Abstract
BackgroundSmoking 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.MethodWe 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.ResultsMore 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.ConclusionThe 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 registrationNo.: NCT02627872, retrospectively registered on December 9, 2015.
Highlights
Smoking is the main risk factor for chronic obstructive pulmonary disease (COPD)
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
Summary
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. Chronic obstructive pulmonary disease (COPD) is reported to be a leading cause of mortality worldwide and represents an important socioeconomic burden [1, 2]. A number of studies have demonstrated pronounced gender differences in susceptibility, respiratory symptoms, and lung function as well as in molecular markers of inflammation in COPD [4,5,6], with a higher frequency of hospitalization and mortality among women [7, 8]. In our Karolinska COSMIC cohort, we have previously reported molecular gender differences in COPD in several compartments, including the BAL cell proteome using two-dimensional differential gel electrophoresis (2D–DIGE) [15]. Shotgun proteomics facilitates investigation of a different proteome compartment than the previously reported 2D–DIGE approaches, and provides complementary information about the BAL cell proteome alterations due to smoking and COPD. Results related to the effects of smoking prior to disease manifestations are reported in a companion paper [16]
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