Lysine attenuates acute lung injury by restoring α-tubulin acetylation and ciliary activity.

Summary

Integrating human ALI datasets with metabolomics, the authors found marked lysine depletion and mitochondrial metabolic deficiency in injured epithelium. Lysine supplementation restored α-tubulin acetylation and ciliary TRPC1 signaling, limited pathological Ca2+ influx, preserved epithelial junctions, and improved survival (0% to 62.5%) while reducing fibrosis and inflammation in murine and non-human primate ALI models.

Key Findings

• Lysine levels were markedly decreased in injured pulmonary epithelium alongside mitochondrial metabolic deficiency, based on scRNA-seq mining and targeted metabolomics.
• Lysine supplementation improved mouse survival from 0% to 62.5%, reduced extracellular matrix deposition and alveolitis, and suppressed inflammation in murine and non-human primate ALI models.
• Mechanistically, lysine replenished acetyl-CoA, restored α-tubulin acetylation and ciliary TRPC1 localization, prevented pathological STIM1-TRPC1 complex formation, limited Ca2+ influx, preserved E-cadherin/ZO-1, and promoted regenerative activation of SFTPC+ AT2 cells.

Clinical Implications

Although preclinical, the data support piloting lysine supplementation strategies in patients at risk for or with early ARDS, with careful dosing, metabolic monitoring, and safety evaluation within clinical trials.

Limitations

• Preclinical study; human dosing, pharmacokinetics, and safety of lysine supplementation for ALI/ARDS are unknown.
• Model-specific contexts may limit generalizability across diverse ARDS etiologies; detailed sample sizes and observation windows are not provided in the abstract.

Future Directions

Conduct dose-ranging, safety, and early efficacy trials of lysine in at-risk or early ARDS; develop pharmacodynamic biomarkers (plasma lysine, acetyl-CoA, α-tubulin acetylation, ciliary markers) and assess interactions with nutrition support.