MASLD Exacerbates Chronic Low-dose PM2.5-induced Lung Injury, Inflammation, and Fibrosis.

Abstract

BACKGROUND/AIM: Fine particulate matter (PM2.5) and metabolic dysfunction-associated steatotic liver disease (MASLD) are independent risk factors for respiratory disease. However, the combined impact of chronic, low-dose PM2.5 exposure and Western diet (WD)-induced metabolic dysfunction on pulmonary health remains poorly understood. We investigated whether this metabolic state exacerbates PM2.5-driven pathologies using an environmentally relevant PM2.5 dosage (~50 μg/m3). MATERIALS AND METHODS: C57BL/6J mice were fed a WD or normal diet (ND) for 28 weeks and concurrently received intratracheal instillations of PM2.5 (0.5 mg/kg diesel particulate matter) or vehicle three times per week. The MASLD phenotype was confirmed through metabolic and histological analyses. Pulmonary injury, fibrosis, and inflammation were assessed via histology (hematoxylin and eosin, and Masson's trichrome staining) and cytokine quantification in both bronchoalveolar lavage fluid using Luminex multiplex assay and lung tissue using enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. RESULTS: The WD successfully induced MASLD characterized by weight gain, hepatic steatosis, and dyslipidemia. While PM2.5 exposure did not significantly worsen the primary features of MASLD, its combination with a WD markedly exacerbated pulmonary injury and fibrosis compared to PM2.5 exposure alone. This exacerbation was driven by a surge in pro-inflammatory chemokines, including C-X-C motif chemokine ligands 1 and 2 (CXCL1 and CXCL2), and C-C motif chemokine ligand 5 (CCL5), confirmed by Luminex analysis of lavage fluid and mRNA/protein quantification in lung tissue. CONCLUSION: Diet-induced metabolic dysfunction primes the lung for a hyper-inflammatory response to chronic PM2.5 exposure. These findings identify individuals with MASLD as a population with heightened susceptibility to air pollution-related respiratory diseases and underscore the critical interplay between metabolic health and environmental toxicology.