AlCl3 Aerosol Exposure Is Associated With Pulmonary Lactate Accumulation, Neutrophil Dysfunction, and Fibrosis-Like Remodeling.

Aluminum-associated interstitial lung disease is an exposure-related fibrotic lung disorder, but the metabolic and innate immune mechanisms underlying persistent pulmonary remodeling after aluminum exposure remain incompletely understood. We investigated whether lactate-associated neutrophil dysfunction contributes to lung injury and fibrosis-like remodeling following AlCl3 aerosol exposure. Rats were subjected to repeated AlCl3 aerosol exposure with or without pharmacological inhibition of lactate transport using the monocarboxylate transporter 1 inhibitor AZD3965. Pulmonary injury, lactate accumulation, inflammatory responses, oxidative stress, DNA damage response signaling, and fibrosis-like remodeling were assessed. Bone marrow-derived rat neutrophils were treated with sodium L-lactate in the presence or absence of AZD3965 to evaluate chemotaxis, oxidative burst, mitochondrial membrane potential, calcium signaling, intracellular lactate accumulation, and neutrophil extracellular trap (NET)-associated responses. In addition, a supportive human cohort comprising patients with aluminum exposure-related interstitial lung disease (Al-ILD), patients with nonaluminum interstitial lung disease (non-Al-ILD), and healthy controls was analyzed using quantitative chest computed tomography (CT), pulmonary function testing, and peripheral blood transcriptomics. Repeated AlCl3 aerosol exposure was associated with pulmonary aluminum deposition, lactate accumulation, inflammatory injury, oxidative stress, DNA damage response signaling, neutrophil abnormalities, and collagen-rich fibrosis-like remodeling in rats. In vitro, high-lactate-associated metabolic stress impaired neutrophil chemotaxis, oxidative burst, mitochondrial membrane potential, calcium signaling, and NET-associated responses. AZD3965 reduced intracellular and pulmonary lactate accumulation and partially ameliorated neutrophil dysfunction, inflammatory injury, oxidative stress, and fibrosis-like remodeling in experimental models. In the supportive human cohort, patients with Al-ILD showed greater quantitative CT-defined parenchymal abnormality burden and lower forced vital capacity and diffusing capacity for carbon monoxide than patients with non-Al-ILD. Peripheral blood transcriptomic analysis revealed enrichment of innate immune, cytokine signaling, extracellular matrix organization, and NET-related pathways in Al-ILD. Collectively, these findings indicate that AlCl3 aerosol exposure is associated with pulmonary lactate accumulation, neutrophil dysfunction, and fibrosis-like remodeling. Pharmacological modulation of lactate transport provides supportive evidence for the involvement of lactate-associated metabolic regulation in this process, although further studies are required to define the specific molecular targets involved. The integration of experimental and supportive human findings suggests that the lactate-neutrophil dysfunction axis may represent a mechanistically relevant feature of aluminum-associated lung injury and remodeling.