Mannose-6-phosphate attenuates acute lung injury by competitive release of acid sphingomyelinase from the mannose-6-phosphate receptor in endothelial caveolae.
Summary
The study identifies CI-M6PR as the caveolar anchor for ASM and shows that mannose-6-phosphate, but not glucose-6-phosphate, releases ASM, reducing its caveolar content and activity. This mechanistic insight positions M6P as a tractable approach to protect endothelial barrier function in ASM-driven lung edema.
Key Findings
- ASM interacts with CI-M6PR within endothelial caveolae, and this interaction is enhanced by PAF.
- Mannose-6-phosphate, but not glucose-6-phosphate, releases ASM, decreasing caveolar ASM content and enzymatic activity.
- CI-M6PR serves as the anchoring receptor for ASM in caveolae, suggesting M6P as a therapeutic lever for ASM-related lung injury and edema.
Clinical Implications
Targeting CI-M6PR–ASM interactions with M6P or analogs could reduce ASM activity within caveolae and help prevent endothelial barrier failure in acute lung injury; dosing and delivery strategies need clinical investigation.
Why It Matters
Revealing CI-M6PR–ASM coupling in endothelial caveolae and its competitive displacement by M6P offers a precise molecular target for lung edema. The work bridges fundamental membrane biology to potential therapy.
Limitations
- Abstract-provided details on in vivo functional outcomes are limited; magnitude and durability of barrier protection are not fully delineated.
- Translational aspects (pharmacokinetics, dosing, safety) remain to be established.
Future Directions
Quantify edema and barrier function in diverse ALI models, evaluate M6P analogs and delivery routes, and assess safety and efficacy in translational models.
Study Information
- Study Type
- Basic/Mechanistic research
- Research Domain
- Pathophysiology/Treatment
- Evidence Level
- IV - Experimental mechanistic work in cells and isolated organs without clinical outcomes
- Study Design
- OTHER