GPR81 Activation by Lactate Delays Inflammation Resolution in Acute Lung Injury.

Summary

In LPS-induced acute lung injury, exogenous lactate worsened lung injury and delayed inflammation resolution, while inhibiting lactate metabolism ameliorated inflammatory features. Genetic evidence implicates GPR81 as the receptor mediating these effects, and in vitro AM studies suggest impaired efferocytosis under lactate signaling. The work links hyperlactatemia to impaired resolution via GPR81, identifying a potential therapeutic target.

Key Findings

• Exogenous lactate delayed inflammation resolution and exacerbated lung injury in an LPS-induced mouse model.
• Inhibiting lactate dehydrogenase attenuated inflammatory cell infiltration and injury.
• Effects of lactate were abrogated in GPR81-deficient mice, implicating GPR81 signaling.
• Primary alveolar macrophage assays indicated lactate impairs efferocytosis-related metabolism.

Clinical Implications

Suggests GPR81 antagonism or modulation of lactate metabolism as potential strategies to accelerate inflammation resolution in ARDS. Highlights the need to reassess permissive hyperlactatemia in critical care through mechanistic trials.

Limitations

• Preclinical LPS-induced model may not fully recapitulate clinical ARDS heterogeneity
• Dose–exposure relationships of exogenous lactate may differ from human hyperlactatemia; exact group sizes not reported in abstract

Future Directions

Test GPR81 antagonists or metabolic modulators in diverse ARDS/ALI models; correlate lactate–GPR81 axis with patient outcomes and alveolar macrophage function in clinical samples; evaluate safety/efficacy in early-phase trials.