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
刚刚
SciGPT应助guohuameike采纳,获得10
1秒前
minever白完成签到,获得积分10
2秒前
天天快乐应助阆州采纳,获得10
2秒前
TCAcycle发布了新的文献求助10
2秒前
Jason发布了新的文献求助10
2秒前
学术天后发布了新的文献求助10
3秒前
Wwt发布了新的文献求助10
3秒前
3秒前
3秒前
4秒前
李爱国应助slj采纳,获得10
5秒前
5秒前
xiekunwhy完成签到,获得积分10
5秒前
5秒前
酷波er应助机智海冬采纳,获得10
6秒前
skill完成签到,获得积分10
6秒前
感动城发布了新的文献求助10
6秒前
顾矜应助无奈的鞋子采纳,获得10
7秒前
7秒前
benbenx发布了新的文献求助10
7秒前
可爱的函函应助执着新蕾采纳,获得10
7秒前
7秒前
澄碧星林完成签到,获得积分10
8秒前
8秒前
建新发布了新的文献求助30
8秒前
李爱国应助小豆子采纳,获得10
9秒前
9秒前
9秒前
今夜小楼一曲完成签到,获得积分10
9秒前
打工肥仔应助汪洋采纳,获得10
9秒前
今后应助开放觅夏采纳,获得30
9秒前
iiiid发布了新的文献求助10
9秒前
Cici发布了新的文献求助10
10秒前
桐桐应助我想@科研采纳,获得10
11秒前
wanci应助令狐远航采纳,获得10
11秒前
量子星尘发布了新的文献求助10
11秒前
chen完成签到,获得积分10
11秒前
xiaozhouning发布了新的文献求助30
12秒前
12秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
Picture Books with Same-sex Parented Families: Unintentional Censorship 500
Nucleophilic substitution in azasydnone-modified dinitroanisoles 500
不知道标题是什么 500
A Preliminary Study on Correlation Between Independent Components of Facial Thermal Images and Subjective Assessment of Chronic Stress 500
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 360
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 3971078
求助须知:如何正确求助?哪些是违规求助? 3515742
关于积分的说明 11179305
捐赠科研通 3250852
什么是DOI,文献DOI怎么找? 1795501
邀请新用户注册赠送积分活动 875868
科研通“疑难数据库(出版商)”最低求助积分说明 805207