@article {Koba00658-2020, author = {Taro Koba and Yoshito Takeda and Ryohei Narumi and Takashi Shiromizu and Yosui Nojima and Mari Ito and Muneyoshi Kuroyama and Yu Futami and Takayuki Takimoto and Takanori Matsuki and Ryuya Edahiro and Satoshi Nojima and Yoshitomo Hayama and Kiyoharu Fukushima and Haruhiko Hirata and Shohei Koyama and Kota Iwahori and Izumi Nagatomo and Mayumi Suzuki and Yuya Shirai and Teruaki Murakami and Kaori Nakanishi and Takeshi Nakatani and Yasuhiko Suga and Kotaro Miyake and Takayuki Shiroyama and Hiroshi Kida and Takako Sasaki and Koji Ueda and Kenji Mizuguchi and Jun Adachi and Takeshi Tomonaga and Atsushi Kumanogoh}, title = {Proteomics of serum extracellular vesicles identifies a novel COPD biomarker, fibulin-3 from elastic fibres}, volume = {7}, number = {1}, elocation-id = {00658-2020}, year = {2021}, doi = {10.1183/23120541.00658-2020}, publisher = {European Respiratory Society}, abstract = {There is an unmet need for novel biomarkers in the diagnosis of multifactorial COPD. We applied next-generation proteomics to serum extracellular vesicles (EVs) to discover novel COPD biomarkers.EVs from 10 patients with COPD and six healthy controls were analysed by tandem mass tag-based non-targeted proteomics, and those from elastase-treated mouse models of emphysema were also analysed by non-targeted proteomics. For validation, EVs from 23 patients with COPD and 20 healthy controls were validated by targeted proteomics.Using non-targeted proteomics, we identified 406 proteins, 34 of which were significantly upregulated in patients with COPD. Of note, the EV protein signature from patients with COPD reflected inflammation and remodelling. We also identified 63 upregulated candidates from 1956 proteins by analysing EVs isolated from mouse models. Combining human and mouse biomarker candidates, we validated 45 proteins by targeted proteomics, selected reaction monitoring. Notably, levels of fibulin-3, tripeptidyl-peptidase 2, fibulin-1, and soluble scavenger receptor cysteine-rich domain-containing protein were significantly higher in patients with COPD. Moreover, six proteins; fibulin-3, tripeptidyl-peptidase 2, UTP-glucose-1-phosphate uridylyl transferase, CD81, CD177, and oncoprotein-induced transcript 3, were correlated with emphysema. Upregulation of fibulin-3 was confirmed by immunoblotting of EVs and immunohistochemistry in lungs. Strikingly, fibulin-3 knockout mice spontaneously developed emphysema with age, as evidenced by alveolar enlargement and elastin destruction.We discovered potential pathogenic biomarkers for COPD using next-generation proteomics of EVs. This is a novel strategy for biomarker discovery and precision medicine.This study identified novel biomarkers for COPD using next-generation proteomics of serum extracellular vesicles. Notably, the expression of fibulin-3 is correlated with lung function and emphysema. This could be useful for personalised medicine. https://bit.ly/2JfRCgk}, URL = {https://openres.ersjournals.com/content/7/1/00658-2020}, eprint = {https://openres.ersjournals.com/content/7/1/00658-2020.full.pdf}, journal = {ERJ Open Research} }