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Excessive release of NETs has been reported in chronic lung diseases, including chronic obstructive pulmonary disease (COPD). However, the role of NETs in the pathogenesis of COPD remains unclear. Peptidylarginine deaminase 4 (PAD4) contributes to NET formation. Therefore, in an elastase (ELS)-induced emphysema mouse model, we examined the role of PAD4 using Padi4 gene knockout (KO) mice. First, we confirmed that ELS induced NET formation in the parenchyma of the lungs. PAD4 deficiency suppressed ELS-induced NET expression and tended to ameliorate the lung tissue injury. The cellular profile of bronchoalveolar lavage fluid (BALF) did not differ between the two groups. Additionally, PAD4 deficiency ameliorated emphysema and apoptosis in lung cells. Finally, we examined the effects of PAD4 on comprehensive gene expression signatures using RNA sequencing. Enrichment analysis of the transcriptomic data revealed that the expression of several genes associated with COPD pathogenesis was altered in the KO mice. Overall, the results suggest that PAD4 deficiency improves NET formation and emphysema in the lungs; this pathway can be a potential therapeutic target for the treatment of COPD.<\/jats:p>","DOI":"10.3390\/ijms26125573","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T03:44:58Z","timestamp":1749613498000},"page":"5573","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Peptidylarginine Deiminase 4 Deficiency Suppresses Neutrophil Extracellular Trap Formation and Ameliorates Elastase-Induced Emphysema in Mouse Lung"],"prefix":"10.3390","volume":"26","author":[{"given":"Megumi","family":"Katsumata","sequence":"first","affiliation":[{"name":"Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Ikari","sequence":"additional","affiliation":[{"name":"Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Urano","sequence":"additional","affiliation":[{"name":"Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiko","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuto","family":"Kugou","sequence":"additional","affiliation":[{"name":"Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu 292-0818, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu 292-0818, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9484-7912","authenticated-orcid":false,"given":"Koichiro","family":"Tatsumi","sequence":"additional","affiliation":[{"name":"Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuji","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan"},{"name":"Synergy Institute for Futuristic Mucosal Vaccine Research and Development, Chiba University, Chiba 260-8670, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1146\/annurev-biochem-061516-045037","article-title":"Oxidative Stress","volume":"86","author":"Sies","year":"2017","journal-title":"Annu. 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