PMID- 29482159 OWN - NLM STAT- MEDLINE DCOM- 20180910 LR - 20180910 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 57 DP - 2018 Apr TI - Substance P-regulated leukotriene B4 production promotes acute pancreatitis-associated lung injury through neutrophil reverse migration. PG - 147-156 LID - S1567-5769(18)30087-0 [pii] LID - 10.1016/j.intimp.2018.02.017 [doi] AB - 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) alpha 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 PKCalpha/MAPK pathway, which further promotes AP-associated ALI through neutrophil rTEM. CI - Copyright (c) 2018 Elsevier B.V. All rights reserved. FAU - Li, Bin AU - Li B AD - 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. FAU - Han, Xiao AU - Han X AD - 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. FAU - Ye, Xin AU - Ye X AD - 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. FAU - Ni, Jianbo AU - Ni J AD - 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. FAU - Wu, Jianghong AU - Wu J AD - 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. FAU - Dai, Juanjuan AU - Dai J AD - 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. FAU - Wu, Zengkai AU - Wu Z AD - 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. FAU - Chen, Congying AU - Chen C AD - 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. FAU - Wan, Rong AU - Wan R AD - 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. FAU - Wang, Xingpeng AU - Wang X AD - 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. FAU - Hu, Guoyong AU - Hu G AD - 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. Electronic address: huguoyongsh@sina.com. LA - eng PT - Journal Article DEP - 20180224 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (Benzoates) RN - 0 (LY 293111) RN - 0 (Ltb4r1 protein, mouse) RN - 0 (Receptors, Leukotriene B4) RN - 0 (Receptors, Neurokinin-1) RN - 1HGW4DR56D (Leukotriene B4) RN - 33507-63-0 (Substance P) RN - 888Y08971B (Ceruletide) RN - EC 2.7.11.13 (Protein Kinase C) SB - IM MH - Acinar Cells/*physiology MH - Acute Lung Injury/chemically induced/complications/*metabolism MH - Animals MH - Benzoates/pharmacology MH - Cells, Cultured MH - Ceruletide MH - Disease Models, Animal MH - Humans MH - Leukotriene B4/*metabolism MH - MAP Kinase Signaling System MH - Male MH - Mice MH - Mice, Inbred BALB C MH - Neutrophils/*physiology MH - Pancreatitis, Acute Necrotizing/chemically induced/complications/*metabolism MH - Protein Kinase C/metabolism MH - Receptors, Leukotriene B4/antagonists & inhibitors/metabolism MH - Receptors, Neurokinin-1/metabolism MH - Substance P/*metabolism MH - Transendothelial and Transepithelial Migration OTO - NOTNLM OT - Acute lung injury OT - Acute pancreatitis OT - Leukotriene B4 OT - Reverse transendothelial cell migration OT - Substance P EDAT- 2018/02/27 06:00 MHDA- 2018/09/11 06:00 CRDT- 2018/02/27 06:00 PHST- 2017/11/07 00:00 [received] PHST- 2018/02/01 00:00 [revised] PHST- 2018/02/20 00:00 [accepted] PHST- 2018/02/27 06:00 [pubmed] PHST- 2018/09/11 06:00 [medline] PHST- 2018/02/27 06:00 [entrez] AID - S1567-5769(18)30087-0 [pii] AID - 10.1016/j.intimp.2018.02.017 [doi] PST - ppublish SO - Int Immunopharmacol. 2018 Apr;57:147-156. doi: 10.1016/j.intimp.2018.02.017. Epub 2018 Feb 24.