Early life elevations of methionine oxidation and ornithine track and predict cystic fibrosis structural lung disease
Year: 2025
Type: article
Study design: Observational Study
Abstract: Introduction: Early cystic fibrosis (CF) lung disease monitoring is crucial for understanding responses to therapy and preventing progressive pulmonary decline. Structural lung disease (SLD) is a major cause of pulmonary decline in CF. We aimed to identify metabolites in CF bronchoalveolar lavage (BAL) associated with and predictive of SLD. Methods: We applied untargeted metabolomics to 84 BAL samples from a cross-sectional cohort of 67 clinically stable children with CF aged 1-5 years across two sites. We used a linear mixed-effects model to select metabolites associated with SLD, BAL neutrophils, and myeloperoxidase (MPO) and neutrophil elastase (NE) activities. An independent longitudinal cohort of infants who either did or did not exhibit bronchiectasis by age 9 years was analysed to determine whether metabolites associated with SLD could also predict future lung disease. Results: -acetylmethionine (NAcMet), were associated with SLD, neutrophils, MPO and NE. The percentage of methionine oxidation (%OxMet) and the arginine-ornithine ratio were also associated with these outcomes. In the longitudinal cohort, MetO, %OxMet, ornithine and NAcMet predicted bronchiectasis development, and MetO plus ornithine was a more sensitive predictor than either alone. At age 0-2 years, these metabolites outperformed established biomarkers such as NE, MPO and interleukin-8. Conclusions: We identified BAL metabolites associated with SLD, MPO and NE, detectable in the earliest stages of CF. MetO, %OxMet, NAcMet and ornithine predicted bronchiectasis development, outperforming established biomarkers. These metabolites reflect oxidising, proteolytic and other enzymatic activities of neutrophils, highlighting potential therapeutic avenues.
Source: ERJ Open Research
Authors: Sarah Mansour, Lisa J.M. Slimmen, George L. Silva, Genoah L. Collins, Vincent D. Giacalone, Camilla Margaroli, Badies H.A.N. Manai, David Mager, Silvia C. Estevão, Susan O. Kim, Diego Moncada-Giraldo, James T. Lyles, Wendy W.J. Unger, Limin Peng, Charles R. Esther, Daan Caudri, Padma Rao, Shivanthan Shanthikumar, Sarath Ranganathan, Stephen M. Stick, Lokesh Guglani, Rabindra Tirouvanziam, Hettie M. Janssens, Joshua D. Chandler
Institutions: Emory University, Erasmus MC, Erasmus MC - Sophia Children’s Hospital, Children's Healthcare of Atlanta, University of North Carolina at Chapel Hill, Royal Children's Hospital, The University of Melbourne, Murdoch Children's Research Institute, Princess Margaret Hospital for Children, Perth Children's Hospital
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $808
Funders: Expertise France, Hubei Provincial Key Laboratory of Green Materials for Light Industry, AstraZeneca UK, Deanship of Scientific Research, King Khalid University, Grand Canyon Conservancy, Cystic Fibrosis Foundation, American Society of Hematology, Sanofi, World Health Organization, National Geographic Society, Velux Stiftung, University of Washington, Victorian Cancer Agency, Alaska Department of Fish and Game, Kræftens Bekæmpelse, European Respiratory Society, Wellcome Trust, Børnecancerfonden, Vertex Pharmaceuticals, Scottish Government, Milwaukee Metropolitan Sewerage District, Nederlandse Cystic Fibrosis Stichting, Korea University Guro Hospital, Korea University Medicine, Health Commission of Hunan Province, Chiesi España, Leverhulme Trust, European Commission, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Fundação de Amparo à Pesquisa do Estado de São Paulo, National Natural Science Foundation of China, Chonnam National University, Aarhus Universitets Forskningsfond, Ministry of Science and Technology of the People's Republic of China, Hubei University of Technology, Ministero della Salute, Natural Science Foundation of Guangdong Province, Korea Institute for Advancement of Technology, National Research Foundation of Korea, Natural Science Foundation of Hebei Province, Natural Science Foundation of Hubei Province, Regione Campania, Khon Kaen University, Kuwait University, University of Waterloo, Natural Science Foundation of Jiangsu Province, National Research Council of Thailand, NordForsk, Norges Forskningsråd, Dansk Kræftforsknings Fond, Riisfort Fonden, Lung Foundation Australia, Wenzhou Municipal Science and Technology Bureau, Torben og Alice Frimodts Fond, Frimodt-Heineke Fonden, Animal Free Research UK, Anders Hasselbalchs Fond til Leukæmiens Bekæmpelse, Michaelsen Fonden, Ingeniør Otto Christensens Fond, Fabrikant Einar Willumsens Mindelegat, Bundesamt für Naturschutz, Science, Technology and Innovation Commission of Shenzhen Municipality, Key Research and Development Program of Jiangxi Province, Menarini Group, Luoyang Institute of Science and Technology, Grifols, Semnan University of Medical Sciences and Health Services, Key Research and Development Program of Hunan Province of China, Foundation TKI Horticulture, Perpetual, Ministero dell'Università e della Ricerca, Fundación de la Universidad Autónoma de Madrid, National Institutes of Health, Centers for Disease Control and Prevention, Directorate for Biological Sciences, U.S. Geological Survey, National Park Service, Smithsonian Tropical Research Institute, Warner College of Natural Resources, Colorado State University, Pan American Health Organization, Natural Sciences and Engineering Research Council of Canada, Medical Research Council, Biotechnology and Biological Sciences Research Council, Economic and Social Research Council, Australian Research Council, National Health and Medical Research Council, Japan Society for the Promotion of Science, Beijing Nova Program, Fonden til Lægevidenskabens Fremme, Directorate-General for Health and Food Safety, British Columbia Knowledge Development Fund, National Key Research and Development Program of China, Jiangxi Academy of Sciences, Guangxi Key Research and Development Program, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Basic and Applied Basic Research Foundation of Guangdong Province, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Allergy and Infectious Diseases, National Institute of Biomedical Imaging and Bioengineering, Division of Ocean Sciences, Division of Environmental Biology, Beijing National Laboratory for Molecular Sciences, Natural Science Foundation of Zhejiang Province, National Science Foundation Graduate Research Fellowship Program, Sophia Foundation, Social Sciences and Humanities Research Council, Health Commission of Chengdu Municipality, Office of the Permanent Secretary, Ministry of Higher Education, Science, Research and Innovation, Thailand
OpenAlex ID: W4408831418