Shen Weifeng, Gan Jianxin, Xu Shaowen, Jiang Guanyu, Wu Honghai
Department of Emergency, Second Hospital Affiliated to Medical College, Zhejiang University, Hangzhou 310009, China.
Pharmacol Res. 2009 Oct;60(4):296-302. doi: 10.1016/j.phrs.2009.04.007. Epub 2009 Apr 19.
To investigate the protective effects of penehyclidine hydrochloride (PHC) in lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the underlying molecular mechanism. ALI was induced by intravenous injection of LPS (5mg/kg). Male Sprague-Dawley (SD) rats challenged with or without LPS were pretreated with varied doses of PHC 0.5h before injection of LPS or saline. Blood gas in arterial blood, lung weight gain, bronchoalveolar lavage fluid (BALF), and neutrophils sequestration were examined 6h after administration of LPS. Pathological changes of lung tissue were measured by light microscopy. Phosphorylation of mitogen-activated protein kinase (MAPK) family and NF-kappaB were detected by western blot. All animals demonstrated drops in arterial oxygen tension (PaO(2)) after LPS application, which were significantly reversed by PHC pretreatment. Administration of PHC reduced lung water gain, bronchoalveolar lavage protein content, infiltration of neutrophils, malondialdehyde (MDA) content, and lactate dehydrogenase (LDH) activity and enhanced superoxide dismutase (SOD) activity. Histopathological study also indicated that PHC treatment markedly attenuated lung histopathological changes, alveolar hemorrhage, and inflammatory cells infiltration with evidence of decreasing of myeloperoxidase (MPO) activity. Furthermore, p38MAPK, ERK, and NF-kappaB were activated in 6h after LPS treatment, which could be blunted by PHC, while JNK remained unchanged. These findings confirmed significant protection by PHC against LPS-induced lung vascular leak and inflammation and implicated inhibition of p38MAPK activation signaling a potential role for PHC in the management of ALI.
探讨盐酸戊乙奎醚（PHC）对脂多糖（LPS）诱导的急性肺损伤（ALI）的保护作用及其潜在分子机制。通过静脉注射LPS（5mg/kg）诱导ALI。在注射LPS或生理盐水前0.5小时，用不同剂量的PHC对雄性Sprague-Dawley（SD）大鼠进行预处理，这些大鼠分别接受或未接受LPS攻击。在给予LPS后6小时，检测动脉血血气、肺重量增加、支气管肺泡灌洗液（BALF）以及中性粒细胞滞留情况。通过光学显微镜观察肺组织的病理变化。采用蛋白质免疫印迹法检测丝裂原活化蛋白激酶（MAPK）家族和核因子κB（NF-κB）的磷酸化水平。所有动物在应用LPS后动脉血氧分压（PaO₂）均下降，而PHC预处理可显著逆转这一情况。给予PHC可减少肺水含量增加、支气管肺泡灌洗蛋白含量、中性粒细胞浸润、丙二醛（MDA）含量以及乳酸脱氢酶（LDH）活性，并增强超氧化物歧化酶（SOD）活性。组织病理学研究还表明，PHC治疗可显著减轻肺组织病理学变化、肺泡出血以及炎症细胞浸润，同时髓过氧化物酶（MPO）活性降低。此外，LPS处理后6小时p38MAPK、ERK和NF-κB被激活，而PHC可使其钝化，而JNK保持不变。这些发现证实了PHC对LPS诱导的肺血管渗漏和炎症具有显著保护作用，并提示抑制p38MAPK激活表明PHC在ALI治疗中具有潜在作用。
