The European respiratory journal · 2025
Mannose-6-phosphate attenuates acute lung injury by competitive release of acid sphingomyelinase from the mannose-6-phosphate receptor in endothelial caveolae.
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Jiang Tian, Samapati Rudi, Klassen Sergej, Winoto-Morbach Supandi, Mohamed Zain H, Göggel Rolf, Yin Jun, Tan Lijie, Arenz Christoph, Schulz Sabrina, Erfinanda Lasti, Preissner Robert, Simmons Szandor, Schütze Stefan, Uhlig Stefan, Kuebler Wolfgang M
Аннотация
BACKGROUND: Platelet-activating factor (PAF)-induced pulmonary endothelial barrier failure is mediated by acid sphingomyelinase (ASM) translocation to caveolae. ASM, however, lacks a transmembrane domain for anchoring inside caveolae. We hypothesised that ASM anchors to cation-independent mannose-6-phosphate (M6P) receptor (CI-M6PR) in caveolae, from where it can be competitively released by M6P.
METHODS: We explored ASM-CI-M6PR interactions using co-immunoprecipitation and proximity ligation assay in isolated lungs and human pulmonary microvascular endothelial cells. ASM release by M6P was determined in human pulmonary microvascular endothelial cells, isolated lungs and in vivo. The effects of M6P on 1) PAF-induced lung oedema formation and endothelial Ca2+ concentration and 2) lung injury in acid instilled, overventilated mouse lungs were examined. ASM levels were measured in serum and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome. The TriNetX database was probed for associations of ASM-inhibiting tricyclic antidepressants with outcomes.
RESULTS: Co-immunoprecipitation and proximity ligation assay revealed an ASM interaction with CI-M6PR in endothelial caveolae, which was further increased by PAF. M6P, but not glucose-6-phosphate, caused ASM release, thereby decreasing ASM content and activity in caveolae in vitro, in situ and in vivo. Analogously, M6P, yet not glucose-6-phosphate, attenuated PAF-induced endothelial Ca2+ influx and lung oedema in situ, and acute lung injury in vivo. ASM levels were increased in serum but not bronchoalveolar lavage fluid in patients with acute respiratory distress syndrome. Use of tricyclic antidepressants was associated with better outcomes in patients with severe respiratory infections.
CONCLUSIONS: CI-M6PR anchors ASM in caveolae. M6P may hence present a promising target in ASM-related lung injury and oedema.
METHODS: We explored ASM-CI-M6PR interactions using co-immunoprecipitation and proximity ligation assay in isolated lungs and human pulmonary microvascular endothelial cells. ASM release by M6P was determined in human pulmonary microvascular endothelial cells, isolated lungs and in vivo. The effects of M6P on 1) PAF-induced lung oedema formation and endothelial Ca2+ concentration and 2) lung injury in acid instilled, overventilated mouse lungs were examined. ASM levels were measured in serum and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome. The TriNetX database was probed for associations of ASM-inhibiting tricyclic antidepressants with outcomes.
RESULTS: Co-immunoprecipitation and proximity ligation assay revealed an ASM interaction with CI-M6PR in endothelial caveolae, which was further increased by PAF. M6P, but not glucose-6-phosphate, caused ASM release, thereby decreasing ASM content and activity in caveolae in vitro, in situ and in vivo. Analogously, M6P, yet not glucose-6-phosphate, attenuated PAF-induced endothelial Ca2+ influx and lung oedema in situ, and acute lung injury in vivo. ASM levels were increased in serum but not bronchoalveolar lavage fluid in patients with acute respiratory distress syndrome. Use of tricyclic antidepressants was associated with better outcomes in patients with severe respiratory infections.
CONCLUSIONS: CI-M6PR anchors ASM in caveolae. M6P may hence present a promising target in ASM-related lung injury and oedema.