Background: Chronic obstructive pulmonary disease (COPD) is a major clinical problem; it is the 4th leading cause of chronic morbidity and death worldwide. Histone acetyltransferases (HATs) & histone deacetylases (HDACs), the enzymes which regulate protein acetylation, are emerging as critical regulators of inflammatory diseases. One emerging bromodomain and extra terminal domain (BET) protein inhibitor I-BET151 (GSK1210151), has been shown to displace BET proteins from acetylated histone tails on chromatin and inhibit the transcription of pro-inflammatory genes and therefore may be effective in COPD. Objective: We hypothesise that histone acetylation plays a substantial role in the development and progression of COPD and that there is aberrant expression and activity in the regulatory enzymes. Additionally, the use of the bromodomain inhibitor I-BET151 will suppress inflammation and prevent pathogenesis in experimental COPD. Methods: Tightly controlled amounts of cigarette smoke were delivered to the airways of mice. Histone acetylation, and the regulatory enzymes (HATs & HDACs) were assessed by quantitative assays, activity assays, and qPCR. I-BET151 was given to the mice daily (30mg/kg ip) during smoke exposure (prophylactically and therapeutically). Results: There was increased HAT and decreased HDAC activity and expression in lung tissue after smoke exposure, which was associated with increased global histone H4 acetylation. Prophylactic I-BET151 reduced the inflammatory response in the bronchoalveolar fluid, in particular neutrophil number, as well as emphysema-like alveolar enlargement and restored lung functional parameters. Conclusion: Inhibition of bromodomains using I-BET151 plays a significant role in the development of COPD; by reducing inflammation and alveolar enlargement and restoring lung function parameters. This could have the potential of therapeutic options to improve management for patients with COPD.