PMID- 35383125 OWN - NLM STAT- MEDLINE DCOM- 20220617 LR - 20220711 IS - 1521-0103 (Electronic) IS - 0022-3565 (Linking) VI - 381 IP - 3 DP - 2022 Jun TI - Anisodamine Enhances Macrophage M2 Polarization through Suppressing G9a-Mediated Interferon Regulatory Factor 4 Silencing to Alleviate Lipopolysaccharide-Induced Acute Lung Injury. PG - 247-256 LID - 10.1124/jpet.121.001019 [doi] AB - Acute lung injury (ALI) is a serious inflammatory lung disease. Imbalances in the polarization of classically activated (M1) and alternatively activated (M2) macrophages are closely related to ALI. Anisodamine has a promising therapeutic effect for septic shock. Nevertheless, the role of anisodamine in progression of ALI remains to be investigated. Our results showed that anisodamine significantly reduced lung damage, myeloperoxidase (MPO) activity, lung wet/dry ratio, total cell number, and protein concentrations in bronchoalveolar lavage fluid and decreased interleukin (IL)-6 level and the levels of M1 phenotypic markers, whereas it increased IL-10 level and the levels of M2 phenotypic markers in mice with a nasal instillation of lipopolysaccharide (LPS). Bone marrow-derived macrophages (BMDMs) were stimulated or transfected with LPS plus anisodamine or LPS plus G9a short hairpin RNA. Anisodamine and downregulation of G9a both promoted BMDM M2 polarization caused by IL-4 treatment and inhibited M1 polarization resulting from LPS treatment. Chromatin immunoprecipitation assay revealed that anisodamine inhibited G9a-mediated methylation and expression suppression on interferon regulatory factory 4 (IRF4). Overexpression of G9a or silence of IRF4 reversed the improvement effect of anisodamine on lung tissue injury, evidenced by an increase of MPO activity and the restoration of LPS-induced alterations of M1 and M2 polarization. In conclusion, anisodamine protected against LPS-induced ALI, during which anisodamine suppressed the LPS-stimulated alterations of macrophage M1 and M2 polarization through inhibiting G9a-mediated methylation of IRF4, suggesting that anisodamine was a potential therapeutic drug to alleviate ALI. SIGNIFICANCE STATEMENT: Anisodamine treatment was able to attenuate lung injury and pulmonary edema caused by lipopolysaccharide (LPS) stimulation, and the specific mechanism was that anisodamine reversed the LPS-induced alterations of M1 and M2 polarization by inhibiting G9a-mediated methylation and expression suppression of interferon regulatory factor 4, which suggests that anisodamine has the potential to alleviate acute lung injury. CI - Copyright (c) 2022 by The American Society for Pharmacology and Experimental Therapeutics. FAU - Zhang, Yunfeng AU - Zhang Y AD - Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China (Y.Z., D.S., Z.P., R.W., K.L., H.R., X.S., N.D.) and Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, Mississippi (S.-C.T.). FAU - Song, Dingli AU - Song D AD - Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China (Y.Z., D.S., Z.P., R.W., K.L., H.R., X.S., N.D.) and Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, Mississippi (S.-C.T.). FAU - Peng, Ziyang AU - Peng Z AD - Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China (Y.Z., D.S., Z.P., R.W., K.L., H.R., X.S., N.D.) and Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, Mississippi (S.-C.T.). FAU - Wang, Rui AU - Wang R AD - Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China (Y.Z., D.S., Z.P., R.W., K.L., H.R., X.S., N.D.) and Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, Mississippi (S.-C.T.). FAU - Li, Kai AU - Li K AD - Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China (Y.Z., D.S., Z.P., R.W., K.L., H.R., X.S., N.D.) and Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, Mississippi (S.-C.T.). FAU - Ren, Hong AU - Ren H AD - Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China (Y.Z., D.S., Z.P., R.W., K.L., H.R., X.S., N.D.) and Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, Mississippi (S.-C.T.). FAU - Sun, Xin AU - Sun X AD - Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China (Y.Z., D.S., Z.P., R.W., K.L., H.R., X.S., N.D.) and Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, Mississippi (S.-C.T.). FAU - Du, Ning AU - Du N AD - Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China (Y.Z., D.S., Z.P., R.W., K.L., H.R., X.S., N.D.) and Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, Mississippi (S.-C.T.) duning43@21cn.com tangsc7@21cn.com. FAU - Tang, Shou-Ching AU - Tang SC AD - Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China (Y.Z., D.S., Z.P., R.W., K.L., H.R., X.S., N.D.) and Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, Mississippi (S.-C.T.) duning43@21cn.com tangsc7@21cn.com. LA - eng PT - Journal Article DEP - 20220405 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 0 (Interferon Regulatory Factors) RN - 0 (Lipopolysaccharides) RN - 0 (Solanaceous Alkaloids) RN - 01343Q8EL8 (anisodamine) SB - IM MH - *Acute Lung Injury/chemically induced/drug therapy MH - Animals MH - Interferon Regulatory Factors/genetics/metabolism MH - *Lipopolysaccharides/pharmacology MH - Lung MH - Macrophages/metabolism MH - Mice MH - Solanaceous Alkaloids EDAT- 2022/04/07 06:00 MHDA- 2022/06/18 06:00 CRDT- 2022/04/06 05:23 PHST- 2021/11/15 00:00 [received] PHST- 2022/03/31 00:00 [accepted] PHST- 2022/04/07 06:00 [pubmed] PHST- 2022/06/18 06:00 [medline] PHST- 2022/04/06 05:23 [entrez] AID - jpet.121.001019 [pii] AID - 10.1124/jpet.121.001019 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2022 Jun;381(3):247-256. doi: 10.1124/jpet.121.001019. Epub 2022 Apr 5.