A mechanism for matrikine regulation in acute inflammatory lung injury.
A mechanism for matrikine regulation in acute inflammatory lung injury.
复制标题
急性炎症性肺损伤中苦参碱调节的机制。
DOI：
10.1172/jci.insight.140750
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发表时间：
2021
期刊：
影响因子：
8
通讯作者：
Xu,Xin
中科院分区：
文献类型：
--
作者：
Robison,SarahW;Li,JinDong;Viera,Liliana;Blackburn,JonathanP;Patel,RakeshP;Blalock,JEdwin;Gaggar,Amit;Xu,Xin
脯氨酸-甘氨酸-脯氨酸(PGP)及其乙酰化形式(Ac-PGP)是胶原降解产生的中性粒细胞趋化物质，已被证明在慢性炎症性疾病中发挥作用。然而，Matrikine在急性炎症中的调节机制尚未完全建立。在这里，我们证明了这些多肽是通过寡肽转运蛋白PEPT2从肺中主动转运出来的。在小鼠模型中，气管内滴注Ac-PGP后，随着时间的推移，支气管肺泡灌洗液(BAL)中标记多肽的浓度迅速下降，并重新分布到肺外部位。在体外，在呼吸道上皮细胞中抑制PEPT2转运体或使用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加头孢羟氨丁酸的动物在BAL和肺组织中的Ac-Pgp水平较高。利用急性脂多糖诱导的肺损伤模型，我们证明了PEPT2阻断了肺Ac-Pgp水平的升高和肺部炎症。我们使用急性肺损伤患者的临床样本与呼吸道上皮细胞共培养进一步验证了这一效果。据我们所知，这是第一次确定主动Matrikine转运作为调节急性炎症的机制的体内外意义，并证明它可能作为潜在的治疗靶点。
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.