肾素抑制剂阿利吉仑可保护大鼠肺部免受脂肪栓塞的组织病理学影响。
The renin inhibitor aliskiren protects rat lungs from the histopathologic effects of fat embolism.
作者信息
Fletcher Amanda N, Molteni Agostino, Ponnapureddy Rakesh, Patel Chirag, Pluym Mark, Poisner Alan M
机构信息
From the University of Kansas Medical Center, Department of Preventive Medicine and Public Health (A.N.F.); Department of Pathology (A.M., C.P.); Department of Internal Medicine (R.P., M.P.), University of Missouri; and Department of Pharmacology and Toxicology (A.M.P.), University of Kansas Medical Center, Kansas, MO.
出版信息
J Trauma Acute Care Surg. 2017 Feb;82(2):338-344. doi: 10.1097/TA.0000000000001278.
BACKGROUND
Fat embolism (FE) and the consequent FE syndrome occurring after trauma or surgery can lead to serious pulmonary injury, including ARDS and death. Current treatment of FE syndrome is limited to supportive therapy. We have shown in a rat model that the renin angiotensin system plays a significant role in the pathophysiology of FE because drugs interfering with the renin angiotensin system, captopril and losartan reduce the histopathologic pulmonary damage. The purpose of the current study was to determine if inhibition of renin by aliskiren, an FDA-approved drug for treating hypertension, would produce effective protection in the same model.
METHODS
The FE model used intravenous injection of the neutral fat triolein in unanesthetized rats. Intraperitoneal injections of saline or aliskiren at either 50 or 100 mg/kg were performed 1 hour after FE induction via triolein. Rats were euthanized at 48 hours, and various histologic stains were used to examine the lungs.
RESULTS
(1) Fibrosis: rats treated with triolein showed significant fibrotic changes with increased collagen and myofibroblast activation (p < 0.0001 for both trichrome and α-smooth muscle actin staining). Aliskiren blocked this inflammatory and profibrotic process to a level indistinguishable from the controls (p < 0.0001 for both trichrome and α-smooth muscle actin staining). (2) Fat: rats treated with triolein showed a statistically significant increase in fat (p = 0.0006). Subsequent aliskiren administration at both doses reduced the size, distribution, and amount of fat droplets (low dose, p = 0.0095; high dose, p = 0.0028). (3) Vessel patency: the low dose of aliskiren blocked the reduction of lumen patency observed after triolein administration (p = 0.0058).
CONCLUSIONS
Aliskiren protected the lungs of rats from gross and histopathologic FE-induced pulmonary damage at 48 hours. Clinical implications include the use of aliskiren both prophylactically (before certain orthopedic procedures) and therapeutically (after severe trauma) to prevent the consequent severe pulmonary pathologic sequelae.
背景
创伤或手术后发生的脂肪栓塞（FE）及随之而来的FE综合征可导致严重的肺损伤，包括急性呼吸窘迫综合征（ARDS）甚至死亡。目前FE综合征的治疗仅限于支持性治疗。我们在大鼠模型中已表明，肾素-血管紧张素系统在FE的病理生理学中起重要作用，因为干扰肾素-血管紧张素系统的药物，卡托普利和氯沙坦可减轻肺组织病理学损伤。本研究的目的是确定阿利吉仑（一种经美国食品药品监督管理局批准用于治疗高血压的药物）对肾素的抑制作用在同一模型中是否能产生有效的保护作用。
方法
FE模型采用在未麻醉大鼠静脉注射中性脂肪三油酸甘油酯。在通过三油酸甘油酯诱导FE 1小时后，腹腔注射生理盐水或50或100 mg/kg的阿利吉仑。48小时后对大鼠实施安乐死，并使用各种组织学染色方法检查肺部。
结果
（1）纤维化：用三油酸甘油酯处理的大鼠显示出明显的纤维化改变，胶原蛋白增加且肌成纤维细胞活化（三色染色和α-平滑肌肌动蛋白染色均p < 0.0001）。阿利吉仑将这种炎症和促纤维化过程阻断至与对照组无差异的水平（三色染色和α-平滑肌肌动蛋白染色均p < 0.0001）。（2）脂肪：用三油酸甘油酯处理的大鼠脂肪含量有统计学意义的增加（p = 0.0006）。随后给予两种剂量的阿利吉仑均减少了脂肪滴的大小、分布和数量（低剂量，p = 0.0095；高剂量，p = 0.0028）。（3）血管通畅性：低剂量的阿利吉仑阻止了三油酸甘油酯给药后观察到的管腔通畅性降低（p = 0.0058）。
结论
阿利吉仑可保护大鼠肺部在48小时免受FE引起的肉眼可见和组织病理学肺损伤。临床意义包括在预防性（某些骨科手术前）和治疗性（严重创伤后）使用阿利吉仑以预防随之而来的严重肺部病理后遗症。
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