{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T11:59:05Z","timestamp":1791806345168,"version":"4.3.4"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Excessive oxidative burst and dysregulated neutrophil extracellular trap (NET) formation contribute to tissue damage in acute lung injury (ALI) and are largely driven by the combined actions of NADPH oxidase 2 (NOX2) and myeloperoxidase (MPO). While lactoferrin (LTF) is a known multifunctional immunomodulatory glycoprotein, its precise role in modulating the NOX2\u2013MPO\u2013NETosis axis in ALI remains undefined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed a time-course model of lipopolysaccharide (LPS)-induced ALI in C57BL\/6N mice, combined with quantitative label-free lung proteomics and downstream bioinformatic analyses to map dynamic molecular changes. At the inflammatory peak, aerosolized bovine lactoferrin (bLF) was administered in vivo, and histological lung injury, pulmonary inflammatory cytokine levels, neutrophil infiltration, and markers related to the NOX2\u2013MPO\u2013NETosis axis were evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>LPS induced typical ALI pathology that peaked between days 1 and 3 (D1\u2013D3). Proteomic and network analyses consistently highlighted NET formation as a centrally enriched early KEGG pathway and identified LTF as a key protein\u2013protein interaction hub closely connected to p47phox (encoded by Ncf1) and MPO. Evaluation of aerosolized bLF demonstrated significant mitigation of ALI pathology, reducing lung injury, pro-inflammatory cytokines, and neutrophil recruitment. Mechanistically, bLF suppressed NETosis by reducing p47phox and MPO expression and, crucially, diminished p47phox phosphorylation in vivo, consistent with reduced NOX2 activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings identify LTF as a critical dynamic regulator of the p47phox\u2013MPO\u2013NETosis axis in LPS-induced ALI. They also highlight bLF as a promising candidate for further translational evaluation and support the rationale for developing bioengineered, lactoferrin-based nanomedicines aimed at modulating innate immunity and mitigating neutrophil-driven lung injury in respiratory infectious diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1760949","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T06:55:01Z","timestamp":1772088901000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Inhaled bovine lactoferrin modulates the p47phox\u2013MPO\u2013NETosis axis in acute lung injury: implications for bioengineered nanomedicine in respiratory infections"],"prefix":"10.3389","volume":"17","author":[{"given":"GuoAn","family":"Xiang","sequence":"first","affiliation":[{"name":"College of Pulmonary & Critical Care Medicine, The Eighth Medical Center of Chinese PLA General 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China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ZhongKuo","family":"Yu","sequence":"additional","affiliation":[{"name":"College of Pulmonary & Critical Care Medicine, The Eighth Medical Center of Chinese PLA General Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YaRu","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Pulmonary & Critical Care Medicine, The Eighth Medical Center of Chinese PLA General Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"XiaoXiang","family":"Hu","sequence":"additional","affiliation":[{"name":"College of Biological Sciences, China Agricultural University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ShouLong","family":"Deng","sequence":"additional","affiliation":[{"name":"National Science Center for Model Animals, China Agricultural University","place":["Beijing, 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