Enhancing tristetraprolin activity reduces the severity of cigarette smoke‐induced experimental chronic obstructive pulmonary disease

Clinical & Translational Immunology

卷:8

Andrew R Clark¹  Peter A. Wark²  Malcolm R Starkey²  Nikki M Verrills²  Joerg Mattes²  Adam M Collison²  Prema M Nair²  Gang Liu²  Philip M Hansbro²  Tatt Jhong Haw²  Jonathan C Morris³  Alaina J Ammit⁴ 

[1] Institute of Inflammation and Ageing College of Medical and Dental Sciences University of Birmingham Birmingham UK;

[2] Priority Research Centres for Healthy Lungs, Grow Up Well and Cancer Research, Innovation and Translation Hunter Medical Research Institute University of Newcastle NSW Australia;

[3] School of Chemistry University of New South Wales Sydney NSW Australia;

[4] Woolcock Emphysema Centre Woolcock Institute of Medical Research University of Sydney NSW Australia;

关键词: chronic obstructive pulmonary disease;    inflammation;    protein phosphatase 2A;    tristetraprolin;    ubiquitin–proteasome system;   

DOI  :  10.1002/cti2.1084

来源: DOAJ

【 摘 要 】

Abstract Objective Chronic obstructive pulmonary disease (COPD) is a progressive disease that causes significant mortality and morbidity worldwide and is primarily caused by the inhalation of cigarette smoke (CS). Lack of effective treatments for COPD means there is an urgent need to identify new therapeutic strategies for the underlying mechanisms of pathogenesis. Tristetraprolin (TTP) encoded by the Zfp36 gene is an anti‐inflammatory protein that induces mRNA decay, especially of transcripts encoding inflammatory cytokines, including those implicated in COPD. Methods Here, we identify a novel protective role for TTP in CS‐induced experimental COPD using Zfp36aa/aa mice, a genetically modified mouse strain in which endogenous TTP cannot be phosphorylated, rendering it constitutively active as an mRNA‐destabilising factor. TTP wild‐type (Zfp36+/+) and Zfp36aa/aa active C57BL/6J mice were exposed to CS for four days or eight weeks, and the impact on acute inflammatory responses or chronic features of COPD, respectively, was assessed. Results After four days of CS exposure, Zfp36aa/aa mice had reduced numbers of airway neutrophils and lymphocytes and mRNA expression levels of cytokines compared to wild‐type controls. After eight weeks, Zfp36aa/aa mice had reduced pulmonary inflammation, airway remodelling and emphysema‐like alveolar enlargement, and lung function was improved. We then used pharmacological treatments in vivo (protein phosphatase 2A activator, AAL(S), and the proteasome inhibitor, bortezomib) to promote the activation and stabilisation of TTP and show that hallmark features of CS‐induced experimental COPD were ameliorated. Conclusion Collectively, our study provides the first evidence for the therapeutic potential of inducing TTP as a treatment for COPD.

【 授权许可】

Unknown