, the diameter of the aorta remained or even decreased, and continued to expand.

　　 Xenograft model: Inferior renal artery transplantation from one species to another, such as guinea pigs to rats, to induce aneurysms. Before aortic implantation, the donor aorta is decellularized with detergent, such as sodium dodecyl sulfate (SDS). The decellularization of the donor graft needs to trigger a slower immune response rather than an acute lethal rejection. During the preparation of the donor graft, all cells were removed from the three layers of the aorta, but the ECM collagen and elastin network were preserved. The formation of AAA is related to the interspecies immunogenicity of aortic ECM, because the removal of all arterial wall cells with a detergent that only leaves fibrous ECM proteins (such as elastin and collagen) does not prevent xenograft expansion. The donor graft AAAS is infiltrated by intimal monocytes and T lymphocytes. ECM pre-immunization of guinea pig aorta accelerates xenograft destruction and triggers AAA rupture. Rupture does not always occur during AAA formation. A 100% increase in AAA diameter was observed after 10 days. Allaire et al. examined the role of vascular smooth muscle cells (VSMC) in xenograft models. VSMCs inoculated with donor grafts have protective effects in ECM, including preservation of elastin, thereby preventing the formation of AAA. VSMC vaccination also reduced medial inflammation. These results are consistent with the lack of VSMC in human AAAS.

　　 Angiotensin II model: Angiotensin II infusion is the most commonly used mouse AAA model. In most cases, apolipoprotein E deficiency (ApoE -/-) mice are used. Low-density lipoprotein receptor-deficient (LDLR-/-) mice and wild-type mice are also used in this model. Continuous subcutaneous infusion of AngII for 28 days induced the formation of adrenal artery AAA. This model is also the most commonly used transgenic AAA mouse model. Apolipoprotein E-/- mice are hyperlipidemia mice with C57BL/6 mice as the background. C57BL/6 mice also developed AAA, but the frequency was lower than that of ApoE-/- or LDLR-/- mice. This shows that hyperlipidemia is not necessary, but it is beneficial to the development of AAA. AngII stimulates the inflammatory response of blood vessel walls independently of changes in blood pressure. AngII promotes adrenal aorta expansion, atherosclerosis, medial hypertrophy, accumulation of macrophages in the outer elastic layer, and thrombosis in ApoE//- mice, which mimics the development of human AAA. In the elastase model, the AngII model was used to show the AAA development preference of male mice. In addition, the neonatal exposure of female mice to testosterone leads to the development of AAA, and its incidence is similar to that of male mice.

　　AAA transgenic model: Traditionally, C57BL/6 mice have become the background strain for the selection and breeding of AAA model genetic mice. The deletion of different genes promotes aneurysm degeneration in different mouse models. The purpose of the transgenic model is to test the impact of specific genes on the formation or development of AAA. Use one of the above four induction methods to induce AAA, such as the elastase model. The results of Pyo et al. showed that the knockout of MMP-9 and the double knockout of MMP-9 and MMP-12 can inhibit the formation of AAA in mice induced by elastase. Research by Longo et al. showed that the lack of MMP-12 alone did not cause AAA. Knockout of MMP-2 or MMP-9 prevented the formation of AAA in the calcium chloride model. This article reports the preservation of the inner elastic sheet of AAA-induced MMP-9 knockout mice. Tissue inhibitor of metalloproteinases (TIMP-) 1 has a protective effect in elastase-induced AAA mice. Compared with wild-type mice, TIMP-1-deficient mice produced larger AAAS after elastase AAA induction.

　　 Non-rodents: The introduction of endovascular treatment of AAA has created a demand for large animal AAA models, and AAA models have now been established. The complications of endovascular stent implantation were also tested on animals with similar human anatomy.

　　Chemical induction model: In the rabbit model, elastase is induced through the subrenal abdominal aorta for 5 minutes. When intimal damage is induced, the peak pressure during the induction process is 300-400 mmHg. Elastase-induced rabbits are all AAAs. In addition to the effect in the ANIDJARS initial elastase model, they also show intimal thickening caused by intimal damage. The porcine model elastase angioplasty and angioplasty cause intimal damage. Canine inferior renal artery injection of elastase induces AAAS. Over 8 weeks, 15 dogs developed aneurysms. Compared with the original aorta, the diameter increased by nearly 50%. ? This increase is significantly smaller than other studies on elastase AAA formation. Canine chymase inhibitors are used to test whether chymase inhibitors have any effect on the activation of MMP-9 in AAAS. Chymotrypsin inhibitors can prevent the occurrence of AAA, but the formation of AAA does not occur after elastase induction. In addition, the activity of MMP-9 in the chymotrypsin inhibitor treatment group was significantly reduced, suggesting that chymotrypsin plays a role in the progression of AAA by increasing MMP-9. They did not successfully induce AAA alone by applying 0.25 M CaCl2 to the inferior renal artery. The application of thioglycolate peri-aorta in rabbits with hypercholesterolemia causes the development of AAA. Except for the treatment of rabbits with elastase, collagenase or CaCl2 alone, no studies have been able to induce an increase in the abdominal aorta of large animals by more than 50%. Different changes in chemical changes and dilatation and/or aneurysmal stenosis have been tested. Except that the aorta was enlarged by 2.14 times after 21 days, no aortic enlargement was found in the animals treated with saline infusion and stenosis cuff. Histological changes were also found, such as intimal thickening, damage and fragmentation of the inner elastic layer. And the entire media elastic membrane is damaged. Proliferating cells of mesenchymal origin (fibroblasts and smooth muscle cells) and the proliferation of these cells are signs of aortic disease. In dogs and pigs, the combination of elastase, collagenase, and angioplasty has the potential for AAA formation. Hynck et al. used this combination to produce AAA in 10 pigs. Direct external measurement showed that the diameter of the aorta increased during the operation (62±35%). After 6 weeks, the diameter of the aorta increased by 94±37%. Although the studies discussed above can undoubtedly induce aneurysms in larger animals, long-term results beyond 6 weeks after induction of AAA in animal models are still lacking. Different concentrations of elastase were used to induce rabbit AAAS. After 3 months, the aneurysm was stable. After 5 months, the aneurysm showed signs of regeneration. Smooth muscle cells and elastin fibers increased, indicating that regeneration is possible when the balance is favorable for repair. Kloster et al. reported AAA lasting more than 28 days in a pig model. They performed an elastase infusion, followed by angioplasty and cuff placement close to the AAA. They proposed that the narrow cuff is responsible for expansion by creating continuous wall stress that prevents the regeneration process. Unfortunately, the study did not report the long-term results of AAA expansion after 28 days, so we can only guess whether the expansion will continue. Compared with human AAA, neutrophils are the main inflammatory cell type when elastase is used to induce AAA, which may be due to acute inflammation in these models.

　　Patch model: There are different versions of this model, but what all versions have in common is the application of the patch through longitudinal aorticotomy. The patch is oval in shape and inserted in the front to preserve the lumbar artery and prevent spinal cord ischemia. The bag is made of venous material and inserted into the aorta through a side-to-side anastomosis to form a large aneurysm sac. The most commonly used materials are veins, prosthetic vascular grafts and rectus fascia. Generally speaking, the expansion potential is low. Patches made of autologous materials, such as jejunum and peritoneal patches, have a higher risk of rupture. Other biological materials, such as the rectus abdominis fascia and vein patches, have rupture characteristics similar to those of humans. The irregular thickening of the serosal area is mainly caused by collagen fibers and fibroblasts, which is inconsistent with human findings.

　　 Conclusion: There is no perfect model of human AAA. Therefore, the quality of different models and species must be kept in mind when designing AAA studies in order to use the best model to support the purpose of the research. It is also necessary to understand the different induction methods and perform blind end-point measurements, which must be more effective than ±50% diameter expansion.