Proteomic profiling of lung immune cells reveals dysregulation of phagocytotic pathways in female-dominated molecular COPD phenotype
Mingxing Yang, Maxie Kohler, Tina Heyder, Helena Forsslund, Hilde K Garberg, Reza Karimi, Johan Grunewald, Frode S Berven, Sven Nyrén, C Magnus Sköld, Åsa M Wheelock, Mingxing Yang, Maxie Kohler, Tina Heyder, Helena Forsslund, Hilde K Garberg, Reza Karimi, Johan Grunewald, Frode S Berven, Sven Nyrén, C Magnus Sköld, Åsa M Wheelock
Abstract
Background: Smoking is the main risk factor for chronic obstructive pulmonary disease (COPD). Women with COPD who smoke experienced a higher risk of hospitalization and worse decline of lung function. Yet the mechanisms of these gender-related differences in clinical presentations in COPD remain unknown. The aim of our study is to identify proteins and molecular pathways associated with COPD pathogenesis, with emphasis on elucidating molecular gender difference.
Method: We employed shotgun isobaric tags for relative and absolute quantitation (iTRAQ) proteome analyses of bronchoalveolar lavage (BAL) cells from smokers with normal lung function (n = 25) and early stage COPD patients (n = 18). Multivariate modeling, pathway enrichment analysis, and correlation with clinical characteristics were performed to identify specific proteins and pathways of interest.
Results: More pronounced alterations both at the protein- and pathway- levels were observed in female COPD patients, involving dysregulation of the FcγR-mediated phagocytosis-lysosomal axis and increase in oxidative stress. Alterations in pathways of the phagocytosis-lysosomal axis associated with a female-dominated COPD phenotype correlated well with specific clinical features: FcγR-mediated phagocytosis correlated with FEV1/FVC, the lysosomal pathway correlated with CT < -950 Hounsfield Units (HU), and regulation of actin cytoskeleton correlated with FEV1 and FEV1/FVC in female COPD patients. Alterations observed in the corresponding male cohort were minor.
Conclusion: The identified molecular pathways suggest dysregulation of several phagocytosis-related pathways in BAL cells in female COPD patients, with correlation to both the level of obstruction (FEV1/FVC) and disease severity (FEV1) as well as emphysema (CT < -950 HU) in women.
Trial registration: No.: NCT02627872 , retrospectively registered on December 9, 2015.
Keywords: Bronchoalveolar lavage; Chronic obstructive pulmonary disease; Gender difference; Isobaric tags for relative and absolute quantitation; Orthogonal projection to latent structure-discriminant analysis; Proteomics; Smoking.
Conflict of interest statement
Ethics approval and consent to participateThe study was approved by the Stockholm regional ethical board (Case no. 2006/959–31/1), and written informed consent was obtained from all subjects.
Consent for publicationNot applicable
Competing interestsThe authors declare that they have no competing interests.
Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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