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Gender specific airway gene expression in COPD sub-phenotypes supports a role of mitochondria and of different types of leukocytes.

ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a destructive inflammatory disease and the genes expressed within the lung are crucial to its pathophysiology. We have determined the RNAseq transcriptome of bronchial brush cells from 312 stringently defined ex-smoker patients. Compared to healthy controls there were for males 40 differentially expressed genes (DEGs) and 73 DEGs for females with only 26 genes shared. The gene ontology (GO) term "response to bacterium" was shared, with several different DEGs contributing in males and females. Strongly upregulated genes TCN1 and CYP1B1 were unique to males and females, respectively. For male emphysema (E)-dominant and airway disease (A)-dominant COPD (defined by computed tomography) the term "response to stress" was found for both sub-phenotypes, but this included distinct up-regulated genes for the E-sub-phenotype (neutrophil-related CSF3R, CXCL1, MNDA) and for the A-sub-phenotype (macrophage-related KLF4, F3, CD36). In E-dominant disease, a cluster of mitochondria-encoded (MT) genes forms a signature, able to identify patients with emphysema features in a confirmation cohort. The MT-CO2 gene is upregulated transcriptionally in bronchial epithelial cells with the copy number essentially unchanged. Both MT-CO2 and the neutrophil chemoattractant CXCL1 are induced by reactive oxygen in bronchial epithelial cells. Of the female DEGs unique for E- and A-dominant COPD, 88% were detected in females only. In E-dominant disease we found a pronounced expression of mast cell-associated DEGs TPSB2, TPSAB1 and CPA3. The differential genes discovered in this study point towards involvement of different types of leukocytes in the E- and A-dominant COPD sub-phenotypes in males and females.

SUBMITTER: Esteve-Codina A

PROVIDER: S-EPMC8213687 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Gender specific airway gene expression in COPD sub-phenotypes supports a role of mitochondria and of different types of leukocytes.

Esteve-Codina Anna A Hofer Thomas P TP Burggraf Dorothe D Heiss-Neumann Marion S MS Gesierich Wolfgang W Boland Anne A Olaso Robert R Bihoreau Marie-Therese MT Deleuze Jean-Francois JF Moeller Winfried W Schmid Otmar O Soler Artigas María M Renner Kathrin K Hohlfeld Jens M JM Welte Tobias T Fuehner Thomas T Jerrentrup Lukas L Koczulla Andreas Rembert AR Greulich Timm T Prasse Antje A Müller-Quernheim Joachim J Gupta Sumit S Brightling Christopher C Subramanian Deepak R DR Parr David G DG Kolsum Umme U Gupta Vandana V Barta Imre I Döme Balázs B Strausz János J Stendardo Mariarita M Piattella Marco M Boschetto Piera P Korzybski Damian D Gorecka Dorota D Nowinski Adam A Dabad Marc M Fernández-Callejo Marcos M Endesfelder David D Zu Castell Wolfgang W Hiemstra Pieter S PS Venge Per P Noessner Elfriede E Griebel Thasso T Heath Simon S Singh Dave D Gut Ivo I Ziegler-Heitbrock Loems L

Scientific reports 20210618 1

Chronic obstructive pulmonary disease (COPD) is a destructive inflammatory disease and the genes expressed within the lung are crucial to its pathophysiology. We have determined the RNAseq transcriptome of bronchial brush cells from 312 stringently defined ex-smoker patients. Compared to healthy controls there were for males 40 differentially expressed genes (DEGs) and 73 DEGs for females with only 26 genes shared. The gene ontology (GO) term "response to bacterium" was shared, with several diff ...[more]

PMID: 34145303

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Project description:BackgroundOxidative injury to the airway has been proposed as an important underlying mechanism in the pathogenesis of chronic obstructive pulmonary disease (COPD). As the extent of oxidant-mediated damage is dependent on the endogenous antioxidant defences within the airways, we examined whether COPD was associated with deficiencies in the antioxidant network within the respiratory tract lining fluids (RTLFs) and resident airway leukocytes. We hypothesised that COPD would be associated with both basal depression of antioxidant defences and impaired adaptive antioxidant responses to cigarette smoke.MethodsLow molecular weight and enzymatic antioxidants together with metal-handling proteins were quantified in bronchoalveolar lavage fluid and airway leukocytes, derived from current (n=9) and ex-smoking COPD patients (n=15), as well as from smokers with normal lung function (n=16) and healthy never smokers (n=13).ResultsCurrent cigarette smoking was associated with an increase in ascorbate and glutathione within peripheral RTLFs in both smokers with normal lung function compared with healthy never smokers and in COPD smokers compared with COPD ex-smokers. In contrast, intra-cellular antioxidant enzyme activities (glutathione peroxidase, glutathione reductase, and catalase) were only up-regulated in smokers with normal lung function compared with healthy never smokers and not in actively smoking COPD patients relative to COPD ex-smokers.ConclusionsWe found no evidence of impaired basal antioxidant defences, within either the RTLFs or airway leukocytes in stable ex-smoking COPD patients compared with healthy never smoking controls. Current cigarette smoking induced an up-regulation of low molecular weight antioxidants in the RTLFs of both control subjects with normal lung function and patients with COPD. Importantly, the present data demonstrated a cigarette smoke-induced increase in intra-cellular antioxidant enzyme activities only within the smokers with normal lung function, implying that patients with COPD who continue to smoke will experience enhanced oxidative stress, prompting disease progression.

Dataset Information

Gender specific airway gene expression in COPD sub-phenotypes supports a role of mitochondria and of different types of leukocytes.

Publications

Gender specific airway gene expression in COPD sub-phenotypes supports a role of mitochondria and of different types of leukocytes.

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