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Proteomic Profiling of the Airway Epithelium in COPD Reveals Sex-Enhanced Alterations Linked to Xenobiotic Metabolism and ER Stress, Correlated to Airway Wall Thickening and Goblet Cell Density in Women
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A7790 - Proteomic Profiling of the Airway Epithelium in COPD Reveals Sex-Enhanced Alterations Linked to Xenobiotic Metabolism and ER Stress, Correlated to Airway Wall Thickening and Goblet Cell Density in Women
Author Block: A. M. Wheelock1, T. Heyder1, M. Yang1, M. Kohler1, H. Merikallio1, C. Li1, R. Karimi1, C. Sihlbom2, S. Nyren1, C. M. Skold1; 1Medicine, Karolinska Institutet, Stockholm, Sweden, 2Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Rationale: Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous condition, and sex differences related to genotype, molecular phenotype and manifestations of clinical symptoms have been reported. Over the past 20 years there has been an increased incidence of COPD, driven primarily by the female population. Although smoking represents the main risk factor, increased smoking among women does not fully explain the observed trends: Female smokers have a significantly faster annual decline in lung function than men after age 45-50, even after correction for smoking habits. In the Karolinska COSMIC cohort, we have identified sex-related molecular differences in mild-moderate COPD at several molecular levels from several anatomical locations, including the BAL cell proteomes, eicosanoids from BAL fluid and serum, and the serum metabolome. The objective of this study was to investigate alterations in the airway epithelial proteome in smoking-induce mild-to-moderate COPD, with emphasis on sex differences.
Method: The airway epithelial proteome from age- and sex- matched smoking COPD patients (COPD) (GOLD I-II/A-B), smokers with normal lung function (Smokers), and healthy never-smokers from the Karolinska COSMIC cohort (www.clinicaltrials.gov/ct2/show/NCT02627872) were analyzed by tandem mass tag-based shotgun proteomics (n=90) and Difference Gel Electrophoresis (n=85). Multivariate statistical modelling and pathway enrichment analyses were performed stratified by sex- and proteomic approach.
Measurements and Main Results: Significant sex-differences in alterations of the epithelial proteome between Smokers and COPD groups was evident by both proteomics platforms, with distinct subsets of proteins providing significant classification of Smokers vs. COPD both in females (p=1.5×10-4) and males (p=2.2×10-5). Alterations were linked to dysregulation in protein folding in the ER, xenobiotic metabolism and oxidative phosphorylation. The latter correlated to lung density measured by computed tomography (CT (-750) - (-900) HU) (r=0.82, p=0.01) in females. Protein processing in the ER correlated to lung density measured by computed tomography (r=0.75, p=0.03), and goblet cell density (r=0.72, p=0.03) in female COPD patients.
Conclusions: These investigations provide evidence of sex-enhanced alterations in xenobiotic metabolism pathways in the airway epithelium in smoking-induced COPD. Associated sex-differences in the protection against noxious chemicals in tobacco smoke may be a link to divergent molecular COPD sub-phenotypes and differences in disease incidence and disease course between men and women.
Author Block: A. M. Wheelock1, T. Heyder1, M. Yang1, M. Kohler1, H. Merikallio1, C. Li1, R. Karimi1, C. Sihlbom2, S. Nyren1, C. M. Skold1; 1Medicine, Karolinska Institutet, Stockholm, Sweden, 2Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Rationale: Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous condition, and sex differences related to genotype, molecular phenotype and manifestations of clinical symptoms have been reported. Over the past 20 years there has been an increased incidence of COPD, driven primarily by the female population. Although smoking represents the main risk factor, increased smoking among women does not fully explain the observed trends: Female smokers have a significantly faster annual decline in lung function than men after age 45-50, even after correction for smoking habits. In the Karolinska COSMIC cohort, we have identified sex-related molecular differences in mild-moderate COPD at several molecular levels from several anatomical locations, including the BAL cell proteomes, eicosanoids from BAL fluid and serum, and the serum metabolome. The objective of this study was to investigate alterations in the airway epithelial proteome in smoking-induce mild-to-moderate COPD, with emphasis on sex differences.
Method: The airway epithelial proteome from age- and sex- matched smoking COPD patients (COPD) (GOLD I-II/A-B), smokers with normal lung function (Smokers), and healthy never-smokers from the Karolinska COSMIC cohort (www.clinicaltrials.gov/ct2/show/NCT02627872) were analyzed by tandem mass tag-based shotgun proteomics (n=90) and Difference Gel Electrophoresis (n=85). Multivariate statistical modelling and pathway enrichment analyses were performed stratified by sex- and proteomic approach.
Measurements and Main Results: Significant sex-differences in alterations of the epithelial proteome between Smokers and COPD groups was evident by both proteomics platforms, with distinct subsets of proteins providing significant classification of Smokers vs. COPD both in females (p=1.5×10-4) and males (p=2.2×10-5). Alterations were linked to dysregulation in protein folding in the ER, xenobiotic metabolism and oxidative phosphorylation. The latter correlated to lung density measured by computed tomography (CT (-750) - (-900) HU) (r=0.82, p=0.01) in females. Protein processing in the ER correlated to lung density measured by computed tomography (r=0.75, p=0.03), and goblet cell density (r=0.72, p=0.03) in female COPD patients.
Conclusions: These investigations provide evidence of sex-enhanced alterations in xenobiotic metabolism pathways in the airway epithelium in smoking-induced COPD. Associated sex-differences in the protection against noxious chemicals in tobacco smoke may be a link to divergent molecular COPD sub-phenotypes and differences in disease incidence and disease course between men and women.
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