Benzyloxycarbonyl-proline-prolinal (ZPP): Dual complementary roles for neutrophil inhibition.
Benzyloxycarbonyl-proline-prolinal (ZPP): Dual complementary roles for neutrophil inhibition.
复制标题
苄氧羰基-脯氨酸-脯氨酸 (ZPP)：中性粒细胞抑制的双重互补作用。
DOI：
10.1016/j.bbrc.2019.07.111
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发表时间：
2019
影响因子：
3.1
通讯作者：
Noerager,BD
中科院分区：
文献类型：
--
作者：
Russell,DW;Hardison,M;Genschmer,KR;Szul,T;Bratcher,PE;AbdulRoda,M;Xu,X;Viera,L;Blalock,JE;Gaggar,A;Noerager,BD
中性粒细胞流入和激活会导致几种主要肺部疾病的器官损伤。这种炎症涌入是由经典趋化因子（例如白细胞介素 8）和下游介质（例如胶原片段兼中性粒细胞趋化因子 Pro-Gly-Pro (PGP)）引发和传播的，它们共享 ELR + CXC 受体家族。已知苄氧羰基-脯氨酸-脯氨酸 (ZPP) 通过抑制脯氨酰内肽酶 (PE)（胶原蛋白生成 PGP 的末端酶）来抑制 PGP 途径。然而，ZPP 和 PGP 的结构同源性表明，ZPP 也可能直接影响经典的谷氨酸-亮氨酸-精氨酸阳性 (ELR+) CXC 趋化因子信号传导。在这项研究中，我们证实 ZPP 在体外抑制 PE，证明 ZPP 抑制人类和小鼠中性粒细胞中 ELR + CXC 和 PGP 介导的趋化性，消除小鼠气管内用 LPS 激发诱导的中性粒细胞流入，并减弱人类中性粒细胞对囊性纤维化人类受试者痰样本的趋化性。总而言之，这些数据表明，ZPP 对中性粒细胞趋化因子/苦参碱信号传导具有双重、互补的抑制作用，这使其成为在证明趋化因子和苦参素信号传导同时有害增加的病症（如囊性纤维化和慢性阻塞性肺疾病）中性粒细胞抑制的临床研究中有吸引力的化合物。
Neutrophil influx and activation contributes to organ damage in several major lung diseases. This inflammatory influx is initiated and propagated by both classical chemokines such as interleukin-8 and by downstream mediators such as the collagen fragment cum neutrophil chemokine Pro-Gly-Pro (PGP), which share use of the ELR + CXC receptor family. Benzyloxycarbonyl-proline-prolinal (ZPP) is known to suppress the PGP pathway via inhibition of prolyl endopeptidase (PE), the terminal enzyme in the generation of PGP from collagen. However, the structural homology of ZPP and PGP suggests that ZPP might also directly affect classical glutamate-leucine-arginine positive (ELR+) CXC chemokine signaling. In this investigation, we confirm that ZPP inhibits PEin vitro, demonstrate that ZPP inhibits both ELR + CXC and PGP-mediated chemotaxis in human and murine neutrophils, abrogates neutrophil influx induced by murine intratracheal challenge with LPS, and attenuates human neutrophil chemotaxis to sputum samples of human subjects with cystic fibrosis. Cumulatively, these data demonstrate that ZPP has dual, complementary inhibitory effects upon neutrophil chemokine/matrikine signaling which make it an attractive compound for clinical study of neutrophil inhibition in conditions (such as cystic fibrosis and chronic obstructive pulmonary disease) which evidence concurrent harmful increases of both chemokine and matrikine signaling.