{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T13:32:28Z","timestamp":1791639148912,"version":"4.3.4"},"reference-count":43,"publisher":"Portland Press Ltd.","issue":"1","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":5,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"crossref","award":["\u201cFondo per il Programma Nazionale di Ricerca e Progetti di Rilevante Interesse Nazionale (PRIN) - 20222PKF9S; PNC0000003 - ANTHEM - Cascade Call launched by SPOKE 3 POLIMI: CARELUNG"],"award-info":[{"award-number":["\u201cFondo per il Programma Nazionale di Ricerca e Progetti di Rilevante Interesse Nazionale (PRIN) - 20222PKF9S; PNC0000003 - ANTHEM - Cascade Call launched by SPOKE 3 POLIMI: CARELUNG"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,1,14]]},"abstract":"<jats:p>The onset of chronic lung allograft dysfunction (CLAD) represents the greatest long-term challenge in lung transplantation (LT). Here we aimed to identify early molecular signals of CLAD by analyzing the effects of bronchoalveolar lavage (BAL)-derived extracellular vesicles (EVs) on airway cells and validating these findings in patient lung tissues. In our BAL biobank, we identified 13 LT patients with a BAL sample at CLAD diagnosis and 13 patients with a stable graft function and a BAL sample obtained at least 12 months post LT (Ctrl). All patients were then followed for at least 18 months. EVs were isolated, immunophenotyped, and co-cultured with airway cells. The cells\u2019 transcriptome and proteome were profiled. Selected targets were validated by immunohistochemistry. Logistic regression and survival analyses were performed for prediction of CLAD progression. During follow-up, 7 CLAD patients experienced allograft dysfunction aggravation, and one control developed CLAD. CLAD patients showed more EVs originating from epithelial cells and leukocytes than stable LT recipients. Exposure of airway cells to CLAD-EVs led to the up-regulation of p70S6K and canonical NF-\u03baB signaling, altering their intracellular and extracellular proteome. Activation of NF-\u03baB was also detected at the onset of CLAD in transbronchial biopsies and BAL cytology, and it persisted throughout the progression to end-stage CLAD. RelA overexpression was associated with poorer graft performance and worse outcomes. RelA-driven NF-\u03baB activation is a key factor in the development of CLAD by promoting persistent inflammation. This pathway may be a promising therapeutic target to improve long-term graft survival after LT.<\/jats:p>","DOI":"10.1042\/cs20258651","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T06:55:42Z","timestamp":1767682542000},"page":"97-114","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Analysis of BAL extracellular vesicles unveils NF-\u03baB activation at the onset of chronic lung allograft dysfunction"],"prefix":"10.1042","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9705-0618","authenticated-orcid":false,"given":"Alessandra Maria","family":"Storaci","sequence":"first","affiliation":[{"name":"1Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy"},{"name":"2Division of Pathology, Fondazione IRCCS Ca\u2019 Granda-Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rosaria","family":"de Filippo","sequence":"additional","affiliation":[{"name":"3Laboratory of OMIC Science, Scientific Direction, Fondazione IRCCS Ca\u2019 Granda-Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Franzi","sequence":"additional","affiliation":[{"name":"4Division of Thoracic Surgery and Lung Transplantation, Fondazione IRCCS Ca\u2019 Granda- Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Mansour","sequence":"additional","affiliation":[{"name":"1Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy"},{"name":"3Laboratory of OMIC Science, Scientific Direction, Fondazione IRCCS Ca\u2019 Granda-Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Lopez","sequence":"additional","affiliation":[{"name":"2Division of Pathology, Fondazione IRCCS Ca\u2019 Granda-Ospedale Maggiore Policlinico, Milan, Italy"},{"name":"5Department of Biomedical Surgical and Dental Sciences, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Takeko","family":"Molisso","sequence":"additional","affiliation":[{"name":"3Laboratory of OMIC Science, Scientific Direction, Fondazione IRCCS Ca\u2019 Granda-Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Zadra","sequence":"additional","affiliation":[{"name":"6Institute of Molecular Genetics, National Research Council (CNR-IGM), Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Brevi","sequence":"additional","affiliation":[{"name":"5Department of Biomedical Surgical and Dental Sciences, University of Milan, Milan, 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Italy"},{"name":"4Division of Thoracic Surgery and Lung Transplantation, Fondazione IRCCS Ca\u2019 Granda- Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Mendogni","sequence":"additional","affiliation":[{"name":"4Division of Thoracic Surgery and Lung Transplantation, Fondazione IRCCS Ca\u2019 Granda- Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Nosotti","sequence":"additional","affiliation":[{"name":"1Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy"},{"name":"4Division of Thoracic Surgery and Lung Transplantation, Fondazione IRCCS Ca\u2019 Granda- Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Blasi","sequence":"additional","affiliation":[{"name":"1Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy"},{"name":"8Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca\u2019 Granda-Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letizia Corinna","family":"Morlacchi","sequence":"additional","affiliation":[{"name":"1Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy"},{"name":"8Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca\u2019 Granda-Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4510-5167","authenticated-orcid":false,"given":"Alessandro","family":"Palleschi","sequence":"additional","affiliation":[{"name":"1Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy"},{"name":"4Division of Thoracic Surgery and Lung Transplantation, Fondazione IRCCS Ca\u2019 Granda- Ospedale Maggiore Policlinico, Milan, 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