肺泡巨噬细胞连接蛋白-43决定肺部的机械免疫。

Liberty Mthunzi, Mohammad N Islam, Galina A Gusarova, Sunita Bhattacharya, Brian Karolewski, Jahar Bhattacharya
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引用次数: 0

摘要

虽然肺部免疫是病原体诱导的,但肺部的机械变形也可以诱导免疫。肺部机械敏感性免疫的因果基础尚不清楚。在这里,通过对小鼠肺部的实时光学成像,我们发现由于过度充气引起的肺泡拉伸诱导了固着肺泡巨噬细胞(AM)中延长的胞质Ca2+增加。敲除研究表明,Ca2+的增加是由Ca2+通过含有连接蛋白43(Cx43)的间隙连接从肺泡上皮扩散到固着AM引起的。暴露于损伤性机械通气的小鼠的肺部炎症和损伤通过AM特异性Cx43敲除或AM特异性递送钙抑制剂来抑制。我们的结论是,固定AM中的Cx43间隙连接和钙动员决定了肺的机械敏感性免疫,为对抗过度充气诱导的肺损伤提供了一种治疗策略。
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Macrophage-specific lipid nanoparticle therapy blocks the lung's mechanosensitive immunity due to macrophage-epithelial interactions.

The lung's mechanosensitive immune response, which occurs when pulmonary alveoli are overstretched, is a major impediment to ventilation therapy for hypoxemic respiratory failure. The cause is not known. We tested the hypothesis that alveolar stretch causes stretch of alveolar macrophages (AMs), leading to the immune response. In lungs viewed by optical imaging, sessile AMs expressed gap junctional protein connexin-43 (Cx43), and they communicated with the alveolar epithelium through gap junctions. Alveolar hyperinflation increased Ca 2+ in the AMs but did not stretch the AMs. The Ca 2+ response, and concomitant TNFα secretion by AMs were blocked in mice with AM-specific deletion of Cx43. The AM responses, as also lung injury due to mechanical ventilation at high tidal volume, were inhibited by AM-specific delivery of lipid nanoparticles containing Xestospongin C, which blocked the induced Ca 2+ increases. We conclude, Cx43- and Ca 2+ -dependent AM-epithelial interactions determine the lung's mechanosensitive immunity, providing a basis for therapy for ventilator- induced lung injury.

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