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Systemic Immuno-metabolic alterations in chronic obstructive pulmonary disease (COPD)

BACKGROUND: Metabolic adaptation in immune cells is necessary to modulate immune cell function as it is intricately coupled with intracellular metabolism. We aimed to characterize the metabolic state of human peripheral blood mononuclear cells (PBMCs) after long-term exposure to tobacco smoke in smo...

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Autores principales: Agarwal, Amit R, Kadam, Smita, Brahme, Ankita, Agrawal, Manas, Apte, Komalkirti, Narke, Govinda, Kekan, Kushal, Madas, Sapna, Salvi, Sundeep
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668083/
https://www.ncbi.nlm.nih.gov/pubmed/31362724
http://dx.doi.org/10.1186/s12931-019-1139-2
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author Agarwal, Amit R
Kadam, Smita
Brahme, Ankita
Agrawal, Manas
Apte, Komalkirti
Narke, Govinda
Kekan, Kushal
Madas, Sapna
Salvi, Sundeep
author_facet Agarwal, Amit R
Kadam, Smita
Brahme, Ankita
Agrawal, Manas
Apte, Komalkirti
Narke, Govinda
Kekan, Kushal
Madas, Sapna
Salvi, Sundeep
author_sort Agarwal, Amit R
collection PubMed
description BACKGROUND: Metabolic adaptation in immune cells is necessary to modulate immune cell function as it is intricately coupled with intracellular metabolism. We aimed to characterize the metabolic state of human peripheral blood mononuclear cells (PBMCs) after long-term exposure to tobacco smoke in smokers with preserved lung function and COPD subjects. METHODS: PBMCs were isolated from healthy non-smokers (HNS), healthy smokers (HS) and COPD subjects, cultured and the mitochondrial respiration while utilizing glucose (glycolysis), fatty acids (β-oxidation) or pyruvate (direct Krebs’ cycle substrate) was measured using the XFp Extracellular Flux Analyzer. Plasma levels of inflammatory cytokines IFN-γ, IL-17, TNF-α, IL-5, IL-9 and IFN-α were measured using flow cytometry. RAW264.7 cells were exposed to cigarette smoke condensate (CSC) for 1 h and its effect on cell viability, cellular metabolism and phagocytosis ability were also studied. Patient’s data was analyzed using the Mann Whitney U test, whereas Student’s t test was performed to analyze the in-vitro data. RESULTS: PBMCs from COPD subjects showed a significant decrease in extracellular acidification rate (ECAR) while utilizing glucose as compared to HNS (151.9 Vs 215%). Mitochondrial oxygen consumption rate (OCR) on palmitate or pyruvate was also found to be significantly lower in COPD subjects as compared to HS and a strong positive correlation between palmitate OCR in PBMCs and FEV(1) (r = 0.74, p < 0.05) and FVC (r = 0.79, p < 0.05) values in HS was observed. The metabolic shift towards fatty acid metabolism in healthy smokers promoted an inflammatory cytokine response with a greater increase in the levels of IL-5, IL-9 and IFN-α as compared to IFN-γ, IL-17 and TNF-α. In-vitro experiments with RAW 264.7 cells showed similar metabolic alterations and a reduced ability to phagocytose Streptococcus pneumonia and Haemophilus influenza after cigarette smoke exposure in the presence of glucose or palmitate. CONCLUSIONS: These findings indicate a metabolic basis for the inflammatory response in COPD and could suggest a new therapeutic target for controlling the immune response and delaying the onset of disease. TRIAL REGISTRATION: This observational study was retrospectively registered in the Clinical Trails Registry – India (ICMR – NIMS) on 19th January 2018 with the registration number CTRI/2018/01/011441. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12931-019-1139-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-66680832019-08-05 Systemic Immuno-metabolic alterations in chronic obstructive pulmonary disease (COPD) Agarwal, Amit R Kadam, Smita Brahme, Ankita Agrawal, Manas Apte, Komalkirti Narke, Govinda Kekan, Kushal Madas, Sapna Salvi, Sundeep Respir Res Research BACKGROUND: Metabolic adaptation in immune cells is necessary to modulate immune cell function as it is intricately coupled with intracellular metabolism. We aimed to characterize the metabolic state of human peripheral blood mononuclear cells (PBMCs) after long-term exposure to tobacco smoke in smokers with preserved lung function and COPD subjects. METHODS: PBMCs were isolated from healthy non-smokers (HNS), healthy smokers (HS) and COPD subjects, cultured and the mitochondrial respiration while utilizing glucose (glycolysis), fatty acids (β-oxidation) or pyruvate (direct Krebs’ cycle substrate) was measured using the XFp Extracellular Flux Analyzer. Plasma levels of inflammatory cytokines IFN-γ, IL-17, TNF-α, IL-5, IL-9 and IFN-α were measured using flow cytometry. RAW264.7 cells were exposed to cigarette smoke condensate (CSC) for 1 h and its effect on cell viability, cellular metabolism and phagocytosis ability were also studied. Patient’s data was analyzed using the Mann Whitney U test, whereas Student’s t test was performed to analyze the in-vitro data. RESULTS: PBMCs from COPD subjects showed a significant decrease in extracellular acidification rate (ECAR) while utilizing glucose as compared to HNS (151.9 Vs 215%). Mitochondrial oxygen consumption rate (OCR) on palmitate or pyruvate was also found to be significantly lower in COPD subjects as compared to HS and a strong positive correlation between palmitate OCR in PBMCs and FEV(1) (r = 0.74, p < 0.05) and FVC (r = 0.79, p < 0.05) values in HS was observed. The metabolic shift towards fatty acid metabolism in healthy smokers promoted an inflammatory cytokine response with a greater increase in the levels of IL-5, IL-9 and IFN-α as compared to IFN-γ, IL-17 and TNF-α. In-vitro experiments with RAW 264.7 cells showed similar metabolic alterations and a reduced ability to phagocytose Streptococcus pneumonia and Haemophilus influenza after cigarette smoke exposure in the presence of glucose or palmitate. CONCLUSIONS: These findings indicate a metabolic basis for the inflammatory response in COPD and could suggest a new therapeutic target for controlling the immune response and delaying the onset of disease. TRIAL REGISTRATION: This observational study was retrospectively registered in the Clinical Trails Registry – India (ICMR – NIMS) on 19th January 2018 with the registration number CTRI/2018/01/011441. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12931-019-1139-2) contains supplementary material, which is available to authorized users. BioMed Central 2019-07-30 2019 /pmc/articles/PMC6668083/ /pubmed/31362724 http://dx.doi.org/10.1186/s12931-019-1139-2 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Agarwal, Amit R
Kadam, Smita
Brahme, Ankita
Agrawal, Manas
Apte, Komalkirti
Narke, Govinda
Kekan, Kushal
Madas, Sapna
Salvi, Sundeep
Systemic Immuno-metabolic alterations in chronic obstructive pulmonary disease (COPD)
title Systemic Immuno-metabolic alterations in chronic obstructive pulmonary disease (COPD)
title_full Systemic Immuno-metabolic alterations in chronic obstructive pulmonary disease (COPD)
title_fullStr Systemic Immuno-metabolic alterations in chronic obstructive pulmonary disease (COPD)
title_full_unstemmed Systemic Immuno-metabolic alterations in chronic obstructive pulmonary disease (COPD)
title_short Systemic Immuno-metabolic alterations in chronic obstructive pulmonary disease (COPD)
title_sort systemic immuno-metabolic alterations in chronic obstructive pulmonary disease (copd)
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668083/
https://www.ncbi.nlm.nih.gov/pubmed/31362724
http://dx.doi.org/10.1186/s12931-019-1139-2
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