Ishii Kenjiro, Takeuchi Hiroya, Fukunaga Koichi, Hirano Yuki, Suda Koichi, Hagiwara Tomoko, Miyasho Taku, Yamada Shingo, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Saikawa Yoshiro, Omori Tai, Betsuyaku Tomoko, Ichihara Atsuhiro, Kitagawa Yuko
1Department of Surgery, School of Medicine, Keio University, Tokyo, Japan.
Exp Lung Res. 2015 May;41(4):199-207. doi: 10.3109/01902148.2014.993444. Epub 2015 Apr 6.
PURPOSE/AIM: We performed a randomized, prospective animal study to investigate whether inhibiting the renin-angiotensin system with a (pro)renin receptor blocker (PRRB) prevents acute lung injury (ALI) in a rodent model.
We used Thirty-six male Sprague-Dawley rats. We administered lipopolysaccharide (LPS; 2 mg/kg) intratracheally with or without PRRB pretreatment (1 mg/kg/d).
We performed bronchoalveolar lavage (BAL) and lung removal at 4 h after LPS administration and measured levels of inflammatory cytokines, high mobility group box 1 (HMGB-1) protein, and total protein in bronchoalveolar lavage fluid (BALF). Myeloperoxidase (MPO) activity was detected in lung tissue homogenates using a sensitive ELISA. We performed hematoxylin and eosin staining and immunohistochemical staining for nonproteolytically activated prorenin in the left lung.
The PRRB decreased leukocyte counts and total protein, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-2, IL-6, and IL-10 levels in the BALF and MPO activity in lung tissue. The PRRB reduced interstitial edema, hemorrhage, and the neutrophil count in the lung tissues. Consistent with the reduction in lung tissue damage, immunohistochemical staining showed that the PRRB decreased the amount of nonproteolytically activated prorenin.
The PRRB blocked LPS-induced inflammatory response in the lung and protected against ALI. Therefore, it is a potential therapeutic agent for preventing ALI.
我们进行了一项随机、前瞻性动物研究，以调查使用（前）肾素受体阻滞剂（PRRB）抑制肾素 - 血管紧张素系统是否能在啮齿动物模型中预防急性肺损伤（ALI）。
我们使用了36只雄性Sprague-Dawley大鼠。我们经气管内给予脂多糖（LPS；2mg/kg），同时或不进行PRRB预处理（1mg/kg/d）。
在给予LPS后4小时进行支气管肺泡灌洗（BAL）和肺切除，测量支气管肺泡灌洗液（BALF）中炎性细胞因子、高迁移率族蛋白B1（HMGB-1）蛋白和总蛋白的水平。使用灵敏的酶联免疫吸附测定法（ELISA）检测肺组织匀浆中的髓过氧化物酶（MPO）活性。我们对左肺进行苏木精和伊红染色以及非蛋白水解激活的前肾素的免疫组织化学染色。
PRRB降低了BALF中的白细胞计数、总蛋白、肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β、IL-2、IL-6和IL-10水平以及肺组织中的MPO活性。PRRB减轻了肺组织中的间质水肿、出血和中性粒细胞计数。与肺组织损伤的减轻一致，免疫组织化学染色显示PRRB减少了非蛋白水解激活的前肾素的量。
PRRB阻断了LPS诱导的肺部炎症反应并预防了ALI。因此，它是预防ALI的一种潜在治疗药物。
