Blockade of the protease ADAM17 ameliorates experimental pancreatitis

胰腺炎 促炎细胞因子 急性胰腺炎 医学 肿瘤坏死因子α 内分泌学 内科学 免疫学 癌症研究 炎症
作者
Mohamed I. Saad,Teresa Weng,Joanne Lundy,Linden J. Gearing,Alison C. West,Christopher M. Harpur,Mohammad Alanazi,Christopher Hodges,Daniel Croagh,Beena Kumar,Irit Sagi,Stefan Rose‐John,Brendan J. Jenkins
出处
期刊:Proceedings of the National Academy of Sciences of the United States of America [National Academy of Sciences]
卷期号:119 (42) 被引量:14
标识
DOI:10.1073/pnas.2213744119
摘要

Acute and chronic pancreatitis, the latter associated with fibrosis, are multifactorial inflammatory disorders and leading causes of gastrointestinal disease-related hospitalization. Despite the global health burden of pancreatitis, currently, there are no effective therapeutic agents. In this regard, the protease A Disintegrin And Metalloproteinase 17 (ADAM17) mediates inflammatory responses through shedding of bioactive inflammatory cytokines and mediators, including tumor necrosis factor α (TNFα) and the soluble interleukin (IL)-6 receptor (sIL-6R), the latter of which drives proinflammatory IL-6 trans-signaling. However, the role of ADAM17 in pancreatitis is unclear. To address this, Adam17 ex/ex mice—which are homozygous for the hypomorphic Adam17 ex allele resulting in marked reduction in ADAM17 expression—and their wild-type (WT) littermates were exposed to the cerulein-induced acute pancreatitis model, and acute (1-wk) and chronic (20-wk) pancreatitis models induced by the cigarette smoke carcinogen nicotine-derived nitrosamine ketone (NNK). Our data reveal that ADAM17 expression was up-regulated in pancreatic tissues of animal models of pancreatitis. Moreover, the genetic ( Adam17 ex/ex mice) and therapeutic (ADAM17 prodomain inhibitor [A17pro]) targeting of ADAM17 ameliorated experimental pancreatitis, which was associated with a reduction in the IL-6 trans-signaling/STAT3 axis. This led to reduced inflammatory cell infiltration, including T cells and neutrophils, as well as necrosis and fibrosis in the pancreas. Furthermore, up-regulation of the ADAM17/IL-6 trans-signaling/STAT3 axis was a feature of pancreatitis patients. Collectively, our findings indicate that the ADAM17 protease plays a pivotal role in the pathogenesis of pancreatitis, which could pave the way for devising novel therapeutic options to be deployed against this disease.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
执笔完成签到,获得积分10
刚刚
手可摘星辰完成签到 ,获得积分10
1秒前
量子星尘发布了新的文献求助10
1秒前
李健应助大帅采纳,获得10
2秒前
3秒前
冷艳的火龙果完成签到,获得积分10
3秒前
不知完成签到 ,获得积分10
3秒前
Zard发布了新的文献求助10
5秒前
清仔发布了新的文献求助10
5秒前
6秒前
大地上的鱼完成签到,获得积分10
6秒前
6秒前
上官若男应助平常的路人采纳,获得10
6秒前
小花发布了新的文献求助10
7秒前
庸俗完成签到,获得积分10
8秒前
9秒前
论文顺利发布了新的文献求助10
9秒前
9秒前
砚行书完成签到,获得积分10
9秒前
CodeCraft应助Qsss采纳,获得10
9秒前
情怀应助葫芦娃采纳,获得10
10秒前
小慈爱鸡完成签到 ,获得积分10
10秒前
ttelsa完成签到,获得积分10
10秒前
年轻小之完成签到 ,获得积分10
10秒前
10秒前
snowdream发布了新的文献求助10
11秒前
xiaoying完成签到,获得积分10
11秒前
13秒前
大帅发布了新的文献求助10
13秒前
深情丸子发布了新的文献求助10
13秒前
通通真行完成签到,获得积分10
14秒前
16秒前
JamesPei应助科研通管家采纳,获得10
16秒前
科研通AI2S应助科研通管家采纳,获得10
16秒前
英姑应助科研通管家采纳,获得10
16秒前
研友_VZG7GZ应助科研通管家采纳,获得10
16秒前
脑洞疼应助科研通管家采纳,获得10
17秒前
爆米花应助科研通管家采纳,获得10
17秒前
乐乐应助科研通管家采纳,获得10
17秒前
乐乐应助科研通管家采纳,获得10
17秒前
高分求助中
【提示信息,请勿应助】关于scihub 10000
Les Mantodea de Guyane: Insecta, Polyneoptera [The Mantids of French Guiana] 3000
徐淮辽南地区新元古代叠层石及生物地层 3000
The Mother of All Tableaux: Order, Equivalence, and Geometry in the Large-scale Structure of Optimality Theory 3000
Global Eyelash Assessment scale (GEA) 1000
Picture Books with Same-sex Parented Families: Unintentional Censorship 550
Research on Disturbance Rejection Control Algorithm for Aerial Operation Robots 500
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 4038524
求助须知:如何正确求助?哪些是违规求助? 3576221
关于积分的说明 11374737
捐赠科研通 3305912
什么是DOI,文献DOI怎么找? 1819354
邀请新用户注册赠送积分活动 892688
科研通“疑难数据库(出版商)”最低求助积分说明 815048