With an enhanced understanding of the human metabolome and the identification and investigation of metabolites in the human body, the field of immunometabolism can advance rapidly and provide a more comprehensive overview of the relationship between metabolic interactions and immune cell functions.¹ During the ERS International Congress 2023, Dr.1 Suzanne Cloonan from the School of Medicine Trinity College Dublin and Tallaght University Hospital Dublin, Ireland summarized the recent discoveries of metabolic alterations related to chronic obstructive pulmonary disease (COPD) and provided her insights on their interactions with the metabolic microenvironment of the lungs and the implications for potential therapy options.¹

The metabolic microenvironment of the lungs is the first target of investigation to glean an overall understanding of COPD-related metabolic alterations and their potential effects.¹ Dr.1 Cloonan mentioned a study published in 2021 which had established that various sections of the lungs possessed unique metabolic microenvironmental characteristics.¹ For instance, the concentration of glucose declines from the nasal mucosa to the alveoli.¹ On the contrary, fatty acids and lipids are scarce in the nasal mucosa and mostly accumulate in the surfactant of the alveoli.¹ As such, each compartment of the lungs is comprised of a unique cellular and metabolic niche, accompanied by its complex network of metabolic interactions.¹

In the realm of COPD, a complex, heterogeneous disease consisting of multiple endotypes, recent studies have identified serval distinct modifications in the metabolic microenvironment of the lungs of COPD patients.¹ For example, the SPIROMICS study published in 2019 was able to correlate certain groups of metabolites and microbes with specific COPD clinical features and exacerbation frequency.¹ Other studies also concluded that patients with COPD were associated with declined surfactant lipid levels, contrasting airway sputum metabolome profiles, and altered transcription of metabolic genes in alveolar macrophages.¹ These findings led to a shift in the understanding of metabolic landscape in the alveolar macrophages of COPD patients.¹

In particular, patients with COPD were characterized as having significantly lower mitochondrial metabolic activity compared to non-smokers (Spare Respiratory Capacity: 37.121pmol/min/ng  DNA vs. 27.101pmol/min/ng DNA; p=0.1029, Max Respiration:  71.159pmol/min/ng DNA vs. 60.101pmol/min/ng DNA; p=0.1088) and smokers (Spare Respiratory Capacity: 43.171pmol/min/ng DNA vs. 27.101pmol/min/ng DNA; p=0.10075, Max Respiration:  85.108pmol/min/ng DNA vs. 60.101pmol/min/ng DNA; p=0.1014).¹ Additionally, COPD patients were significantly less likely to initiate compensatory glycolysis when compared to healthy smokers  (54.122% vs. 78.163%; p=0.1028).¹ These findings suggested that the impaired mitochondrial metabolic activity and engagement in compensatory glycolysis may be the consequences of a diminished mitochondrial gene expression in the basal cells of COPD lungs, which may explain the suboptimal glycogen cycling properties observed in neutrophils from COPD patients.¹

The aforementioned characteristics caused by COPD-related metabolic alterations may manifest as complications in patients with COPD.¹ First of all, COPD triggers a shift in cellular metabolism from glycolysis to fatty acid oxidation (FAO), affecting basal cell differentiation and hindering the development of fully differentiated airway epithelium.¹ Secondly, the impaired mitochondrial metabolic activity of lung epithelial cells can produce integrated stress responses that serve as obstacles to alveolar formation, development, and the maintenance of homeostasis.¹ Furthermore, COPD-induced loss of fatty acid synthesis in alveolar type II cells can lead to age-associated airspace enlargement and elevated risk of cell injury under the influence of smoke.¹ Overall, these manifestations further increase the risk of lung inflammation and result in undesirable survival outcomes for alveolar epithelial cells.¹

In response to these findings, a handful of therapeutic approaches tailored around the immunometabolic characteristics of patients with COPD can be initiated, including restoring the airway metabolome, rebalancing the surfactant lipid levels and sustaining mitochondrial health.¹ Treatment approaches that activate the nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor can reprogram the alveolar macrophages in COPD patients, enhancing their efferocytosis abilities.¹ Itaconate, a therapeutic metabolite, exhibits promising potential as a biomarker in the treatment of COPD.¹

To conclude, advancements in immunometabolism have unwrapped the potential mechanisms of COPD that alter the metabolome of the lungs, despite the relative novelty of this research field.¹ As such, future therapies can examine these findings as a blueprint and target these metabolic alterations of COPD, thus alleviating clinical symptoms and improving patient outcomes.¹