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

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.