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

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 CSinduced experimental COPD using Zfp36 aa/aa mice, a genetically modified mouse strain in which endogenous TTP cannot be phosphorylated, rendering it constitutively active as an mRNAdestabilising factor. TTP wild-type (Zfp36 +/+ ) and Zfp36 aa/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, Zfp36 aa/aa mice had reduced numbers of airway neutrophils and lymphocytes and mRNA expression levels of cytokines compared to wild-type controls. After eight weeks, Zfp36 aa/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 ª

Time‐resolved proteomic profiling of cigarette smoke‐induced experimental chronic obstructive pulmonary disease

“…Future studies will strengthen our observations by assessing the levels of these factors in the lung tissues of COPD patients with different levels of severity using immunohistochemistry. Importantly, our laboratory has consistently demonstrated that the inhalational exposure of mice to 8 weeks of CS recapitulates the hallmark features of human COPD 2,4,18,25,26,28–30,84,95 . To our knowledge, this study represents the most comprehensive CS‐induced COPD pulmonary proteome to date.…”

“…Strikingly, after 8 weeks of chronic CS exposure in experimental COPD, the proteomic profiles of lung tissue revealed 269 unique dysregulated proteins, of which 264 were significantly upregulated. All of the chronic pathological features of human COPD develop at this time point including chronic pulmonary inflammation, airway remodelling with mucus hypersecretion, emphysema and impaired lung function 2–4,18,22,23,25–31,56 . This time point is representative of early GOLD stages 1/2 of COPD, 62 allowing changes to be validated in clinically relevant samples.…”

“…Given these challenges, sophisticated animal models have been developed and widely used to provide insights into COPD pathogenesis with results validated in human tissues 2,18–26 . These powerful tools provide lung tissues during the development and progression of the hallmark features of COPD that can be investigated in multi‐organ systems in reasonable time frames 3,27 .…”

Role of Tristetraprolin in the Resolution of Inflammation

“…Consequently, modulating TTP might provide a promising avenue for the development of inflammation regulatory therapies. Specifically, therapeutic approaches to increase the TTP activity can be expected to ameliorate the course of numerous chronic inflammatory diseases with a previously shown connection to TTP, such as rheumatoid arthritis [ 108 , 114 , 115 ], atherosclerosis [ 116 ], diabetes [ 117 ], inflammatory bowel disease [ 118 ], chronic obstructive pulmonary disease [ 119 ], and autoimmune diseases [ 108 , 120 ]. Since chronic inflammatory diseases are a major health care burden, such approaches appear extremely appealing.…”

Tristetraprolin Overexpression in Non-hematopoietic Cells Protects Against Acute Lung Injury in Mice

“…Our findings are in line with previous reports in other tissues. For instance, massive infiltration of neutrophils has been shown to occur in the skin of TTP KO mice subjected to psoriasis-like inflammation ( 30 ), whereas reduced airway neutrophilic infiltration was shown in mice genetically modified to express constitutively active endogenous unphosphorylated TTP following challenge with cigarette smoke ( 31 ).…”