生长激素对急性肺损伤的影响

目的探讨应激反应阶段生长激素（GH）对脂多糖（LPS）诱导急性肺损伤（ALI）的影响及其机制。方法112只雄性SD大鼠随机均分为ALI组和GH组，按致伤与否及致伤后的观察时间又随机均分为0、0．5、1、2、4、6和24h7个亚组。分别测定大鼠肺泡隔面积密度（PASAD），肺泡隔中性粒细胞数，肺局部肿瘤坏死因子（TNF）和白细胞介素-6（IL-6）水平，肺组织核转录因子-κB（NF-κB）阳性细胞数和肺匀浆液中NF-κB抑制蛋白（I-κBα）含量。结果致伤后ALI组大鼠PASAD进行性增大，肺泡隔中性粒细胞数进行性增多，两者均于6h达峰值，24h基本恢复正常；GH组大鼠PASAD较ALI组同时间点进一步增大，中性粒细胞数增多更明显。ALI组致伤后0．5h肺局部TNF水平开始迅速升高，1h达峰值，其后维持在较高水平，6h后逐渐恢复；致伤后1h IL-6水平开始明显升高，4h达峰值，6h后逐渐恢复；GH组大鼠IL-6水平升高更明显。ALI组致伤后0．5h肺组织中NF-κB阳性细胞数明显增多，4h达峰值，6h开始恢复；GH组大鼠肺组织NF-κB阳性细胞数明显多于ALI组同时间点。伤后0．5h I-κBn含量开始明显下降，4h达最低值，6h后开始回升；GH组大鼠肺组织I-κBa含量下降更明显。相关性分析显示，PASAD、肺组织TNF和IL-6水平及肺泡隔中性粒细胞浸润程度与NF-κB的表达、活化程度呈正相关。结论NF-κB表达、活化在LPS诱导ALI的发病过程中有重要作用。应激反应阶段应用GH可加剧LPS诱导的ALI。其机制与促进肺局部NF-κB表达与活化而加剧肺局部炎症反应有关。

Effect of growth hormone on acute lung injury

OBJECTIVE: To study the effect of growth hormone (GH) on acute lung injury (ALI) induced by endotoxemia, and its potential therapeutic mechanism. METHODS: One hundred and twelve male Sprague-Dawley rats were randomly divided into ALI group and GH group. The rats in two groups were further divided into seven subgroups determined by the length of interval after lipopolysaccharide (LPS) challenge: 0 (before injection of LPS, served as control group), 0.5, 1, 2, 4, 6 and 24 hours subgroups respectively. Pulmonary alveolar septum area density (PASAD) and the number of neutrophil in lungs of rats were analyzed morphometrically. The levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6) were determined by immunoradioassay. The expression and activation of nuclear factor-kappaB (NF-kappaB) were analyzed, NF-kappaB positive cells in lungs were counted after immunofluorescence staining, and the levels of NF-kappaB inhibition (I-kappaBalpha) in lung homogenates of rats were assayed by Western blot. RESULTS: Half an hour after intravenous injection of LPS, both the PASAD and the number of neutrophil in lungs of ALI rats began to increase, and peaked at 6 hours post-injury, then began to recover and reached the normal levels at 24 hours. The content of TNF in lung homogenates showed immediate elevation after LPS injection, becoming higher than that of the control after 0.5 hour, reaching the peak value at 1 hour, maintaining high levels until 6 hours, then gradually recovered. The content of TNF in lung homogenates of the GH group increased significantly more than that in the LPS group. The contents of IL-6 in rats' lung homogenates began to increase significantly 1 hour post-injury, peaked at 4 hours, then gradually returned to normal level 6 hours post-injury. The content of IL-6 in the lung homogenates of GH group was higher than that in the LPS group at different time intervals post-injury, showing significant difference at 0.5, 6 and 24 hours (P<0.05 or P<0.01). The number of NF-kappaB positive cells increased dramatically at 0.5 hour post-injury. The intensity of fluorescence was enhanced. Both of them peaked at 4 hours post-injury. The number of NF-kappaB positive cells and the enhanced intensity of fluorescence began to decrease at 6 hours post-injury. But the number of NF-kappaB cells at 24 hours post-injury was still larger than that in the control group. The number of NF-kappaB cells in lungs of GH group was significantly larger than that in the LPS group at different time intervals post-injury (P<0.05 or P<0.01). I-kappaBalpha contents in lung homogenates of ALI rats decreased dramatically 0.5 hour post-injury, nadir at 4 hours, and then began to recover. Correlation analysis indicated that PASAD, the levels of TNF and IL-6 and the extent of neutrophil infiltration in lung were positively correlated to the extent of the expression and the activation of NF-kappaB. CONCLUSION: The application of GH during early stage of endotoxin challenge can deteriorate the lung injury induced by LPS through enhancing the expression and activation of NF-kappaB, thus enhances the inflammatory response in lungs.