Connexin 43 mediates spread of Ca2+-dependent proinflammatory responses in lung capillaries
Connexin 43 mediates spread of Ca2+-dependent proinflammatory responses in lung capillaries
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DOI：
10.1172/jci26605
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发表时间：
2006-08-01
影响因子：
15.9
通讯作者：
Bhattacharya, Jahar
中科院分区：
文献类型：
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作者：
Parthasarathi, Kaushik;Ichimura, Hideo;Bhattacharya, Jahar
急性肺损伤(ALI)与30%-40%的死亡率相关，可归因于跨越肺的巨大血管表面迅速发展的炎症，累及整个肺甚至两个肺。没有特定的机制来解释这种广泛的炎症扩散，可能是因为缺乏检测肺毛细血管内信号传导的方法。在这里，我们通过应用光解去老化方法来诱导目标肺泡毛细血管内皮细胞内钙水平的局灶性增加来解决这个问题。去势不仅导致靶细胞内钙离子水平升高，而且在距靶部位150度以下的血管部位也升高，表明钙离子是从毛细血管传导到邻近血管的。在缺乏内皮连接蛋白43(Cx43)的小鼠肺中没有明显的这种传导，在我们用Cx43的多肽抑制剂预处理血管的大鼠肺中也没有明显的这种传导。这些发现为我们提供了第一个直接证据，证明内皮细胞间钙离子传导发生在肺毛细血管床上，并且含有Cx43的缝隙连接介导了这一传导。促炎症作用明显，诱导毛细血管内钙离子水平升高，激活小静脉内白细胞黏附受体P-选择素的表达。此外，Cx43的多肽抑制剂可完全阻断凝血酶诱导的微血管通透性增加。总之，我们的发现揭示了Cx43介导的缝隙连接的一个新角色，即作为促炎信号在肺毛细血管床中传播的管道。缝隙连接机制需要在对ALI的理解中进一步考虑。
Acute lung injury (ALI), which is associated with a mortality of 30-40%, is attributable to inflammation that develops rapidly across the lung's vast vascular surface, involving an entire lung or even both lungs. No specific mechanism explains this extensive inflammatory spread, probably because of the lack of approaches for detecting signal conduction in lung capillaries. Here, we addressed this question by applying the photolytic uncaging approach to induce focal increases in Ca2+ levels in targeted endothelial cells of alveolar capillaries. Uncaging caused Ca2+ levels to increase not only in the targeted cell, but also in vascular locations up to 150 burn from the target site, indicating that Ca2+ was conducted from the capillary to adjacent vessels. No such conduction was evident in mouse lungs lacking endothelial connexin 43 (Cx43), or in rat lungs in which we pretreated vessels with peptide inhibitors of Cx43. These findings provide the first direct evidence to our knowledge that interendothelial Ca2+ conduction occurs in the lung capillary bed and that Cx43-containing gap junctions mediate the conduction. A proinflammatory effect was evident in that induction of increases in Ca2+ levels in the capillary activated expression of the leukocyte adherence receptor P-selectin in venules. Further, peptide inhibitors of Cx43 completely blocked thrombin-induced microvascular permeability increases. Together, our findings reveal a novel role for Cx43-mediated gap junctions, namely as conduits for the spread of proinflammatory signals in the lung capillary bed. Gap junctional mechanisms require further consideration in the understanding of ALI.