Nicotine Exacerbates TAAD Formation Induced by Smooth Muscle-Specific Deletion of the TGF-β Receptor 2.
Nicotine Exacerbates TAAD Formation Induced by Smooth Muscle-Specific Deletion of the TGF-β Receptor 2.
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DOI：
10.1155/2021/6880036
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发表时间：
2021
影响因子：
4.1
通讯作者：
Jiang Z
中科院分区：
文献类型：
--
作者：
Chun C;Qi X;Wang F;Madrid KB;Saldarriaga LA;Fisch MR;Brantly ML;Upchurch GR Jr;Jiang Z
吸烟是胸主动脉瘤和夹层（TAAD）的一个确定的危险因素。然而，由于缺乏有效的动物模型，对其潜在机制知之甚少。本研究建立了一种小鼠模型，可用于研究烟草烟雾模拟物对TAAD形成的加剧。TAADs是通过诱导删除平滑肌细胞特异性Tgfbr2受体而产生的。利用该模型，第一组实验评估了尼古丁盐（34.0 mg/kg/day）、无尼古丁碱（NFB， 5.0 mg 90天颗粒）和香烟烟雾提取物（0.1 ml/小鼠/day）的疗效。与各自的对照组相比，只有NFB颗粒促进TAAD扩张（23±3% vs. 12±2%,P = 0.014），并且这种效果是以bb50 %的急性死亡率为代价实现的。渗透性微型泵以极高但非致死剂量（15.0或45.0 mg/kg/天）输注NFB未能加速TAAD扩张。有趣的是，与β-氨基丙腈（BAPN）共刺激分别在3.0和45.0 mg/kg/天的剂量下促进TAAD扩张和主动脉破裂，表明BAPN使TAAD对NFB的反应增感。在随后的分析中，NFB的有害影响与巨噬细胞、中性粒细胞和t细胞聚集在结构破坏区域，增强基质金属蛋白酶- (MMP-) 2的产生，以及外膜纤维化减弱的病理性血管生成有关。综上所述，尼古丁加剧TAAD形成的建模需要优化药物的化学形态、给药途径、剂量以及TAAD的病理复杂性。在本研究的优化条件下，慢性炎症和外膜异常重塑是NFB加剧TAAD形成的关键途径。
Tobacco smoke is an established risk factor for thoracic aortic aneurysms and dissections (TAAD). However, little is known about its underlying mechanisms due to the lack of validated animal models. The present study developed a mouse model that may be utilized to investigate exacerbation of TAAD formation by mimetics of tobacco smoke. TAADs were created via inducible deletion of smooth muscle cell-specific Tgfbr2 receptors. Using this model, the first set of experiments evaluated the efficacy of nicotine salt (34.0 mg/kg/day), nicotine free base (NFB, 5.0 mg 90-day pellets), and cigarette smoke extract (0.1 ml/mouse/day). Compared with their respective control groups, only NFB pellets promoted TAAD dilation (23 ± 3% vs. 12 ± 2%, P = 0.014), and this efficacy was achieved at a cost of >50% acute mortality. Infusion of NFB with osmotic minipumps at extremely high, but nonlethal, doses (15.0 or 45.0 mg/kg/day) failed to accelerate TAAD dilation. Interestingly, costimulation with β-aminopropionitrile (BAPN) promoted TAAD dilation and aortic rupture at dosages of 3.0 and 45.0 mg/kg/day, respectively, indicating that BAPN sensitizes the response of TAADs to NFB. In subsequent analyses, the detrimental effects of NFB were associated with clustering of macrophages, neutrophils, and T-cells in areas with structural destruction, enhanced matrix metalloproteinase- (MMP-) 2 production, and pathological angiogenesis with attenuated fibrosis in the adventitia. In conclusion, modeling nicotine exacerbation of TAAD formation requires optimization of chemical form, route of delivery, and dosage of the drug as well as the pathologic complexity of TAADs. Under the optimized conditions of the present study, chronic inflammation and adventitial mal-remodeling serve as critical pathways through which NFB exacerbates TAAD formation.
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影响因子：
4.2
作者：
HENNINGFIELD, JE;STAPLETON, JM;LONDON, ED
通讯作者：
LONDON, ED
影响因子：
4.6
作者：
Guo ZZ;Cao QA;Li ZZ;Liu LP;Zhang Z;Zhu YJ;Chu G;Dai QY
通讯作者：
Dai QY
影响因子：
20.1
作者：
Humphrey JD;Schwartz MA;Tellides G;Milewicz DM
通讯作者：
Milewicz DM
DOI：
10.1126/science.1192152
发表时间：
2011-04-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Habashi JP;Doyle JJ;Holm TM;Aziz H;Schoenhoff F;Bedja D;Chen Y;Modiri AN;Judge DP;Dietz HC
通讯作者：
Dietz HC
DOI：
10.1016/j.jmbbm.2020.104264
发表时间：
2021-04
影响因子：
3.9
作者：
Kawamura Y;Murtada SI;Gao F;Liu X;Tellides G;Humphrey JD
通讯作者：
Humphrey JD