Macrophage Immunometabolism in Pulmonary Homeostasis and Chronic Lung Diseases

Macrophages play a central role in maintaining pulmonary immune homeostasis and responding to injury. In the lung, alveolar macrophages modulate their metabolic profiles to support essential functions such as microbial clearance, inflammation resolution, and tissue repair. Recent studies have shown that these metabolic adaptations are not merely byproducts of activation but represent key regulators of macrophage behavior. In chronic lung diseases including asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF), macrophage metabolism is pathologically reprogrammed, contributing to persistent inflammation in asthma and COPD, or to unrestrained fibrotic remodeling in IPF, and ultimately leading to ongoing tissue damage. Specifically, in asthma, type 2 cytokine signaling promotes alternative macrophage activation, accompanied by increased fatty acid oxidation and disrupted lipid mediator profiles. COPD-associated macrophages exhibit mitochondrial dysfunction, enhanced glycolysis, and iron overload, impairing bacterial phagocytosis and amplifying oxidative stress. In IPF, macrophages simultaneously engage glycolytic and oxidative pathways while losing regulatory metabolites such as itaconate, supporting persistent fibrogenic signaling. These disease-specific metabolic features sustain maladaptive macrophage phenotypes and constitute promising targets for therapeutic intervention. This review outlines current knowledge of macrophage immunometabolism in the lung and its contribution to chronic respiratory diseases. It also discusses strategies to restore metabolic balance, including the use of antioxidants, metabolic modulators, and targeted drug delivery. Understanding macrophage metabolism may open new avenues for treating chronic lung diseases at the level of cellular function.