Glycolysis drives vascular hyperpermeability in acute lung injury via lactate-GPR81 axis in endothelial cells.

Summary

This mechanistic study shows that lactate produced by enhanced glycolysis activates endothelial GPR81, lowering cAMP, disrupting VE‑cadherin, increasing MLC2 phosphorylation and driving microvascular hyperpermeability in ALI. Endothelial-specific GPR81 deletion protects mice from LPS-induced lung injury; human ARDS BALF lactate correlates with protein leak, cytokines and APACHE II score.

Key Findings

• LPS increases lactate in BALF; pharmacologic suppression of glycolysis or LDH reduces lactate and ameliorates lung injury.
• Exogenous lactate or a GPR81 agonist exacerbates lung injury; global or endothelial-specific GPR81 deletion (but not myeloid-specific deletion) protects mice.
• In endothelial cells lactate lowers cAMP, reduces VE‑cadherin and increases MLC2 phosphorylation; these effects are GPR81-dependent and validated in knockout mice; BALF lactate correlates with protein leak, cytokines and APACHE II in ARDS patients.

Clinical Implications

Provides a translational target (endothelial GPR81 or lactate production) for therapies aimed at reducing microvascular leak in ALI/ARDS; suggests measuring BALF or plasma lactate signaling could stratify patients for metabolic interventions.

Limitations

• Patient correlation is associative; causality in humans not established and BALF sampling limits generalizability.
• Therapeutic targeting of GPR81 requires safety evaluation; systemic effects of GPR81 modulation not fully assessed.

Future Directions

Test pharmacologic GPR81 antagonists or lactate‑lowering strategies in preclinical ARDS models and early-phase clinical trials; assess systemic metabolic effects and biomarkers to stratify patients.