Aerobic Exercise Pretreatment Mitigates Acute Lung Injury through Metabolic Reprogramming, Anti-inflammatory Modulation, and 6-Keto-Prostaglandin F1α Regulation

Wang, Xishuai and Nong, Shunqiang and Zheng, Qibao and Zhao, Congcong and Yi, Chao and Li, Simin and Zhao, Lunan and Kong, Xiliang and Zhou, Yuehui and Dong, Depeng and Niu, Weina and Chen, Zhuo and Liu, Cong and Zhao, Wei and Sun, Zhuo and Wei, Jie and Lv, Yang and Yang, Lichang and Jin, Xin and Cai, Shanshan and Wu, Di and Jiang, Fugao (2025) Aerobic Exercise Pretreatment Mitigates Acute Lung Injury through Metabolic Reprogramming, Anti-inflammatory Modulation, and 6-Keto-Prostaglandin F1α Regulation. Free Radical Biology and Medicine, 238. pp. 550-562. ISSN 0891-5849

Abstract

OBJECTIVE: Although moderate physical exercise improves outcomes in pulmonary diseases such as acute lung injury (ALI), the underlying mechanisms, particularly those involving metabolic reprogramming, remain poorly defined. We investigated the impact of aerobic exercise (AE) pretreatment on metabolic pathways, inflammatory responses, and survival in ALI. METHODS: ALI model mice were induced through intratracheal lipopolysaccharide (LPS) after a 4-week AE protocol. Key assessments included histopathological evaluation, cytokine quantification, survival analysis, and serum metabolomic profiling. RESULTS: AE pretreatment significantly reduced mortality, attenuated lung damage, and suppressed neutrophil-driven inflammation. Mechanistically, AE restored LPS-induced metabolic dysregulation by normalizing ATP/ADP and NAD +/NADH ratios, phosphocreatine levels, and glucose-insulin homeostasis, in addition to decreasing lactate accumulation. Metabolomic analysis identified 991 differentially expressed metabolites (DEMs) between the Con and ALI groups, predominantly enriched in metabolic pathways, biosynthesis of unsaturated fatty acids, and linoleic acid metabolism, with arachidonic acid emerging as a critical upregulated hub node. In addition, 190 DEMs were identified between the AE + ALI and ALI groups, predominantly enriched in linoleic acid metabolism, metabolic pathways, and arachidonic acid metabolism, with linoleic acid and arachidonic acid emerging as critical upregulated hub nodes. AE pretreatment markedly suppressed the LPS-induced activation of the linoleic acid-arachidonic acid-6-keto-PGF1α signaling axis, which was aberrantly upregulated during ALI progression. Suppressing 6-keto-PGF1α activity using U51605 markedly alleviated the inflammatory response and tissue damage associated with ALI. CONCLUSIONS: AE pretreatment confers protection against ALI by orchestrating metabolic reprogramming to enhance anti-inflammatory responses. AE pretreatment attenuates LPS-induced ALI by reprogramming linoleic acid and arachidonic acid metabolism, thereby suppressing 6-keto-PGF1α biosynthesis. Pharmacological inhibition of 6-keto-PGF1α significantly alleviated ALI severity and mortality. These findings highlight AE as a preventive strategy and identify 6-keto-PGF1α as a therapeutic target for inflammatory lung injury.