Mannose-6-phosphate attenuates acute lung injury by competitive release of acid sphingomyelinase from the mannose-6-phosphate receptor in endothelial caveolae.

IF 21 1区医学 Q1 RESPIRATORY SYSTEM

European Respiratory Journal Pub Date : 2025-06-19 Print Date: 2025-06-01 DOI:10.1183/13993003.00003-2024

Tian Jiang, Rudi Samapati, Sergej Klassen, Supandi Winoto-Morbach, Zain H Mohamed, Rolf Göggel, Jun Yin, Lijie Tan, Christoph Arenz, Sabrina Schulz, Lasti Erfinanda, Robert Preissner, Szandor Simmons, Stefan Schütze, Stefan Uhlig, Wolfgang M Kuebler

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引用次数: 0

Abstract

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.

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甘露糖-6-磷酸通过竞争性释放甘露糖-6-磷酸受体的酸性鞘磷脂酶来减轻急性肺损伤。

背景：血小板活化因子（PAF）诱导的肺内皮屏障衰竭是由酸性鞘磷脂酶（ASM）易位到小泡介导的。然而，ASM缺乏用于在小泡内锚定的跨膜结构域。我们假设ASM可能锚定在小泡中的阳离子非依赖性甘露糖-6-磷酸受体（CI-M6PR）上，从那里它可以被M6P竞争性地释放。方法：采用免疫共沉淀法（Co-IP）和近端结扎法（PLA）在离体肺和人肺微血管内皮细胞（hPMVECs）中检测ASM-CI-M6PR的相互作用。测定M6P在hPMVECs、离体肺和体内的ASM释放量。检测了M6P i)对paf诱导的肺水肿形成和内皮细胞Ca2+浓度（[Ca2+]i）的影响，以及ii)对酸灌注、过度通气小鼠肺损伤的影响。测定ARDS患者血清和支气管肺泡灌洗液（BALF）中ASM水平。TriNetX数据库探讨了asm抑制三环抗抑郁药（TCA）与预后的关系。结果：Co-IP和PLA在内皮小泡中发现了ASM与CI-M6PR的相互作用，PAF进一步增强了这种相互作用。M6P引起ASM释放，而葡萄糖-6-磷酸（Glu6P）不引起ASM释放，从而降低了体外、原位和体内小泡中ASM的含量和活性。类似地，M6P，而不是Glu6P，减弱了paf诱导的内皮[Ca2+]i信号和原位肺水肿，以及体内急性肺损伤。急性呼吸窘迫综合征患者血清中ASM水平升高，而BALF水平未见升高。使用TCA与严重呼吸道感染患者的较好预后相关。结论：CI-M6PR在小泡中锚定ASM。因此，M6P可能是一种有希望的治疗asm相关肺损伤和水肿的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Respiratory Journal 医学-呼吸系统

CiteScore

27.50

自引率

3.30%

发文量

345

审稿时长

2-4 weeks

期刊介绍： The European Respiratory Journal (ERJ) is the flagship journal of the European Respiratory Society. It has a current impact factor of 24.9. The journal covers various aspects of adult and paediatric respiratory medicine, including cell biology, epidemiology, immunology, oncology, pathophysiology, imaging, occupational medicine, intensive care, sleep medicine, and thoracic surgery. In addition to original research material, the ERJ publishes editorial commentaries, reviews, short research letters, and correspondence to the editor. The articles are published continuously and collected into 12 monthly issues in two volumes per year.