Moine P, Shenkar R, Kaneko D, Le Tulzo Y, Abraham E
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver 80262, USA.
Am J Physiol. 1997 Jul;273(1 Pt 1):L185-92. doi: 10.1152/ajplung.1997.273.1.L185.
The nuclear regulatory factor (NF)-kappa B is activated in the lungs of patients with acute respiratory distress syndrome (ARDS). In experimental models of acute lung injury, activation of NF-kappa B contributes to the increased expression of immunoregulatory cytokines and other proinflammatory mediators in the lungs. Because of the important role that NF-kappa B activation appears to play in the development of acute lung injury, we examined cytoplasmic and nuclear NF-kappa B counterregulatory mechanisms in lung mononuclear cells, using a murine model in which inflammatory lung injury develops after blood loss. Sustained activation of NF-kappa B was present in lung mononuclear cells over the 4-h period after blood loss. The activation of NF-kappa B after hemorrhage was accompanied by alterations in levels of the NF-kappa B regulatory proteins I kappa B alpha and Bcl-3. Cytoplasmic and nuclear I kappa B alpha were increased and nuclear Bcl-3 was decreased during the first hour after blood loss, but, by 4 h posthemorrhage, cytoplasmic and nuclear I kappa B alpha levels were decreased and nuclear levels of Bcl-3 were increased. Inhibition of xanthine oxidase activity in otherwise unmanipulated unhemorrhaged mice resulted in increased levels of I kappa B alpha and decreased amounts of Bcl-3 in nuclear extracts from lung mononuclear cells. No changes in the levels of nuclear I kappa B alpha or Bcl-3 occurred after hemorrhage when xanthine oxidase activity was inhibited. These results demonstrate that blood loss, at least partly through xanthine oxidase-dependent mechanisms, produces alterations in the levels of both I kappa B alpha and Bcl-3 in lung mononuclear cell populations. The effects of hemorrhage on proteins that regulate activation of NF-kappa B may contribute to the frequent development of inflammatory lung injury in this setting.
核调节因子（NF）-κB在急性呼吸窘迫综合征（ARDS）患者的肺中被激活。在急性肺损伤的实验模型中，NF-κB的激活导致肺中免疫调节细胞因子和其他促炎介质的表达增加。由于NF-κB激活似乎在急性肺损伤的发展中起重要作用，我们使用一种失血后发生炎症性肺损伤的小鼠模型，研究了肺单核细胞中的细胞质和细胞核NF-κB的反调节机制。失血后4小时内，肺单核细胞中持续存在NF-κB的激活。出血后NF-κB的激活伴随着NF-κB调节蛋白IκBα和Bcl-3水平的改变。失血后第一小时内，细胞质和细胞核IκBα增加，细胞核Bcl-3减少，但在出血后4小时，细胞质和细胞核IκBα水平降低，细胞核Bcl-3水平升高。在未进行其他操作的未失血小鼠中抑制黄嘌呤氧化酶活性，导致肺单核细胞核提取物中IκBα水平升高，Bcl-3含量降低。当抑制黄嘌呤氧化酶活性时，出血后细胞核IκBα或Bcl-3水平没有变化。这些结果表明，失血至少部分通过黄嘌呤氧化酶依赖性机制，导致肺单核细胞群体中IκBα和Bcl-3水平发生改变。出血对调节NF-κB激活的蛋白质的影响可能导致这种情况下炎症性肺损伤的频繁发生。
