Nair Prema M, Starkey Malcolm R, Haw Tatt Jhong, Liu Gang, Collison Adam M, Mattes Joerg, Wark Peter A, Morris Jonathan C, Verrills Nikki M, Clark Andrew R, Ammit Alaina J, Hansbro Philip M
Priority Research Centres for Healthy Lungs, Grow Up Well and Cancer Research, Innovation and Translation Hunter Medical Research Institute University of Newcastle NSW Australia.
School of Biomedical Sciences and Pharmacy Faculty of Health and Medicine University of Newcastle Callaghan NSW Australia.
Clin Transl Immunology. 2019 Oct 28;8(10):e01084. doi: 10.1002/cti2.1084. eCollection 2019.
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 gene is an anti-inflammatory protein that induces mRNA decay, especially of transcripts encoding inflammatory cytokines, including those implicated in COPD.
Here, we identify a novel protective role for TTP in CS-induced experimental COPD using 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 ( ) and 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.
After four days of CS exposure, mice had reduced numbers of airway neutrophils and lymphocytes and mRNA expression levels of cytokines compared to wild-type controls. After eight weeks, mice had reduced pulmonary inflammation, airway remodelling and emphysema-like alveolar enlargement, and lung function was improved. We then used pharmacological treatments (protein phosphatase 2A activator, AAL, 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.
Collectively, our study provides the first evidence for the therapeutic potential of inducing TTP as a treatment for COPD.
慢性阻塞性肺疾病（COPD）是一种进行性疾病，在全球范围内导致显著的死亡率和发病率，主要由吸入香烟烟雾（CS）引起。缺乏针对COPD的有效治疗方法意味着迫切需要针对发病机制的潜在机制确定新的治疗策略。由该基因编码的锌指蛋白36（TTP）是一种抗炎蛋白，可诱导mRNA降解，尤其是编码炎性细胞因子的转录本，包括那些与COPD相关的转录本。
在这里，我们使用TTP活性C57BL/6J小鼠（一种内源性TTP不能被磷酸化的基因修饰小鼠品系，使其作为一种mRNA不稳定因子持续激活），确定了TTP在CS诱导的实验性COPD中的一种新的保护作用。将TTP野生型（WT）和TTP活性C57BL/6J小鼠暴露于CS中4天或8周，分别评估对急性炎症反应或COPD慢性特征的影响。
暴露于CS 4天后，与野生型对照相比，TTP活性小鼠气道中性粒细胞和淋巴细胞数量减少，细胞因子的mRNA表达水平降低。8周后，TTP活性小鼠肺部炎症减轻、气道重塑和肺气肿样肺泡扩大减少，肺功能得到改善。然后，我们使用药理学处理（蛋白磷酸酶2A激活剂AAL和蛋白酶体抑制剂硼替佐米）来促进TTP的激活和稳定，并表明CS诱导的实验性COPD的标志性特征得到改善。
总的来说，我们的研究为诱导TTP作为COPD治疗方法的治疗潜力提供了首个证据。
