Institute for Environmental Medicine, Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Int J Mol Sci. 2019 May 15;20(10):2395. doi: 10.3390/ijms20102395.
We have previously derived three related peptides, based on a nine-amino acid sequence in human or rat/mouse surfactant protein A, that inhibit the phospholipase A activity of peroxiredoxin 6 (Prdx6) and prevent the activation of lung NADPH oxidase (type 2). The present study evaluated the effect of these Prdx6-inhibitory peptides (PIP) in a mouse (C57Bl/6) model of acute lung injury following lipopolysaccharide (LPS) administration. All three peptides (PIP-1, 2 and 3) similarly inhibited the production of reactive O species (ROS) in isolated mouse lungs as detected by the oxidation of Amplex red. PIP-2 inhibited both the increased phospholipase A activity of Prdx6 and lung reactive oxygen species (ROS) production following treatment of mice with intratracheal LPS (5 µg/g body wt.). Pre-treatment of mice with PIP-2 prevented LPS-mediated lung injury while treatment with PIP-2 at 12 or 16 h after LPS administration led to reversal of lung injury when evaluated 12 or 8 h later, respectively. With a higher dose of LPS (15 µg/g body wt.), mortality was 100% at 48 h in untreated mice but only 28% in mice that were treated at 12-24 h intervals, with PIP-2 beginning at 12 h after LPS administration. Treatment with PIP-2 also markedly decreased mortality after intraperitoneal LPS (15 µg/g body wt.), used as a model of sepsis. This study shows the dramatic effectiveness of a peptide inhibitor of Prdx6 against lung injury and mouse mortality in LPS models. We propose that the PIP nonapeptides may be a useful modality to prevent or to treat human ALI.
我们之前基于人或鼠/兔表面活性蛋白 A 的九肽序列，衍生出三种相关的肽，这些肽可以抑制过氧化物还原酶 6（Prdx6）的磷脂酶 A 活性并阻止肺 NADPH 氧化酶（Ⅱ型）的激活。本研究评估了这些 Prdx6 抑制肽（PIP）在脂多糖（LPS）给药后急性肺损伤的小鼠（C57Bl/6）模型中的作用。三种肽（PIP-1、2 和 3）均能相似地抑制分离的小鼠肺中活性氧（ROS）的产生，这通过 Amplex red 的氧化来检测。PIP-2 抑制了 LPS 处理后 Prdx6 增加的磷脂酶 A 活性和肺活性氧（ROS）的产生。在 LPS 处理前对小鼠进行 PIP-2 预处理可预防 LPS 介导的肺损伤，而在 LPS 给药后 12 或 16 小时用 PIP-2 处理，则分别在 12 或 8 小时后导致肺损伤逆转。使用更高剂量的 LPS（15 µg/g 体重），未治疗的小鼠在 48 小时时的死亡率为 100%，但在 LPS 处理 12-24 小时间隔后用 PIP-2 治疗的小鼠中仅为 28%。用 PIP-2 治疗后，腹膜内 LPS（15 µg/g 体重），作为脓毒症模型的死亡率也显著降低。这项研究表明 Prdx6 抑制剂肽在 LPS 模型中对肺损伤和小鼠死亡率有显著效果。我们提出 PIP 九肽可能是预防或治疗人类 ALI 的有用方法。
