Jia-Xi Duan , Xin-Xin Guan , Wei Cheng , Ding-Ding Deng , Ping Chen , Cong Liu , Yong Zhou , Bruce D. Hammock , Hui-Hui Yang
{"title":"在慢性阻塞性肺病小鼠模型中,COX-2/SEH 介导的巨噬细胞活化是肺保护的目标。","authors":"Jia-Xi Duan , Xin-Xin Guan , Wei Cheng , Ding-Ding Deng , Ping Chen , Cong Liu , Yong Zhou , Bruce D. Hammock , Hui-Hui Yang","doi":"10.1016/j.labinv.2023.100319","DOIUrl":null,"url":null,"abstract":"<div><p><span><span>Effective inhibition of macrophage activation<span> is critical for resolving inflammation and restoring pulmonary function </span></span>in patients<span><span><span><span> with chronic obstructive pulmonary disease (COPD). In this study, we identified the dual-enhanced cyclooxygenase-2 (COX-2)/soluble </span>epoxide hydrolase (sEH) as a novel regulator of macrophage activation in COPD. Both COX-2 and sEH were found to be increased in patients and mice with COPD and in macrophages exposed to cigarette smoke extract. Pharmacological reduction of the COX-2 and sEH by 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl)-benzenesulfonamide (PTUPB) effectively prevented macrophage activation, downregulated inflammation-related genes, and reduced lung injury, thereby improving </span>respiratory function in a mouse model of COPD induced by cigarette smoke and </span>lipopolysaccharide<span>. Mechanistically, enhanced COX-2/sEH triggered the activation of the NACHT, LRR, and PYD domains-containing protein 3 inflammasome, leading to the cleavage of pro-IL-1β into its active form in macrophages and amplifying inflammatory responses. These findings demonstrate that targeting COX-2/sEH-mediated macrophage activation may be a promising therapeutic strategy for COPD. Importantly, our data support the potential use of the dual COX-2 and sEH inhibitor PTUPB as a therapeutic </span></span></span>drug<span> for the treatment of COPD.</span></p></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":null,"pages":null},"PeriodicalIF":5.1000,"publicationDate":"2023-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"COX-2/sEH-Mediated Macrophage Activation Is a Target for Pulmonary Protection in Mouse Models of Chronic Obstructive Pulmonary Disease\",\"authors\":\"Jia-Xi Duan , Xin-Xin Guan , Wei Cheng , Ding-Ding Deng , Ping Chen , Cong Liu , Yong Zhou , Bruce D. Hammock , Hui-Hui Yang\",\"doi\":\"10.1016/j.labinv.2023.100319\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p><span><span>Effective inhibition of macrophage activation<span> is critical for resolving inflammation and restoring pulmonary function </span></span>in patients<span><span><span><span> with chronic obstructive pulmonary disease (COPD). In this study, we identified the dual-enhanced cyclooxygenase-2 (COX-2)/soluble </span>epoxide hydrolase (sEH) as a novel regulator of macrophage activation in COPD. Both COX-2 and sEH were found to be increased in patients and mice with COPD and in macrophages exposed to cigarette smoke extract. Pharmacological reduction of the COX-2 and sEH by 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl)-benzenesulfonamide (PTUPB) effectively prevented macrophage activation, downregulated inflammation-related genes, and reduced lung injury, thereby improving </span>respiratory function in a mouse model of COPD induced by cigarette smoke and </span>lipopolysaccharide<span>. Mechanistically, enhanced COX-2/sEH triggered the activation of the NACHT, LRR, and PYD domains-containing protein 3 inflammasome, leading to the cleavage of pro-IL-1β into its active form in macrophages and amplifying inflammatory responses. These findings demonstrate that targeting COX-2/sEH-mediated macrophage activation may be a promising therapeutic strategy for COPD. Importantly, our data support the potential use of the dual COX-2 and sEH inhibitor PTUPB as a therapeutic </span></span></span>drug<span> for the treatment of COPD.</span></p></div>\",\"PeriodicalId\":17930,\"journal\":{\"name\":\"Laboratory Investigation\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.1000,\"publicationDate\":\"2023-12-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Laboratory Investigation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0023683723002623\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Laboratory Investigation","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0023683723002623","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
COX-2/sEH-Mediated Macrophage Activation Is a Target for Pulmonary Protection in Mouse Models of Chronic Obstructive Pulmonary Disease
Effective inhibition of macrophage activation is critical for resolving inflammation and restoring pulmonary function in patients with chronic obstructive pulmonary disease (COPD). In this study, we identified the dual-enhanced cyclooxygenase-2 (COX-2)/soluble epoxide hydrolase (sEH) as a novel regulator of macrophage activation in COPD. Both COX-2 and sEH were found to be increased in patients and mice with COPD and in macrophages exposed to cigarette smoke extract. Pharmacological reduction of the COX-2 and sEH by 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl)-benzenesulfonamide (PTUPB) effectively prevented macrophage activation, downregulated inflammation-related genes, and reduced lung injury, thereby improving respiratory function in a mouse model of COPD induced by cigarette smoke and lipopolysaccharide. Mechanistically, enhanced COX-2/sEH triggered the activation of the NACHT, LRR, and PYD domains-containing protein 3 inflammasome, leading to the cleavage of pro-IL-1β into its active form in macrophages and amplifying inflammatory responses. These findings demonstrate that targeting COX-2/sEH-mediated macrophage activation may be a promising therapeutic strategy for COPD. Importantly, our data support the potential use of the dual COX-2 and sEH inhibitor PTUPB as a therapeutic drug for the treatment of COPD.
期刊介绍:
Laboratory Investigation is an international journal owned by the United States and Canadian Academy of Pathology. Laboratory Investigation offers prompt publication of high-quality original research in all biomedical disciplines relating to the understanding of human disease and the application of new methods to the diagnosis of disease. Both human and experimental studies are welcome.