Immune-metabolic positive feedback model in COPD: cross-mechanisms and potential intervention strategies

TL;DR

This paper explores how immune and metabolic changes in COPD create a harmful cycle, and suggests new ways to treat the disease.

Contribution

The paper introduces a new model linking immune and metabolic dysfunctions in COPD and proposes multi-target treatment strategies.

Findings

Mitochondrial injury and reactive oxygen species disrupt energy pathways and weaken lung function.

NF-κB and NLRP3 signals form a feedback loop that causes chronic inflammation and immune cell exhaustion.

A composite biomarker panel could guide new multi-target therapies for COPD.

Abstract

Chronic obstructive pulmonary disease (COPD) is a common chronic condition characterized by chronic bronchitis and/or emphysema with airflow obstruction, which can progress to cor pulmonale and respiratory failure. Associated with abnormal inflammatory responses to harmful gases and particulate matter, it carries high rates of disability and mortality, with a global prevalence among individuals aged 40 and older reaching 9%–10%. It is often regarded as a clinical and molecular model of accelerated lung aging. Age-related drift in immune function and metabolism plays a central part in this process, but how these changes are linked across different biological levels is still not fully clarified. Current work highlights mitochondrial injury and excessive reactive oxygen species as a central node that disrupts energy-sensing pathways, interferes with autophagy and epigenetic control, and weakens mitochondrial biogenesis, together fostering long-term glycolipid imbalance. At the same time, NF-κB–driven senescence-associated secretory activity and mitochondrial damage signals that engage the NLRP3 inflammasome form a reinforcing circuit that promotes macrophage dysfunction and exhaustion-like impairment of T and natural killer cells. These immune–metabolic disturbances stabilize low-grade chronic inflammation and metabolic instability, helping to explain persistent inflammatory sequelae, airway remodeling, and progressive decline in lung function. Building on these insights, we discuss a translational path centered on composite biomarker panels that integrate immune-exhaustion signatures, senescence mediators, NAD+–SIRT1 status, mitochondrial injury markers, and NLRP3 activity, and we consider low-intensity, multi-target therapeutic strategies designed to overcome the limitations of single-pathway treatments in COPD.

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