Inhibition of phosphodiesterase 4 (PDE4) reduces dermal fibrosis by interfering with the release of interleukin-6 from M2 macrophages

医学 博莱霉素 最后 角色扮演 纤维化 银屑病 磷酸二酯酶 免疫学 炎症 托法替尼 药理学 内科学 内分泌学 类风湿性关节炎 银屑病性关节炎 化疗 化学 生物化学
作者
Christiane Maier,Andreas Ramming,Christina Bergmann,Rita Weinkam,Nicolai A. Kittan,Georg Schett,Jörg H W Distler,Christian Beyer
出处
期刊:Annals of the Rheumatic Diseases [BMJ]
卷期号:76 (6): 1133-1141 被引量:69
标识
DOI:10.1136/annrheumdis-2016-210189
摘要

Objectives To investigate the disease-modifying effects of phosphodiesterase 4 (PDE4) inhibition in preclinical models of systemic sclerosis (SSc). Methods We studied the effects of PDE4 inhibition in a prevention and a treatment model of bleomycin-induced skin fibrosis, in the topoisomerase mouse model as well as in a model of sclerodermatous chronic graft-versus-host disease. To better understand the mode of action of PDE4 blockade in preclinical models of SSc, we investigated fibrosis-relevant mediators in fibroblasts and macrophages from healthy individuals and patients suffering from diffuse-cutaneous SSc on blockade of PDE4. Results Specific inhibition of PDE4 by rolipram and apremilast had potent antifibrotic effects in bleomycin-induced skin fibrosis models, in the topoisomerase I mouse model and in murine sclerodermatous chronic graft-versus-host disease. Fibroblasts were not the direct targets of the antifibrotic effects of PDE4 blockade. Reduced leucocyte infiltration in lesional skin on PDE4 blockade suggested an immune-mediated mechanism. Further analysis revealed that PDE4 inhibition decreased the differentiation of M2 macrophages and the release of several profibrotic cytokines, resulting in reduced fibroblast activation and collagen release. Within these profibrotic mediators, interleukin-6 appeared to play a central role. Conclusions PDE4 inhibition reduces inflammatory cell activity and the release of profibrotic cytokines from M2 macrophages, leading to decreased fibroblast activation and collagen release. Importantly, apremilast is already approved for the treatment of psoriasis and psoriatic arthritis. Therefore, PDE4 inhibitors might be further developed as potential antifibrotic therapies for patients with SSc. Our findings suggest that particularly patients with inflammation-driven fibrosis might benefit from PDE4 blockade.
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
大幅提高文件上传限制,最高150M (2024-4-1)

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
冷静花卷完成签到,获得积分10
1秒前
明亮南露发布了新的文献求助10
2秒前
2秒前
were_i_you发布了新的文献求助10
4秒前
4秒前
北斗星的爱完成签到,获得积分10
5秒前
6秒前
BioRick完成签到,获得积分10
7秒前
嗯哼应助给我好好读书采纳,获得20
10秒前
11秒前
赘婿应助crow采纳,获得10
12秒前
甜甜寄凡发布了新的文献求助50
13秒前
cindyyunjie发布了新的文献求助10
14秒前
伶俐的玫瑰完成签到,获得积分20
15秒前
17秒前
18秒前
xjy1521完成签到,获得积分20
19秒前
20秒前
Sonia发布了新的文献求助10
21秒前
上官若男应助Laaakey采纳,获得10
22秒前
做科研的小丸子完成签到,获得积分10
22秒前
LYW发布了新的文献求助10
23秒前
HanH发布了新的文献求助10
23秒前
LHR完成签到,获得积分10
23秒前
ledi完成签到,获得积分10
23秒前
乐乐应助Vicky采纳,获得10
24秒前
十两发布了新的文献求助10
25秒前
顺心晓凡发布了新的文献求助10
25秒前
26秒前
刻苦的芝完成签到 ,获得积分10
26秒前
哈123完成签到,获得积分10
26秒前
27秒前
erich完成签到 ,获得积分10
28秒前
shanage应助天玄一刀采纳,获得10
29秒前
王欣瑶完成签到 ,获得积分10
30秒前
大模型应助无奈采纳,获得10
30秒前
chase完成签到,获得积分10
30秒前
#include应助杜宇采纳,获得20
30秒前
小蘑菇应助Tian采纳,获得10
31秒前
小草完成签到,获得积分10
31秒前
高分求助中
Sustainability in ’Tides Chemistry 2000
Sustainability in ’Tides Chemistry 1500
The ACS Guide to Scholarly Communication 1000
TM 5-855-1(Fundamentals of protective design for conventional weapons) 1000
Handbook of the Mammals of the World – Volume 3: Primates 805
Ethnicities: Media, Health, and Coping 800
Treatise on Geomorphology(2nd Edition - March 1, 2022) 520
热门求助领域 (近24小时)
化学 医学 生物 材料科学 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 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3070593
求助须知:如何正确求助?哪些是违规求助? 2724605
关于积分的说明 7486392
捐赠科研通 2371929
什么是DOI,文献DOI怎么找? 1257605
科研通“疑难数据库(出版商)”最低求助积分说明 610063
版权声明 596891