PMID- 32765805 OWN - NLM STAT- MEDLINE DCOM- 20210514 LR - 20210514 IS - 1942-0994 (Electronic) IS - 1942-0900 (Print) IS - 1942-0994 (Linking) VI - 2020 DP - 2020 TI - Neuregulin-1beta Protects the Rat Diaphragm during Sepsis against Oxidative Stress and Inflammation by Activating the PI3K/Akt Pathway. PG - 1720961 LID - 10.1155/2020/1720961 [doi] LID - 1720961 AB - Sepsis-induced diaphragm dysfunction (SIDD) which is mainly characterized by decrease in diaphragmatic contractility has been identified to cause great harms to patients. Therefore, there is an important and pressing need to find effective treatments for improving SIDD. In addition, acetylcholinesterase (AChE) activity is a vital property of the diaphragm, so we evaluated both diaphragmatic contractility and AChE activity. Though neuregulin-1beta (NRG-1beta) is known to exert organ-protective effects in some inflammatory diseases, little is known about the potential of NRG-1beta therapy in the diaphragm during sepsis. Our study was aimed at exploring the effects of NRG-1beta application on diaphragmatic contractility and AChE activity during sepsis. Proinflammatory cytokines, muscle injury biomarkers in serum, contractile force, AChE activity, proinflammatory cytokines, oxidative parameters, histological condition, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt) signaling proteins in the diaphragm were measured and compared between nonseptic and septic groups with or without NRG-1beta treatment. In vitro, the effects of NRG-1beta on reactive oxygen species (ROS) production in the lipopolysaccharide- (LPS-) stimulated L6 rat muscle skeletal cells with or without the Akt inhibitor MK-2206 were detected. NRG-1beta inhibited proinflammatory cytokine release and muscle injury biomarkers soaring in serum and improved the sepsis-induced diaphragm dysfunction and AChE activity decrease significantly during sepsis. Meanwhile, the inflammatory response, oxidative stress, pathological impairment, and cell apoptosis in the diaphragm were mitigated by NRG-1beta. And NRG-1beta activated the PI3K/Akt signaling in the diaphragm of septic rats. Elevated ROS production in the LPS-stimulated L6 rat skeletal muscle cells was reduced after treatment with NRG-1beta, while MK-2206 blocked these effects of NRG-1beta. In conclusion, our findings underlined that NRG-1beta could reduce circulating levels of proinflammatory cytokines in rats with sepsis, adjust diaphragmatic proinflammatory cytokine level, mitigate diaphragmatic oxidative injury, and lessen diaphragm cell apoptosis, thereby improving diaphragmatic function, and play a role in diaphragmatic protection by activating PI3K/Akt signaling. CI - Copyright (c) 2020 Hua Liu et al. FAU - Liu, Hua AU - Liu H AUID- ORCID: 0000-0001-7950-1227 AD - Department of Anesthesiology and Critical Care Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China. FAU - Weng, Xiao-Jian AU - Weng XJ AD - Department of Anesthesiology and SICU, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China. FAU - Yao, Jun-Yan AU - Yao JY AUID- ORCID: 0000-0002-9553-7868 AD - Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China. FAU - Zheng, Jun AU - Zheng J AD - Department of Pathology Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China. FAU - Lv, Xiang AU - Lv X AD - Department of Anesthesiology and Critical Care Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China. FAU - Zhou, Xu-Hui AU - Zhou XH AD - Department of Anesthesiology and Critical Care Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China. FAU - Jiang, Hong AU - Jiang H AUID- ORCID: 0000-0001-7188-5713 AD - Department of Anesthesiology and Critical Care Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China. FAU - Li, Shi-Tong AU - Li ST AUID- ORCID: 0000-0001-8225-9216 AD - Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China. LA - eng PT - Journal Article DEP - 20200719 PL - United States TA - Oxid Med Cell Longev JT - Oxidative medicine and cellular longevity JID - 101479826 RN - 0 (Neuregulin-1) RN - 0 (Nrg1 protein, rat) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Animals MH - Diaphragm/*drug effects MH - Inflammation MH - Male MH - Neuregulin-1/pharmacology/*therapeutic use MH - Oxidative Stress MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Sepsis/*drug therapy PMC - PMC7387979 COIS- The authors declare that they have no conflicts of interest. EDAT- 2020/08/09 06:00 MHDA- 2021/05/15 06:00 PMCR- 2020/07/19 CRDT- 2020/08/09 06:00 PHST- 2020/04/26 00:00 [received] PHST- 2020/06/15 00:00 [revised] PHST- 2020/07/01 00:00 [accepted] PHST- 2020/08/09 06:00 [entrez] PHST- 2020/08/09 06:00 [pubmed] PHST- 2021/05/15 06:00 [medline] PHST- 2020/07/19 00:00 [pmc-release] AID - 10.1155/2020/1720961 [doi] PST - epublish SO - Oxid Med Cell Longev. 2020 Jul 19;2020:1720961. doi: 10.1155/2020/1720961. eCollection 2020.