Scientific Business Abstracts of the 113th Annual Meeting of the Association of Physicians of Great Britain and Ireland

Cacciottolo, Tessa M.; Perikari, A; Klaauw, Agatha van der; Henning, Elana; Stadler, Lukas Kurt Josef; Keogh, Julia M.; Farooqi, I. Sadaf; Tenin, Gennadiy; Keavney, Bernard; Ryan, Elizabeth P.; Budd, Richard J.; Bewley, Martin A.; Coelho, Patricia; Rumsey, William L.; Sánchez, Yurieth Gallardo; McCafferty, JB; Dockrell, David H.; Liu, Yingjuan; Choy, Mun-Kit; Abraham, Sabu; Black, G. W.; Ford, Tom; Stanley, Bruce A.; Good, Robert A.; Rocchiccioli, Paul; McEntegart, Margaret; Watkins, S; Eteiba, Hany; Shaukat, Aasma; Lindsay, Mitchell; Robertson, Keith; Hood, Stuart; McGeoch, R. J.; McDade, Robert; Sidik, Novalia; McCartney, Peter; Collison, Damien; Rush, Christopher; McConnachie, Alex; Touyz, Rhian M.; Oldroyd, Keith G.; Gazdagh, G; Diver, L; Marshall, John F.; McGowan, Roland C.; Ahmed, F; Study, Ddd; Tobias, Edward S.; Curtis, Elizabeth M; Parsons, Camille; Maslin, Kate; D’Angelo, Stefania; Moon, Rebecca J; Crozier, SR; Gossiel, Fatma; Bishop, N; Kennedy, Stephen; Papageorghiou, Aris T.; Fraser, Robert S.; Gandhi, Saurabh; Prentice, Ann E.; Inskip, H; Godfrey, Kathryn; Schoenmakers, Inez; Javaid, Muhammad Kassim; Eastell, Richard; Cooper, Cyrus; Harvey, Nicholas C; Watt, Ernest; Howden, Andrew J. M.; Mirchandani, Ananda S.; Hukelmann, Jens; Sadiku, Pranvera; Plant, T. M.; Cantrell, Doreen A.; Whyte, Moira K. B.; Walmsley, Sarah R.; Mordi, Ify; Forteath, Calum; Wong, Andrew K.; Mohan, Mohapradeep; Palmer, Colin N.A.; Doney, Alex S.F.; Rena, Graham; Lang, Claudia; Gray, Eve; Azarian, Sarah; Riva, Arianna; Edwards, Harry; McPhail, Mark; Williams, Ruth; Chokshi, Shilpa; Patel, Viren; Edwards, Lindsay A; Page, Donna J.; Miossec, Matthieu J.; Williams, Steven; Monaghan, Richard M.; Fotiou, Elisavet; Santibanez‐Koref, Mauro; Badat, Mary Carol; Mettananda, Sachith; Hua, Peng; Schweßinger, Ron; Hughes, Jenny; Higgs, Deborah; Davies, James O. J.

doi:10.1093/qjmed/hcz175

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“…By activating the anti-oxidant transcription factor NRF2, we were able to rescue ME1 expression and restore metabolic plasticity and function in COPD macrophages. Some of the results of this study have been previously reported in the form of abstracts 15,16,17,18 .…”

Section: Introductionmentioning

confidence: 82%

NRF2 Activation Reprograms Defects in Oxidative Metabolism to Restore Macrophage Function in Chronic Obstructive Pulmonary Disease

Ryan

Sadiku

Coelho

et al. 2023

Am J Respir Crit Care Med

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Rationale: COPD (Chronic Obstructive Pulmonary Disease) is a disease characterized by persistent airway inflammation and disordered macrophage function. The extent to which alterations in macrophage bioenergetics contribute to impaired antioxidant responses and disease pathogenesis has yet to be fully delineated.Objectives: Through the study of COPD alveolar (AM) and peripheral monocytederived (MDM) macrophages, we sought to establish if intrinsic defects in core metabolic processes drive macrophage dysfunction and redox imbalance.Methods: AM and MDM from COPD and healthy donors underwent functional, metabolic and transcriptional profiling. Results:We observe that AM and MDM from COPD donors display a critical depletion in glycolytic and mitochondrial respiration derived energy reserves and an over reliance on glycolysis as a source for ATP, resulting in reduced energy status. Defects in oxidative metabolism extend to an impaired redox balance associated with defective expression of the NADPH generating enzyme, malic enzyme 1, a known target of the anti-oxidant transcription factor NRF2. Consequently, selective activation of NRF2 resets the COPD transcriptome, resulting in increased generation of TCA cycle intermediaries, improved energetic status, favorable redox balance and a recovery of macrophage function. Conclusion:In COPD an inherent loss of metabolic plasticity leads to metabolic exhaustion and reduced redox capacity which can be rescued by activation of the NRF2 2 pathway. Targeting these defects, via NRF2 augmentation, may therefore present an attractive therapeutic strategy for the treatment of the aberrant airway inflammation described in COPD.

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Section: Introductionmentioning

confidence: 82%