Jansson Anne-Helene, Eriksson Christina, Wang Xiangdong
Department of Biological Science, AstraZeneca R&D Lund, S-221 87 Lund, Sweden.
Vascul Pharmacol. 2005 Aug;43(2):101-11. doi: 10.1016/j.vph.2005.03.006.
Leukocyte activation and production of inflammatory mediators and reactive oxygen species are important in the pathogenesis of lipopolysaccharide (LPS)-induced acute lung injury. The present study investigated acute lung hyperinflation, edema, and lung inflammation 4 h after an intratracheal instillation of LPS (0.5, 2.5, 5, 10, 50, 100, 500, 1000, and 5000 microg/ml/kg). Effects of budesonide, an inhaled anti-inflammatory corticosteroids, and N-acetylcysteine (NAC), an antioxidant, were evaluated in Wistar rats receiving either low (2.5 microg/ml/kg) or high (50 microg/ml/kg) concentrations of LPS. This study demonstrates that LPS in a concentration-dependent pattern induces acute lung hyperinflation measured by excised lung gas volume (25-45% above control), lung injury indicated by increased lung weight (10-60%), and lung inflammation characterized by the infiltration of leukocytes (40-14000%) and neutrophils (80-17000%) and the production of cytokines (up to 2700%) and chemokines (up to 350%) in bronchoalveolar lavage fluid (BALF). Pretreatment with NAC partially prevented tumor necrosis factor alpha (TNFalpha) production induced by the low concentration of LPS, while pretreatment with budesonide totally prevented the increased production of TNFalpha, interleukin (IL)-1beta, IL-6, and monocyte chemoattractive protein (MCP)-1 after LPS challenge at both low and high concentrations. Budesonide failed to prevent BALF levels of macrophage inflammatory protein (MIP)-2 and cytokine-induced neutrophil chemoattractant 1 (GRO/CINC-1) as well as lung hyperinflation induced by both low and high concentrations of LPS. Pretreatment with budesonide totally prevented the formation of lung edema at the low concentration of LPS and had partial effects on acute lung injury and leukocyte influx at the high concentrations. Thus, our data indicate that therapeutic effects of budesonide and NAC are dependent upon the severity of the disease.
白细胞活化以及炎症介质和活性氧的产生在脂多糖（LPS）诱导的急性肺损伤发病机制中起着重要作用。本研究调查了气管内滴注LPS（0.5、2.5、5、10、50、100、500、1000和5000微克/毫升/千克）4小时后急性肺过度充气、水肿和肺部炎症情况。在接受低（2.5微克/毫升/千克）或高（50微克/毫升/千克）浓度LPS的Wistar大鼠中评估了吸入性抗炎皮质类固醇布地奈德和抗氧化剂N - 乙酰半胱氨酸（NAC）的作用。本研究表明，LPS以浓度依赖性方式诱导急性肺过度充气（通过切除肺的气体体积测量，比对照高25 - 45%）、肺损伤（以肺重量增加表示，增加10 - 60%）以及肺部炎症（其特征为白细胞浸润（40 - 14000%）和中性粒细胞浸润（80 - 17000%），以及支气管肺泡灌洗液（BALF）中细胞因子产生增加（高达2700%）和趋化因子产生增加（高达350%））。NAC预处理部分预防了低浓度LPS诱导的肿瘤坏死因子α（TNFα）产生，而布地奈德预处理完全预防了低浓度和高浓度LPS攻击后TNFα、白细胞介素（IL）-1β、IL - 6和单核细胞趋化蛋白（MCP）-1产生的增加。布地奈德未能预防巨噬细胞炎性蛋白（MIP）-2和细胞因子诱导的中性粒细胞趋化因子1（GRO/CINC - 1）的BALF水平以及低浓度和高浓度LPS诱导的肺过度充气。布地奈德预处理完全预防了低浓度LPS时肺水肿的形成，对高浓度时的急性肺损伤和白细胞流入有部分作用。因此，我们的数据表明布地奈德和NAC的治疗效果取决于疾病的严重程度。
