P 物质调节的白三烯 B4 产生通过中性粒细胞逆行迁移促进急性胰腺炎相关肺损伤。
Substance P-regulated leukotriene B4 production promotes acute pancreatitis-associated lung injury through neutrophil reverse migration.
机构信息
Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
出版信息
Int Immunopharmacol. 2018 Apr;57:147-156. doi: 10.1016/j.intimp.2018.02.017. Epub 2018 Feb 24.
Leukotriene B4 (LTB4) is a potent chemoattractant and inflammatory mediator involved in multiple inflammatory diseases. Substance P (SP) has been reported to promote production of LTB4 in itch-associated response in vivo and in some immune cells in vitro. Here, we investigated the role of LTB4 in acute pancreatitis (AP), AP-associated acute lung injury (ALI) and the related mechanisms of LTB4 production in AP. In vivo, murine AP model was induced by caerulein and lipopolysaccharide or L-arginine. The levels of LTB4 and its specific receptor BLT1 were markedly upregulated in both AP models. Blockade of BLT1 by LY293111 attenuated the severity of AP, decreased neutrophil reverse transendothelial cell migration (rTEM) into the circulation and alleviated the severity of ALI. In vitro, treatment of pancreatic acinar cells with SP increased LTB4 production. Furthermore, SP treatment increased phosphorylation of protein kinase C (PKC) α and mitogen activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), p-38 MAPK and c-Jun NH2-terminal kinase (JNK). Finally, blockade of neurokinin-1 receptor by CP96345 significantly attenuated the severity of AP and decreased the level of LTB4 when compared to AP group. In summary, these results show that SP regulates the production of LTB4 via PKCα/MAPK pathway, which further promotes AP-associated ALI through neutrophil rTEM.
白三烯 B4（LTB4）是一种有效的趋化因子和炎症介质，参与多种炎症性疾病。有报道称，P 物质（SP）可促进体内瘙痒相关反应和体外某些免疫细胞中 LTB4 的产生。在这里，我们研究了 LTB4 在急性胰腺炎（AP）、AP 相关的急性肺损伤（ALI）中的作用以及 LTB4 在 AP 中产生的相关机制。在体内，通过使用 caerulein 和脂多糖或 L-精氨酸诱导小鼠 AP 模型。在这两种 AP 模型中，LTB4 及其特定受体 BLT1 的水平均明显上调。BLT1 阻断剂 LY293111 可减轻 AP 的严重程度，减少中性粒细胞反向穿过血管内皮细胞迁移（rTEM）进入循环，并减轻 ALI 的严重程度。在体外，用 SP 处理胰腺腺泡细胞可增加 LTB4 的产生。此外，SP 处理可增加蛋白激酶 C（PKC）α和丝裂原活化蛋白激酶（MAPK）的磷酸化，包括细胞外信号调节激酶（ERK）、p38 MAPK 和 c-Jun NH2-末端激酶（JNK）。最后，与 AP 组相比，神经激肽-1 受体阻断剂 CP96345 可显著减轻 AP 的严重程度并降低 LTB4 水平。总之，这些结果表明，SP 通过 PKCα/MAPK 通路调节 LTB4 的产生，进而通过中性粒细胞 rTEM 促进 AP 相关的 ALI。
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