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首页> 美国卫生研究院文献>American Journal of Physiology - Lung Cellular and Molecular Physiology >Translational Research in Acute Lung Injury and Pulmonary Fibrosis: Lipopolysaccharide-induced pulmonary endothelial barrier disruption and lung edema: critical role for bicarbonate stimulation of AC10
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Translational Research in Acute Lung Injury and Pulmonary Fibrosis: Lipopolysaccharide-induced pulmonary endothelial barrier disruption and lung edema: critical role for bicarbonate stimulation of AC10

机译：急性肺损伤和肺纤维化的转化研究：脂多糖诱导的肺内皮屏障破坏和肺水肿：碳酸氢盐刺激AC10的关键作用

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Bacteria-induced sepsis is a common cause of pulmonary endothelial barrier dysfunction and can progress toward acute respiratory distress syndrome. Elevations in intracellular cAMP tightly regulate pulmonary endothelial barrier integrity; however, cAMP signals are highly compartmentalized: whether cAMP is barrier-protective or -disruptive depends on the compartment (plasma membrane or cytosol, respectively) in which the signal is generated. The mammalian soluble adenylyl cyclase isoform 10 (AC10) is uniquely stimulated by bicarbonate and is expressed in pulmonary microvascular endothelial cells (PMVECs). Elevated extracellular bicarbonate increases cAMP in PMVECs to disrupt the endothelial barrier and increase the filtration coefficient (Kf) in the isolated lung. We tested the hypothesis that sepsis-induced endothelial barrier disruption and increased permeability are dependent on extracellular bicarbonate and activation of AC10. Our findings reveal that LPS-induced endothelial barrier disruption is dependent on extracellular bicarbonate: LPS-induced barrier failure and increased permeability are exacerbated in elevated bicarbonate compared with low extracellular bicarbonate. The AC10 inhibitor KH7 attenuated the bicarbonate-dependent LPS-induced barrier disruption. In the isolated lung, LPS failed to increase Kf in the presence of minimal perfusate bicarbonate. An increase in perfusate bicarbonate to the physiological range (24 mM) revealed the LPS-induced increase in Kf, which was attenuated by KH7. Furthermore, in PMVECs treated with LPS for 6 h, there was a dose-dependent increase in AC10 expression. Thus these findings reveal that LPS-induced pulmonary endothelial barrier failure requires bicarbonate activation of AC10.
机译：细菌性败血症是肺血管内皮屏障功能障碍的常见原因，并可发展为急性呼吸窘迫综合征。细胞内cAMP的升高紧密调节肺内皮屏障的完整性；但是，cAMP信号是高度分隔的：cAMP是屏障保护性还是破坏性信号取决于生成信号的区域（分别为质膜或胞质溶胶）。碳酸氢盐可唯一刺激哺乳动物可溶性腺苷酸环化酶同工型10（AC10），并在肺微血管内皮细胞（PMVEC）中表达。升高的细胞外碳酸氢盐会增加PMVEC中的cAMP，从而破坏内皮屏障并增加离体肺中的过滤系数（Kf）。我们测试了脓毒症诱导的内皮屏障破坏和通透性增加取决于细胞外碳酸氢盐和AC10激活的假说。我们的发现表明，LPS诱导的内皮屏障破坏取决于细胞外碳酸氢盐：与低细胞外碳酸氢盐相比，LPS诱导的屏障破坏和通透性增加在碳酸氢盐升高的情况下更为严重。 AC10抑制剂KH7减弱了碳酸氢盐依赖性LPS诱导的屏障破坏。在孤立的肺中，LPS在存在少量灌注液碳酸氢盐的情况下无法增加Kf。灌注液碳酸氢盐增加至生理范围（24 mM）表明，LPS诱导的Kf升高，被KH7减弱。此外，在用LPS处理6小时的PMVEC中，AC10表达呈剂量依赖性增加。因此，这些发现表明，LPS诱导的肺血管内皮屏障衰竭需要AC10的碳酸氢盐活化。

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