Hypercapnic acidosis attenuates endotoxin-induced nuclear factor-κB activation
Hypercapnic acidosis attenuates endotoxin-induced nuclear factor-κB activation
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DOI：
10.1165/rcmb.2002-0126oc
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发表时间：
2003-07-01
影响因子：
6.4
通讯作者：
Yamaguchi, K
中科院分区：
文献类型：
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作者：
Takeshita, K;Suzuki, Y;Yamaguchi, K
尽管允许性高碳酸血症可改善急性呼吸窘迫综合征患者的预后，但尚不能最终确定高碳酸血症酸中毒（HA）对肺部持续炎症是有害还是有益。本研究旨在探讨透明质酸（HA）对肺内皮细胞内脂多糖（LPS）相关信号的影响及其分子机制。LIPS引起抑制蛋白kappaB（IkappaB）-α的降解，但不引起IkappaB-B的降解，导致人肺动脉内皮细胞中核因子（NF）-kappaB的激活。暴露于HA通过抑制IkappaB-α降解显著减弱LPS诱导的NF-κ B活化。等碳酸酸中毒和缓冲高碳酸血症表现出定性相似，但定量较小的影响。HA没有减弱LPS增强的激活蛋白-1的激活。在减少NF-κ B活化后，HA抑制细胞间粘附分子-1和白细胞介素-8的mRNA和蛋白水平，导致乳酸脱氢酶释放到培养基中和中性粒细胞粘附到LPS活化的人肺动脉内皮细胞的减少。相反，HA不抑制LPS增强的中性粒细胞表达的整合素，Mac-1。基于这些发现，我们得出结论，高碳酸血症的酸中毒将主要通过抑制NF-κ B活化的机制产生抗炎作用，导致细胞间粘附分子-1和白细胞介素-8下调，进而抑制中性粒细胞粘附到肺内皮细胞。
Although permissive hypercapnia improves the prognosis of patients with acute respiratory distress syndrome, it has not been conclusively determined whether hypercapnic acidosis (HA) is harmful or beneficial to sustained inflammation of the lung. The present study was designed to explore the molecular mechanism of HA in modifying lipopolysaccharide (LPS)-associated signals in pulmonary endothelial cells. LIPS elicited degradation of inhibitory protein kappaB (IkappaB)-alpha, but not IkappaB-B, resulting in activation of nuclear factor (NF)-kappaB in human pulmonary artery endothelial cells. Exposure to HA significantly attenuated LPS-induced NF-kappaB activation through suppressing IkappaB-alpha degradation. Isocapnic acidosis and buffered hypercapnia showed qualitatively similar but quantitatively smaller effects. HA did not attenuate the LPS-enhanced activation of activator protein-1. Following the reduced NF-kappaB activation, HA suppressed the mRNA and protein levels of intercellular adhesion molecule-1 and interleukin-8, resulting in a decrease in both lactate dehydrogenase release into the medium and neutrophil adherence to LPS-activated human pulmonary artery endothelial cells. In contrast, HA did not inhibit LPS-enhanced neutrophil expression of integrin, Mac-1. Based on these findings, we concluded that hypercapnic acidosis would have anti-inflammatory effects essentially through a mechanism inhibiting NF-kappaB activation, leading to downregulation of intercellular adhesion molecule-1 and interleukin-8, which in turn inhibits neutrophil adherence to pulmonary endothelial cells.