Department of Medicine, Division of Pulmonology, Allergy and Critical Care Medicine, and.
Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
JCI Insight. 2021 Apr 8;6(7):140750. doi: 10.1172/jci.insight.140750.
Proline-glycine-proline (PGP) and its acetylated form (Ac-PGP) are neutrophil chemoattractants generated by collagen degradation, and they have been shown to play a role in chronic inflammatory disease. However, the mechanism for matrikine regulation in acute inflammation has not been well established. Here, we show that these peptides are actively transported from the lung by the oligopeptide transporter, PEPT2. Following intratracheal instillation of Ac-PGP in a mouse model, there was a rapid decline in concentration of the labeled peptide in the bronchoalveolar lavage (BAL) over time and redistribution to extrapulmonary sites. In vitro knockdown of the PEPT2 transporter in airway epithelia or use of a competitive inhibitor of PEPT2, cefadroxil, significantly reduced uptake of Ac-PGP. Animals that received intratracheal Ac-PGP plus cefadroxil had higher levels of Ac-PGP in BAL and lung tissue. Utilizing an acute LPS-induced lung injury model, we demonstrate that PEPT2 blockade enhanced pulmonary Ac-PGP levels and lung inflammation. We further validated this effect using clinical samples from patients with acute lung injury in coculture with airway epithelia. This is the first study to our knowledge to determine the in vitro and in vivo significance of active matrikine transport as a mechanism of modulating acute inflammation and to demonstrate that it may serve as a potential therapeutic target.
脯氨酸-甘氨酸-脯氨酸 (PGP) 和其乙酰化形式 (Ac-PGP) 是由胶原蛋白降解产生的中性粒细胞趋化因子，它们在慢性炎症性疾病中发挥作用。然而，基质细胞衍生因子在急性炎症中的调节机制尚未得到很好的建立。在这里，我们表明这些肽通过寡肽转运蛋白 PEPT2 从肺部主动转运。在小鼠模型中经气管内滴注 Ac-PGP 后，支气管肺泡灌洗液 (BAL) 中标记肽的浓度随时间迅速下降，并重新分布到肺外部位。在气道上皮细胞中敲低 PEPT2 转运蛋白或使用 PEPT2 的竞争性抑制剂头孢羟氨苄，可显著减少 Ac-PGP 的摄取。接受气管内 Ac-PGP 加头孢羟氨苄的动物在 BAL 和肺组织中的 Ac-PGP 水平更高。利用急性 LPS 诱导的肺损伤模型，我们证明了 PEPT2 阻断增强了肺组织中的 Ac-PGP 水平和肺炎症。我们使用与气道上皮细胞共培养的急性肺损伤患者的临床样本进一步验证了这种效果。这是我们所知的第一个确定主动基质细胞衍生因子转运作为调节急性炎症的机制的体外和体内意义的研究，并证明它可能成为一个潜在的治疗靶点。
