Department of Critical Care Medicine, Nanjing Zhong-Da Hospital, Southeast University School of Medicine, Nanjing, People's Republic of China.
J Surg Res. 2013 Dec;185(2):740-7. doi: 10.1016/j.jss.2013.06.052. Epub 2013 Jul 17.
Pulmonary fibrosis occurs in approximately 60% of patients with acute respiratory distress syndrome and has been significantly correlated with a poor outcome. The overexpression of angiotensin (Ang) II can induce lung inflammation and fibrosis. This observation, coupled with the knowledge that Ang-(1-7) is considered to be an endogenous antagonist of Ang II, led us to hypothesize that Ang-(1-7) would prevent lung remodeling in patients with acute respiratory distress syndrome.
The protocol involved five groups: (1) control, (2) lipopolysaccharide (LPS), (3) losartan as a positive control group, (4) Ang-(1-7), and (5) [D-Ala7]-Ang-(1-7) (A779), an antagonist of the Ang-(1-7) receptor. Acute lung injury was induced by an intratracheal injection of LPS 5 mg/kg in C57BL/6 mice. Losartan (10 mg/kg) was administered by gavage daily, starting from 1 d before LPS stimulation. Ang-(1-7) or A779 in saline (100 ng/kg/min) was infused subcutaneously 1 h before acute lung injury induction for 3 or 7 d. The lung tissues were harvested for analysis at day 3 or 7 after injection of LPS.
LPS stimulation resulted in significantly increased inflammation, edema, and lung collagen production. With Ang-(1-7) treatment, the lung fibrosis score and hydroxyproline level were significantly reduced, and the expression of transforming growth factor-β and Smad2/3 were decreased on days 3 and 7. Losartan attenuated lung fibrosis similarly to Ang-(1-7) after LPS exposure. In the A779 group, a tendency was seen to aggravate collagen deposition and lung remodeling.
These findings indicate an antiremodeling role for Ang-(1-7) in acute lung injury, similar to the blocker of Ang II receptor, that might be at least partially mediated through an Ang-(1-7) receptor.
大约 60%的急性呼吸窘迫综合征患者会发生肺纤维化，且其与不良预后显著相关。血管紧张素（Ang）II 的过度表达可诱发肺炎症和纤维化。这一观察结果，再加上 Ang-(1-7)被认为是 Ang II 的内源性拮抗剂这一认识，使我们假设 Ang-(1-7)可预防急性呼吸窘迫综合征患者的肺重塑。
该方案涉及五个组：（1）对照组；（2）脂多糖（LPS）组；（3）氯沙坦作为阳性对照组；（4）Ang-(1-7)组；（5）[D-Ala7]-Ang-(1-7)（A779）组，即 Ang-(1-7)受体拮抗剂。通过气管内注射 LPS 5mg/kg 诱导 C57BL/6 小鼠急性肺损伤。氯沙坦（10mg/kg）灌胃，于 LPS 刺激前 1d 开始每天给药。Ang-(1-7)或 A779 用生理盐水（100ng/kg/min）于急性肺损伤诱导前 1h 皮下输注，持续 3 或 7d。在 LPS 注射后第 3 或 7 天采集肺组织进行分析。
LPS 刺激导致炎症、水肿和肺胶原蛋白产生显著增加。给予 Ang-(1-7)治疗后，肺纤维化评分和羟脯氨酸水平显著降低，转化生长因子-β和 Smad2/3 的表达在第 3 天和第 7 天也降低。氯沙坦在 LPS 暴露后与 Ang-(1-7)类似，可减轻肺纤维化。在 A779 组中，胶原沉积和肺重塑的趋势加重。
这些发现表明，Ang-(1-7)在急性肺损伤中具有抗重塑作用，与 Ang II 受体阻滞剂相似，至少部分是通过 Ang-(1-7)受体介导的。
