ROS/HIF-1 signaling in alveolar macrophages: implications for lung fibrosis

Alveolar macrophages (AMs) in idiopathic pulmonary fibrosis (IPF) display stabilization of hypoxia-inducible factor (HIF)-1α despite their residence within the well-oxygenated alveolar space. This highlights a contradiction between oxygen supply and hypoxic signaling in the fibrotic lung. This inconsistency implies that nonclassical environmental factors may influence macrophage phenotype and reprogramming during the pathogenesis of lung fibrosis. AMs are dynamic, adaptable responders to cues from the inhaled environment and local tissue. In patients with IPF, oxidative stress is a feature of the lung and circulation which may arise from endogenous metabolic activity or inhaled environmental factors. A key signaling intermediate, therefore, may be found in reactive oxygen species (ROS) and their ability to stabilize HIF-1α, inducing a pseudohypoxic environment. This presents a potential link between environmental exposures and HIF-1-mediated transcriptional responses in AMs. This review interrogates ROS-HIF-1α cross talk and how it may shape the AM program in the fibrotic lung. We integrate evidence from cell lines, circulating and tissue-resident macrophages, and experimental fibrosis models to hypothesize how ROS-dependent HIF-1α stabilization could alter the behavior of AMs, inducing profibrotic programmes and limiting normal homeostatic capacity. We synthesize mechanisms from the literature regarding redox-sensitivity of prolyl-hydroxylase enzymes and iron-dependent control of HIF-1α turnover to highlight how regulation could be targeted in future research. Investigating the ROS-HIF-1α axis proposes a link between environmental exposures and how macrophages may accelerate fibrosis in IPF. This review synthesizes evidence to understand how macrophages may translate environmental oxidative stress into cellular responses and fibrosis.