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Emodin attenuates severe acute pancreatitis-associated acute lung injury by suppressing pancreatic exosome-mediated alveolar macrophage activation

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Acta Pharmaceutica Sinica B 2022年第10期12卷 3986-4003页

作者： Qian Hu Jiaqi Yao Xiajia Wu Juan Li Guixiang Li Wenfu Tang Jingping Liu meihua wan Department of Integrated Traditional Chinese and Western Medicine National Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China NHC Key Laboratory of Transplant Engineering and Immunology Frontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan UniversityChengdu 610041China

Severe acute pancreatitis-associated acute lung injury(SAP-ALI) is a serious disease associated with high mortality. Emodin has been applied to alleviate SAP-ALI;however, the mechanism remains unclear. We report that the therapeutic role of emodin in attenuating SAP-ALI is partly dependent on an exosomal mechanism. SAP rats had increased levels of plasma exosomes with altered protein contents compared to the sham rats. These infused plasma exosomes tended to accumulate in the lungs and promoted the hyper-activation of alveolar macrophages and inflammatory damage. Conversely,emodin treatment decreased the plasma/pancreatic exosome levels in the SAP rats. Emodin-primed exosomes showed less pro-inflammatory effects in alveolar macrophages and lung tissues than SAP exosomes. In detail, emodin-primed exosomes suppressed the NF-κB pathway to reduce the activation of alveolar macrophage and ameliorate lung inflammation by regulating PPARγ pathway, while these effects were amplified/abolished by PPARγ agonist/antagonist. Blockage of pancreatic acinar cell exosome biogenesis also exhibited suppression of alveolar macrophage activation and reduction of lung inflammation. This study suggests a vital role of exosomes in participating inflammation-associated organ-injury,and indicates emodin can attenuate SAP-ALI by reducing the pancreatic exosome-mediated alveolar macrophage activation.

关键词： Severe acute pancreatitis Acute lung injury Emodin Exosome Macrophages Lisocitrate dehydrogenase 1 Peroxisome proliferatoractivated receptorγ Nuclear factor kB

Extracellular vesicle activities regulating macrophage- and tissue-mediated injury and repair responses

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Acta Pharmaceutica Sinica B 2021年第6期11卷 1493-1512页

作者： Qian Hu Christopher J.Lyon Jesse K.Fletcher Wenfu Tang meihua wan Tony Y.Hu Department of Integrated Traditional Chinese and Western Medicine West China HospitalSichuan UniversityChengdu 610041China Center of Cellular and Molecular Diagnosis Tulane University School of MedicineNew OrleansLA 70112USA Department of Biochemistry&Molecular Biology Tulane University School of MedicineNew OrleansLA 70112USA

Macrophages are typically identified as classically activated(M1) macrophages and alternatively activated(M2) macrophages,which respectively exhibit pro-and anti-inflammatory phenotypes,and the balance between these two subtypes plays a critical role in the regulation of tissue inflammation,injury,and repair *** studies indicate that tissue cells and macrophages interact via the release of small extracellular vesicles(EVs) in processes where EVs released by stressed tissue cells can promote the activation and polarization of adjacent macrophages which can in turn release EVs and factors that can promote cell stress and tissue inflammation and injury and vice *** review discusses the roles of such EVs in resulating such interactions to influence tissue inflammation and injury in a number of acute and chronic inflammatory disease conditions,and the potential applications,advantage and concerns for using EV-based therapeutic approaches to treat such conditions,including their potential role of drug carriers for the treatment of infectious diseases.

关键词： Extracellular vesicles Macrophage Tissue injury Inflammatory disease Interaction loop Stem cell Sepsis Targeted therapy

Clinical applications of exosome membrane proteins

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Precision Clinical Medicine 2020年第1期3卷 54-66页

作者： Qian Hu Hang Su Juan Li Christopher Lyon Wenfu Tang meihua wan Tony Ye Hu Center of Cellular and Molecular Diagnosis Tulane University School of MedicineNew OrleansLA 70112USA Department of Integrated Traditional Chinese and Western Medicine West China Hospital of Sichuan UniversityChengdu 610041Sichuan ProvinceChina Health Management Center West China Hospital of Sichuan UniversityChengdu 610041Sichuan ProvinceChina Department of Biochemistry&Molecular Biology Tulane University School of MedicineNew OrleansLA 70112USA

Extracellular vesicles(EVs)are small membranous particles that can mediate cell-to-cell communication and which are divided into at least three categories according to their subcellular origin and size:exosomes,microvesicles,and apoptotic *** are the smallest(30–150 nm)of these EVs,and play an important role in EV-mediated cell-to-cell interactions,by transferring proteins,nucleic acids and,lipids from their parental cells to adjacent or distant cells to alter their *** exosome studies in the past two decades have focused on their nucleic acid composition and their transfer ofmRNAs and microRNAs to neighboring ***,exosomes also carry specific membrane proteins that can identify the physiological and pathological states of their parental cells or indicate their preferential target cells or *** membrane protein expression can also be directly employed or modified to allow exosomes to serve as drug delivery systems and therapeutic platforms,including in targeted therapy *** review will briefly summarize information on exosome membrane proteins components and their role in exosome–cell interactions,including proteins associated with specific cell-interactions and diseases,and the potential for using exosome membrane proteins in therapeutic targeting approaches.

关键词： Exosome membrane protein endocytosis membrane fusion diagnostic markers exosome mimetics target therapy

Disease-derived circulating extracellular vesicle preconditioning:A promising strategy for precision mesenchymal stem cell therapy

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Acta Pharmaceutica Sinica B 2024年第10期14卷 4526-4543页

作者： Ke Lv Tian Wu Shuyun Liu Peng Lou Pingya Zhou Yizhuo wang Xiyue Zhou Shu Zhang Dan Du Yanrong Lu meihua wan Jingping Liu Department of Integrated Traditional Chinese and Western Medicine and NHC Key Laboratory of Transplant Engineering and Immunology Frontiers Science Center for Disease-related Molecular NetworkWest China HospitalSichuan UniversityChengdu 610041China Department of Emergency Medicine Emergency Medical LaboratoryWest China HospitalSichuan UniversityChengdu 610041China Advanced Mass Spectrometry Center Research Core FacilityFrontiers Science Center for Disease-related Molecular NetworkWest China HospitalSichuan UniversityChengdu 610041China West China Center of Excellence for Pancreatitis Institute of Integrated Traditional Chinese and Western MedicineWest China HospitalSichuan UniversityChengdu 610041China The First People’s Hospital of Shuangliu District Chengdu 610299China

Mesenchymal stem cell(MSC)-based therapies have emerged as promising methods for regenerative medicine;however,how to precisely enhance their tissue repair effects is still a major question in the *** extracellular vesicles(EVs)from diseased states carry diverse pathological information and affect the functions of recipient *** on this unique property,we report that disease-derived circulating EV(disease-EV)preconditioning is a potent strategy for precisely enhancing the tissue repair potency of MSCs in diverse disease ***,plasma EVs from lung or kidney tissue injuries were shown to contain distinctly enriched molecules and were shown to induce tissue injury-specific gene expression responses in cultured ***-EV preconditioning improved the performance(including proliferation,migration,and growth factor production)of MSCs through metabolic reprogramming(such as via enhanced oxidative phosphorylation and lipid metabolism)without inducing an adverse immune ***,compared with normal MSCs,disease-EV-preconditioned MSCs exhibited superior tissue repair effects(including anti-inflammatory and antiapoptotic effects)in diverse types of tissue injury(such as acute lung or kidney injury).Disease-derived EVs may serve as a type of“off-the-shelf”product due to multiple advantages,such as flexibility,stability,long-term storage,and ease of shipment and *** study highlights the idea that disease-EV preconditioning is a robust strategy for precisely enhancing the regenerative capacity of MSC-based therapies.

关键词： Regenerative medicine Mesenchymal stem cell Circulating extracellular vesicle Tissue injury Metabolic reprogramming Inflammation Cell death Preconditioning

Role of neutrophil extracellular traps in inflammatory evolution in severe acute pancreatitis

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Chinese Medical Journal 2022年第23期135卷 2773-2784页

作者： Hongxin Kang Yue Yang Lv Zhu Xianlin Zhao Juan Li Wenfu Tang meihua wan Department of Integrated Traditional Chinese and Western Medicine National Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduSichuan 610041China

Severe acute pancreatitis(SAP)is a life-threatening acute abdominal disease with two peaks of death:the first in the early stage,characterized by systemic inflammatory response-associated organ failure;and the second in the late stage,characterized by infectious *** are the main immune cells participating in the whole process of *** addition to the traditional recognition of neutrophils as the origination of chemokine and cytokine cascades or phagocytosis and degranulation of pathogens,neutrophil extracellular traps(NETs)also play an important roles in inflammatory *** reviewed the role of NETs in the occurrence and development of SAP and its fatal complications,including multiple organs injury,infected pancreatic necrosis,and *** review provides novel insights into the involvement of NETs throughout the entire process of SAP,showing that targeting NETs might be a promising strategy in SAP ***,precision therapeutic options targeting NETs in different situations require further investigation.

关键词： Inflammation Neutrophil extracellular traps Organ injury Sepsis Severe acute pancreatitis Thrombus

清热解毒法治疗重症急性胰腺炎非感染性高热41例

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陕西中医 2005年第3期26卷 195-196页

作者：唐文富万美华黄熙四川大学华西医院中西医结合科 610041 第四军医大学西京医院中医药研究中心

目的 :探讨清热解毒法治疗重症急性胰腺炎非感染性高热的临床效果。方法 :对并发非感染高热 (≥ 39℃且持续 2 d以上 )的 SAP患者采用清热解毒为主 ,内服中药仙方活命饮和桃红四物汤加减 ,配合西医常规治疗的中西医结合保守治疗 ;结果 ... 详细信息

目的 :探讨清热解毒法治疗重症急性胰腺炎非感染性高热的临床效果。方法 :对并发非感染高热 (≥ 39℃且持续 2 d以上 )的 SAP患者采用清热解毒为主 ,内服中药仙方活命饮和桃红四物汤加减 ,配合西医常规治疗的中西医结合保守治疗 ;结果 :41例 SAP患者中 2例因发生多器官功能衰竭而急症手术后死亡 ,39例经中西医结合保守治疗后好转 ,其中 6例因假性囊肿导致梗阻而进行择期囊肿内引流术 ,总有效率 95 .1 %。结论

关键词：高热中西医结合保守治疗非感染性清热解毒法重症急性胰腺炎患者 SAP 并发发生持续

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高甘油三酯血症与急性胰腺炎

职业卫生与病伤 2007年第2期22卷 104-105页

作者：万美华唐文富夏庆朱林四川大学华西医院中西医结合科四川成都610041

目的探讨高甘油三酯血症在急性胰腺炎病情评价与预后中的作用。方法2003-01/12四川大学华西医院收治了各种原因的急性胰腺炎283例,其中急性胰腺炎合并高脂血症性72例,其他原因所致胰腺炎211例;进行ranson评分、住院天数比较和病死率的... 详细信息

目的探讨高甘油三酯血症在急性胰腺炎病情评价与预后中的作用。方法2003-01/12四川大学华西医院收治了各种原因的急性胰腺炎283例,其中急性胰腺炎合并高脂血症性72例,其他原因所致胰腺炎211例;进行ranson评分、住院天数比较和病死率的比较。结果急性胰腺炎患者血甘油三酯异常升高(TG>3.6mmol/L)占25.4%。其中TG>11.3mmol/L的患者为6.3%。其他原因所致的胰腺炎占74.6%。急性胰腺炎是否合并高脂血症在病情程度(选择ranson评分)和平均住院天数上分别为4.76±1.87,4.32±1.88;25.75±16.7,27.27±20.42,2者比较差异无统计学意义(P>0.05)。不同程度高脂血症的胰腺炎患者在病情程度和平均住院天数分别4.8±2.0,4.67±1.41,26.26±17.05,24.2±15.53,2者比较差异亦没有统计学意义(P>0.05)。2组间病死率亦无明显差别。结论高脂血症性急性胰腺炎临床经过和预后与其他原因的胰腺炎无显著差异,血脂高低与病死率无明显相关性。

关键词：高脂血症急性胰腺炎病情评价

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复发性急性胰腺炎病因分析及防治概述

中国普外基础与临床杂志 2020年第7期27卷 895-900页

作者：康鸿鑫李君仪唐文富万美华四川大学华西医院中西医结合科成都610041

目的总结分析复发性急性胰腺炎(RAP)的病因并概述其防治策略。方法检索近年来Pubmed、CNKI、万方等数据库的相关文献资料,分析总结RAP病因,概述其防治策略。结果 RAP病因包括:胆胰管功能和结构异常、代谢性因素、不良生活习惯、遗传因素... 详细信息

目的总结分析复发性急性胰腺炎(RAP)的病因并概述其防治策略。方法检索近年来Pubmed、CNKI、万方等数据库的相关文献资料,分析总结RAP病因,概述其防治策略。结果 RAP病因包括:胆胰管功能和结构异常、代谢性因素、不良生活习惯、遗传因素等,后基于病因概述其防治策略。结论随着相关研究的进展和临床诊疗技术的进步,RAP的发病因素正被逐渐揭示,基于病因进而防治,这对于减少急性胰腺炎复发有重要意义。

关键词：复发性急性胰腺炎病因防治策略综述

骨髓间充质干细胞衍生的细胞外囊泡改善重症急性胰腺炎小鼠肺组织损伤

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华西医学 2024年第11期39卷 1718-1727页

作者：索朗玉珍胡倩杨月康鸿鑫张蜀万美华四川大学华西医院急诊科成都610041 西藏自治区人民医院急诊科拉萨850000 四川大学华西医院中西医结合中心胰腺炎中心成都610041

目的探讨骨髓间充质干细胞(bone marrow mesenchymal stem cell, BMSC)分泌的细胞外囊泡(extracellular vesicle, EV)对重症急性胰腺炎(severe acute pancreatitis, SAP)小鼠肺组织损伤的效应及潜在机制。方法选择24只无特定病原体级... 详细信息

目的探讨骨髓间充质干细胞(bone marrow mesenchymal stem cell, BMSC)分泌的细胞外囊泡(extracellular vesicle, EV)对重症急性胰腺炎(severe acute pancreatitis, SAP)小鼠肺组织损伤的效应及潜在机制。方法选择24只无特定病原体级雄性C57BL/6小鼠和小鼠原代肺微血管内皮细胞(pulmonary microvascular endothelial cell, PMVEC)。将小鼠分为假手术组、SAP组、BMSC组,每组8只。将小鼠原代PMVEC分为模型组[牛磺胆酸钠(sodium taurocholate, NaTC)组]、BMSC-EV组、对照组。提取并鉴定健康小鼠BMSC及BMSC-EV,建立SAP小鼠模型,将BMSC-EV尾静脉注射到SAP小鼠体内或体外干预小鼠原代PMVEC,观察胰腺和肺组织病理损伤,血清淀粉酶、脂肪酶、炎症因子[肿瘤坏死因子-α(tumor necrosis factor α, TNF-α)、白细胞介素-6(interleukin-6, IL-6)]等变化,肺组织和PMVEC炎症因子、内皮细胞屏障相关蛋白[钙黏蛋白E(E-cadherin)、紧密连接蛋白ZO-1、细胞间黏附分子(intercellular cell adhesion molecule-1, ICAM-1)]等表达,以及PMVEC间紧密连接情况,以探索BMSC-EV对SAP小鼠胰腺、肺组织和体外PMVEC的影响。结果 BMSC具有成骨、成软骨、成脂分化的潜能,其衍生的EV具有典型的杯状结构,直径在60~100 nm,BMSC-EV表达EV阳性蛋白TSG101和CD63,不表达阴性蛋白Calnexin。与假手术组比较,SAP组胰腺发生病理损伤(P<0.05),血清淀粉酶、脂肪酶、IL-6、TNF-α水平均上调(P<0.05);而BMSC-EV改善SAP小鼠胰腺组织损伤(P<0.05),下调外周血清淀粉酶、脂肪酶、IL-6、TNF-α水平(P<0.05),并上调IL-10水平(P<0.05)。除此之外,SAP小鼠还表现肺组织病理损伤(P<0.05),较高水平的炎症因子TGF-β、IL-6(P<0.05),较多的中性粒细胞和巨噬细胞浸润(P<0.05),表达较低水平的E-cadherin、ZO-1(P<0.05)和较高水平的ICAM-1(P<0.05);BMSC-EV改善了SAP小鼠肺组织病理损伤、炎细胞浸润、炎症因子水平和屏障蛋白表达(P<0.05),并抑制ICAM-1表达(P<0.05)。在体外PMVEC实验中,发现NaTC组细胞间紧密连接断裂,TNF-α、IL-6水平上调(P<0.05)、E-cadherin、ZO-1蛋白表达下调(P<0.05)、ICAM-1表达上调(P<0.05),BMSC-EV改善NaTC组细胞间紧密连接,并抑制TNF-α、IL-6分泌(P<0.05)、上调E-cadherin、ZO-1表达和下调ICAM-1的表达(P<0.05)。结论 BMSC衍生的EV通过恢复肺内皮细胞屏障、抑制炎细胞浸润进而改善SAP小鼠肺组织损伤。

关键词：间充质干细胞重症急性胰腺炎肺微血管内皮细胞紧密连接急性肺损伤