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Gasdermin D (GSDMD)\u2010mediated pyroptosis is a critical driver of COPD progression. This study provides insights into COPD pathogenesis and provides a theoretical basis for potential therapeutic targets. Mice were exposed to cigarette smoke (CS) for 16\u2009weeks to establish a COPD model.\n                    <jats:italic>In vitro<\/jats:italic>\n                    , alveolar macrophages (AMs) (MH\u2010S) and alveolar epithelial cells (MLE\u201012) were treated with cigarette smoke extract (CSE). Subsequently, NETs were isolated from phorbol\u201012\u2010myristate\u201013\u2010acetate (PMA)\u2010stimulated neutrophils. Lung histopathology, inflammatory markers, and pyroptosis\u2010related proteins were analyzed. Co\u2010immunoprecipitation analysis was used to verify the binding of GSDMD and ubiquitin molecules in cells. Interventions included DNase1 to degrade NET and GSDMD knockdown. In CS\u2010exposed mice, NETs increased the levels of proinflammatory cells and mediators, and lung structure was further disrupted. Pyroptosis of AMs was increased, while phagocytosis of AMs was inhibited. However, treatment with DNAse1 partially reversed the results caused by CS exposure and NET induction. Consistently, NETs aggravated inflammatory response and pyroptosis in the CSE\u2010induced MH\u2010S cell model. Furthermore, NETs significantly caused an increase in ROS, which promoted the activation of GSDMD deubiquitination and subsequent pyroptosis pathway in AMs. DNase1 treatment or GSDMD silencing attenuated pyroptosis, reduced inflammatory mediators, and improved lung function. NETs aggravated CS\u2010induced lung inflammation and injury by activating GSDMD to promote pyroptosis in AMs. Targeting GSDMD or NETs represents a novel therapeutic strategy for COPD. \u00a9 2026 The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70046","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T12:18:58Z","timestamp":1773404338000},"page":"197-209","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Neutrophil extracellular traps aggravate lung injury by inducing pyroptosis of alveolar macrophages"],"prefix":"10.1002","volume":"269","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9705-4632","authenticated-orcid":false,"given":"Junjuan","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine The Third Xiangya Hospital of Central South University  Changsha PR 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