Preconditioning with β-hydroxybutyrate attenuates lung ischemia-reperfusion injury by suppressing alveolar macrophage pyroptosis through the SIRT1-FOXO3 signaling pathway.
Level 5 - mechanism / opinion, no new human data
Preclinical in vivo animal model and in vitro cell culture study.
PubMed 39221615 · doi:10.1096/fj.202401188R
What was done
The authors investigated the role of alveolar macrophage pyroptosis in lung ischemia-reperfusion injury (LIRI) using a murine model and in vitro experiments with MH-S alveolar macrophage cells. They evaluated the effects of the pyroptosis inhibitor VX-765 and assessed preconditioning with β-hydroxybutyrate (β-OHB) administered via ketone ester supplementation and 3-hydroxybutyrate dehydrogenase 1 (BDH-1) gene knockout. The involvement of the SIRT1-FOXO3 pathway was tested using the SIRT1 inhibitor EX-527 and pCMV-SIRT1 plasmid transfection.
What was found
The abstract reports no numerical values or effect sizes. Qualitatively, alveolar macrophages were identified as the primary site of pyroptosis during LIRI. Chemical inhibition of pyroptosis with VX-765 reduced lung injury severity. Preconditioning with β-OHB attenuated lung injury and decreased pyroptosis markers via upregulation of SIRT1 and FOXO3 deacetylation. In MH-S cells in vitro, β-OHB showed a concentration-dependent reduction in pyroptosis.
Why it matters
This study identifies alveolar macrophage pyroptosis as a key driver of lung ischemia-reperfusion injury and demonstrates that β-OHB preconditioning provides protection through SIRT1-mediated FOXO3 deacetylation.
Limits
The study was conducted exclusively in mice and cell culture, limiting direct applicability to human lung ischemia-reperfusion injury. The abstract does not report sample sizes, specific dosages, or quantitative effect sizes for any of the tested interventions. Long-term functional outcomes were not assessed.
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