盐酸戊乙奎醚对内毒素诱导急性肺损伤大鼠的保护作用及其分子机制研究
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摘要
急性肺损伤(acute lung injury,ALI)是一种多种原因引起的肺部失控性炎症反应导致的肺泡毛细血管损伤为基本病理生理特点的综合征,常继发于休克、严重创伤、感染等,病情凶险、预后差,可进一步发展为多器官功能衰竭,因此,防治本类疾病在外科急危重领域具有非常重要的意义。
药物干预在ALI防治中具有重要作用,目前,较为确定的ALI治疗药物有一氧化氮吸入、外源性肺泡表面活性物质、糖皮质激素等,但存在疗效不满意和/或不良反应严重的问题,至今仍无安全有效的治疗药物。莨菪类药物已应用于ALI治疗多年,但因传统莨菪类药物如山莨菪碱等的作用机制不甚明了和副作用大,限制了莨菪类药物的临床应用。盐酸戊乙奎醚(penehyclidine hydrochloride,PHC)是中国原创的新型选择性的莨菪类药物,因对M胆碱能受体亚型具有选择性,临床应用副作用少,扩大了莨菪类药物的应用范围和适应证,近来研究表明,盐酸戊乙奎醚能改善微循环、降低毛细血管壁的通透性、细胞保护和减少溶酶体释放等作用,提示盐酸戊乙奎醚可能对急性肺损伤具有治疗作用,因此,本项目将对新型莨菪类药物盐酸戊乙奎醚对急性肺损伤的保护作用进行深入的研究。综合大量文献,中性粒细胞大量肺内扣押、活化和进一步的脂质过氧化等造成肺微血管内皮细胞和肺泡上皮细胞等损伤,最终导致
Acute lung injury (ALI) is a cause of acute respiratory failure that develops in patients of all ages from a variety of clinical disorders, including sepsis (pulmonary and nonpulmonary), pneumonia (bacterial, viral, and fungal), aspiration of gastric and oropharyngeal contents, major trauma, and several other clinical disorders including severe acute pancreatitis, drug overdose, and blood products. ALI is common and remains a significant cause of morbidity and mortality in critically ill patients.Penehyclidine hydrochloride (PHC), a new anticholinerigic drug invented by the Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences in the People's Republic of China. It is noteworthy that PHC can decrease significantly the nasal mucosa capillary permeability. Thus, PHC is potentially beneficial for treatment of ALI. Recently, studies have confirmed PHC can improve the function of microcirculation during open heart surgery under cardiopulmonary bypass (CPB) with heart beating. In this study we aimed to investigate whether PHC has in vivo protective effects on ALI induced by LPS.Neutrophils mediate tissue injury and have been implicated in the pathogenesis of several important diseases, including those that may trigger ALI. Neutrophils
sequestered in the lung play a central role in the pathogenesis of ALI induced by LPS. The acute phase of ALI is characterized by the influx of protein-rich edema fluid into the air spaces as a consequence of increased permeability of the alveolar-capillary barrier. The importance of endothelial injury and increased vascular permeability to the formation of pulmonary edema in this disorder has been well established. Therefore, the protective effect of PHC in vivo models of ALI in this study has been examined by these indices as we mentioned above.Elevated levels of proinfiammatory mediators combined with a decreased expression of anti-inflammatory molecules are critical components of lung inflammation and play a main role in ALI. The signals that lead to increased gene expression and biosynthesis of proinflammatory mediators by inflammatory and epithelial cells are thus of considerable interest. Recent experimental studies appeared to have shed some light on the intracellular signaling pathway in the inflammatory cascade in ALI. For example, recent evidence strongly suggested the crucial role of NF-kB in the initiation of ALI. Additionally, recent evidence has also shown that MAP kinases are involved in modulating the expression of many cytokines and other proinflammatory mediators implicated in the development and progression of ALI. An in vitro experiment showed that cytokine expression of PMNs was mediated by two separate signal pathways, i.e, NF-kB and MAP kinase, of which MAP kinase is now suggested to play a major role. Four subfamilies of MAP kinases, i.e. ERK, JNK, p38 and ERK5 participate in intracellular signaling cascades resulting in inflammatory responses. Inhibition of these pathways has been advocated as a novel therapeutic strategy for inflammatory diseases. Inhibition of the MAP kinases pathways may form the basis of a new strategy for treatment of ALI. The coordination and interaction of MAP kinase pathways and NF-kB cascade may play a key role in LPS induced gene expression. In this study, we also aimed to investigate whether the therapeutic effect of PHC in the treatment of ALI could—at
least in part-be brought about by its direct interference with the LPS-induced activation of NF-kappaB, p38, ERK and JNK.This study was divided into two chapters and four parts.Chapter onePartiProtective effect of penehyclidine hydrochloride pretreatment onlipopolysaccharide-induced acute lung injury in ratsObjective The aim of this study was to examine the effects of PHC pretreatmenton LPS-induced ALI in rats.Methods Forty eight adult male Sprague-Dawley rats weighing between 190 and230g were used. ALI was induced by intravenous injection of lipopolysaccharide(LPS). Five groups of rats were treated with LPS (5 mg/kg), LPS plus PHC (3.0, 1.0,0.3 mg/kg) or LPS plus methylprednisolone (MP) (30 mg/kg) for 6 hours. PHC andMP were administered at 30 minutes before LPS challenge. One group of ratsdesigned as control was treated with saline. Arterial blood gas analysis, lungpermeability index (LPI^ wet to dry weight ratio (W/D) and protein content inbronchoalveolar lavage fluid (BALF) were measured. Pathological changes of lungtissue were measured by light and electron microscopy.Results LPS-challenged rats had significantly increased arterial partial pressure ofcarbon dioxiden W/D ratio ^ LPL protein content in BALF and decreased partialpressure of oxygen of arterial blood, compared to controls. Compared with LPStreatment, PHC pretreatment significantly decreased arterial partial pressure ofcarbon dioxide n W/D ratio > LPL protein content in BALF and enhanced partialpressure of oxygen of arterial blood. Lung interstitial edema, diffuse hemorrhage, alarge amount of red blood cells and neutrophils infiltration in the alveoli, increase ofplasma protein exudate, formation of transparent membrane, and thickening of the
alveolar wall were seen under light microscopy and the defects of endothelial cells and type II pneumocytes were shown under transmission electron microscope in LPS-challenged rats, PHC pretreatment significantly attenuated these pathological changes.Conclusions These results demonstrate that PHC can attenuate acute lung injury and exert protective effect on ALI induced by LPS. Further studies are required to evaluate the safety and clinical benefits of penehyclidine hydrochloride administration in ALI.Part IIPretreatment of PHC is beneficial to LPS-induced ALI in rats through inhibiting the lung neutrophil sequestration and oxygen free radicals injury Objective The aim of this study was to examine whether pretreatment of PHC is beneficial to LPS-induced ALI in rats through inhibiting the lung neutrophil sequestration and oxygen free radicals injury.Methods Forty eight adult male Sprague-Dawley rats weighing between 190 and 230g were used. ALI was induced by intravenous injection of LPS. Five groups of rats were treated with LPS (5 mg/kg), LPS plus PHC (3.0, 1.0, 0.3 mg/kg) or LPS plus methylprednisolone (MP) (30 mg/kg) for 6 hours. PHC and MP were administered at 30 minutes before LPS challenge. One group of rats designed as control was treated with saline. The ratio of neutrophiles in bronchoalveolar lavage fluid (BALF^ the activities of superoxide dismutase (SOD^ myeloperoxidase (MPO), lactate dehydrogenase (LDH) and malondialdehyde (MDA) content in blood serum and lung were measured.Results LPS-challenged rats had significantly increased MDA leveK MPO and LDH activity % the ratio of neutrophiles in BALF, and decreased SOD activity compared to controls. Compared with LPS treatment, PHC pretreatment significantly
decreased MDA level > MPO and LDH activity, the ratio of neutrophiles in BALF, and dramatically enhanced SOD activity.Conclusions It is suggested that pretreatment of penehyclidine hydrochloride is beneficial to LPS-induced ALI in rats through inhibiting the lung neutrophil sequestration and oxygen free radicals injury.Chapter two PartiProtective effect of penehyclidine hydrochloride on ALI rats induced by lipopolysaccharide via inhibition of NF-kappaB activation Objective We aimed to investigate whether the therapeutic effect of PHC in the treatment of ALI could~at least in part-be brought about by its direct interference with the LPS-induced activation of NF-kappaB.Methods ALI was induced by intravenous injection of lipopolysaccharide (LPS). It is projected that PHC at dose of 3.0 mg/kg will be administered at 0.5h before injection of LPS or saline and lung tissues at Oh, 2h, 4h, 6h, and 12h were taken for measurement of the levels of phosphorylated NF-kappaB by western blot analysis to examine the effects of PHC on activation of NF-kappaB in time-dependent manners. PHC at doses of 3.0 mg/kg, 1.0 mg/kg, and 0.3 mg/kg were administered at 0.5h before injection of LPS or saline and lung tissues at 6 hours were taken for measurement of the levels of phosphorylated NF-kappaB by western blot analysis to examine the effects of PHC on activation of NF-kappaB in dose-dependent manners. Results Compared to controls, LPS -challenged rats had significantly increased the levels of phosphorylated NF-kB in lung tissues. A high and middle level dose of PHC pretreatment resulted in a drastic down-regulation of phospho-NF-kappaB. PHC significantly attenuated LPS-induced phospho-NF-kappaB expression in dose-dependent and time-dependent manners.
Conclusions These results suggest that NF-kappaB participates in the signal transduction in LPS induced acute lung injury. PHC relieves the inflammation in acute lung injury rats possibly through the inhibition of NF-kappaB activation.Part IIProtective effect of penehyclidine hydrochloride on ALI rats induced by lipopolysaccharide via inhibition of p38 mitogen-activated protein kinase-* c-Jun N-Terminal kinase and extracellular signal-regulated kinase activation Objective We aimed to investigate whether the therapeutic effect of PHC in the treatment of ALI could~at least in part—be brought about by its direct interference with the LPS-induced activation of p38 mitogen-activated protein kinase > c-Jun N-Terminal kinase and extracellular signal-regulated kinase activation. Methods ALI was induced by intravenous injection of lipopolysaccharide (LPS). It is projected that PHC at dose of 3.0 mg/kg will be administered at 0.5h before injection of LPS or saline and lung tissues at Oh, 2h, 4h, 6h, and 12h were taken for measurement of the levels of phosphorylated p38 mitogen-activated protein kinase % c-Jun N-Terminal kinase and extracellular signal-regulated kinase by western blot analysis to examine the effects of PHC on activation of p38 mitogen-activated protein kinase > c-Jun N-Terminal kinase and extracellular signal-regulated kinase in time-dependent manners. PHC at doses of 3.0 mg/kg, 1.0 mg/kg, and 0.3 mg/kg were administered at 0.5h before injection of LPS or saline and lung tissues at 6 hours were taken for measurement of the levels of phosphorylated p38 mitogen-activated protein kinase, c-Jun N-Terminal kinase and extracellular signal-regulated kinase by western blot analysis to examine the effects of PHC on activation of p38 mitogen-activated protein kinase ^ c-Jun N-Terminal kinase and extracellular signal-regulated kinase in dose-dependent manners. Results Compared to controls, LPS-challenged rats had significantly increased
the levels of phosphorylated p38 mitogen-activated protein kinase ^ c-Jun N-Terminal kinase and extracellular signal-regulated kinase activation in lung tissues. A high level dose of PHC pretreatment resulted in a drastic down-regulation of phospho-p38 mitogen-activated protein kinase and phosphor -extracellular signal-regulated kinase. PHC attenuated LPS-induced phospho-p38 mitogen-activated protein kinase > phospho-extracellular signal-regulated kinase expression in dose-dependent and time-dependent manners. The expression of phospho-c-Jun N-Terminal kinase was not significantly down-regulated in PHC pretreatment group. Conclusions These results suggest that p38 mitogen-activated protein kinase and extracellular signal-regulated kinase participate in the signal transduction in LPS induced acute lung injury. PHC relieves the inflammation in acute lung injury rats possibly through the inhibition of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase activation.In conclusion, our data suggest that PHC pretreatment attenuated LPS-induced lung injury in rats. This beneficial effect of PHC may involve, in part, inhibition of lung neutrophil sequestration and oxygen free radicals injury, possibly through inhibition of lung NF-kappaB,p38 mitogen-activated protein kinase and extracellular signal-regulated kinase activation. If these findings are confirmed in additional models, PHC may become a candidate for clinical testing in critical care.
药物干预在ALI防治中具有重要作用,目前,较为确定的ALI治疗药物有一氧化氮吸入、外源性肺泡表面活性物质、糖皮质激素等,但存在疗效不满意和/或不良反应严重的问题,至今仍无安全有效的治疗药物。莨菪类药物已应用于ALI治疗多年,但因传统莨菪类药物如山莨菪碱等的作用机制不甚明了和副作用大,限制了莨菪类药物的临床应用。盐酸戊乙奎醚(penehyclidine hydrochloride,PHC)是中国原创的新型选择性的莨菪类药物,因对M胆碱能受体亚型具有选择性,临床应用副作用少,扩大了莨菪类药物的应用范围和适应证,近来研究表明,盐酸戊乙奎醚能改善微循环、降低毛细血管壁的通透性、细胞保护和减少溶酶体释放等作用,提示盐酸戊乙奎醚可能对急性肺损伤具有治疗作用,因此,本项目将对新型莨菪类药物盐酸戊乙奎醚对急性肺损伤的保护作用进行深入的研究。综合大量文献,中性粒细胞大量肺内扣押、活化和进一步的脂质过氧化等造成肺微血管内皮细胞和肺泡上皮细胞等损伤,最终导致
Acute lung injury (ALI) is a cause of acute respiratory failure that develops in patients of all ages from a variety of clinical disorders, including sepsis (pulmonary and nonpulmonary), pneumonia (bacterial, viral, and fungal), aspiration of gastric and oropharyngeal contents, major trauma, and several other clinical disorders including severe acute pancreatitis, drug overdose, and blood products. ALI is common and remains a significant cause of morbidity and mortality in critically ill patients.Penehyclidine hydrochloride (PHC), a new anticholinerigic drug invented by the Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences in the People's Republic of China. It is noteworthy that PHC can decrease significantly the nasal mucosa capillary permeability. Thus, PHC is potentially beneficial for treatment of ALI. Recently, studies have confirmed PHC can improve the function of microcirculation during open heart surgery under cardiopulmonary bypass (CPB) with heart beating. In this study we aimed to investigate whether PHC has in vivo protective effects on ALI induced by LPS.Neutrophils mediate tissue injury and have been implicated in the pathogenesis of several important diseases, including those that may trigger ALI. Neutrophils
sequestered in the lung play a central role in the pathogenesis of ALI induced by LPS. The acute phase of ALI is characterized by the influx of protein-rich edema fluid into the air spaces as a consequence of increased permeability of the alveolar-capillary barrier. The importance of endothelial injury and increased vascular permeability to the formation of pulmonary edema in this disorder has been well established. Therefore, the protective effect of PHC in vivo models of ALI in this study has been examined by these indices as we mentioned above.Elevated levels of proinfiammatory mediators combined with a decreased expression of anti-inflammatory molecules are critical components of lung inflammation and play a main role in ALI. The signals that lead to increased gene expression and biosynthesis of proinflammatory mediators by inflammatory and epithelial cells are thus of considerable interest. Recent experimental studies appeared to have shed some light on the intracellular signaling pathway in the inflammatory cascade in ALI. For example, recent evidence strongly suggested the crucial role of NF-kB in the initiation of ALI. Additionally, recent evidence has also shown that MAP kinases are involved in modulating the expression of many cytokines and other proinflammatory mediators implicated in the development and progression of ALI. An in vitro experiment showed that cytokine expression of PMNs was mediated by two separate signal pathways, i.e, NF-kB and MAP kinase, of which MAP kinase is now suggested to play a major role. Four subfamilies of MAP kinases, i.e. ERK, JNK, p38 and ERK5 participate in intracellular signaling cascades resulting in inflammatory responses. Inhibition of these pathways has been advocated as a novel therapeutic strategy for inflammatory diseases. Inhibition of the MAP kinases pathways may form the basis of a new strategy for treatment of ALI. The coordination and interaction of MAP kinase pathways and NF-kB cascade may play a key role in LPS induced gene expression. In this study, we also aimed to investigate whether the therapeutic effect of PHC in the treatment of ALI could—at
least in part-be brought about by its direct interference with the LPS-induced activation of NF-kappaB, p38, ERK and JNK.This study was divided into two chapters and four parts.Chapter onePartiProtective effect of penehyclidine hydrochloride pretreatment onlipopolysaccharide-induced acute lung injury in ratsObjective The aim of this study was to examine the effects of PHC pretreatmenton LPS-induced ALI in rats.Methods Forty eight adult male Sprague-Dawley rats weighing between 190 and230g were used. ALI was induced by intravenous injection of lipopolysaccharide(LPS). Five groups of rats were treated with LPS (5 mg/kg), LPS plus PHC (3.0, 1.0,0.3 mg/kg) or LPS plus methylprednisolone (MP) (30 mg/kg) for 6 hours. PHC andMP were administered at 30 minutes before LPS challenge. One group of ratsdesigned as control was treated with saline. Arterial blood gas analysis, lungpermeability index (LPI^ wet to dry weight ratio (W/D) and protein content inbronchoalveolar lavage fluid (BALF) were measured. Pathological changes of lungtissue were measured by light and electron microscopy.Results LPS-challenged rats had significantly increased arterial partial pressure ofcarbon dioxiden W/D ratio ^ LPL protein content in BALF and decreased partialpressure of oxygen of arterial blood, compared to controls. Compared with LPStreatment, PHC pretreatment significantly decreased arterial partial pressure ofcarbon dioxide n W/D ratio > LPL protein content in BALF and enhanced partialpressure of oxygen of arterial blood. Lung interstitial edema, diffuse hemorrhage, alarge amount of red blood cells and neutrophils infiltration in the alveoli, increase ofplasma protein exudate, formation of transparent membrane, and thickening of the
alveolar wall were seen under light microscopy and the defects of endothelial cells and type II pneumocytes were shown under transmission electron microscope in LPS-challenged rats, PHC pretreatment significantly attenuated these pathological changes.Conclusions These results demonstrate that PHC can attenuate acute lung injury and exert protective effect on ALI induced by LPS. Further studies are required to evaluate the safety and clinical benefits of penehyclidine hydrochloride administration in ALI.Part IIPretreatment of PHC is beneficial to LPS-induced ALI in rats through inhibiting the lung neutrophil sequestration and oxygen free radicals injury Objective The aim of this study was to examine whether pretreatment of PHC is beneficial to LPS-induced ALI in rats through inhibiting the lung neutrophil sequestration and oxygen free radicals injury.Methods Forty eight adult male Sprague-Dawley rats weighing between 190 and 230g were used. ALI was induced by intravenous injection of LPS. Five groups of rats were treated with LPS (5 mg/kg), LPS plus PHC (3.0, 1.0, 0.3 mg/kg) or LPS plus methylprednisolone (MP) (30 mg/kg) for 6 hours. PHC and MP were administered at 30 minutes before LPS challenge. One group of rats designed as control was treated with saline. The ratio of neutrophiles in bronchoalveolar lavage fluid (BALF^ the activities of superoxide dismutase (SOD^ myeloperoxidase (MPO), lactate dehydrogenase (LDH) and malondialdehyde (MDA) content in blood serum and lung were measured.Results LPS-challenged rats had significantly increased MDA leveK MPO and LDH activity % the ratio of neutrophiles in BALF, and decreased SOD activity compared to controls. Compared with LPS treatment, PHC pretreatment significantly
decreased MDA level > MPO and LDH activity, the ratio of neutrophiles in BALF, and dramatically enhanced SOD activity.Conclusions It is suggested that pretreatment of penehyclidine hydrochloride is beneficial to LPS-induced ALI in rats through inhibiting the lung neutrophil sequestration and oxygen free radicals injury.Chapter two PartiProtective effect of penehyclidine hydrochloride on ALI rats induced by lipopolysaccharide via inhibition of NF-kappaB activation Objective We aimed to investigate whether the therapeutic effect of PHC in the treatment of ALI could~at least in part-be brought about by its direct interference with the LPS-induced activation of NF-kappaB.Methods ALI was induced by intravenous injection of lipopolysaccharide (LPS). It is projected that PHC at dose of 3.0 mg/kg will be administered at 0.5h before injection of LPS or saline and lung tissues at Oh, 2h, 4h, 6h, and 12h were taken for measurement of the levels of phosphorylated NF-kappaB by western blot analysis to examine the effects of PHC on activation of NF-kappaB in time-dependent manners. PHC at doses of 3.0 mg/kg, 1.0 mg/kg, and 0.3 mg/kg were administered at 0.5h before injection of LPS or saline and lung tissues at 6 hours were taken for measurement of the levels of phosphorylated NF-kappaB by western blot analysis to examine the effects of PHC on activation of NF-kappaB in dose-dependent manners. Results Compared to controls, LPS -challenged rats had significantly increased the levels of phosphorylated NF-kB in lung tissues. A high and middle level dose of PHC pretreatment resulted in a drastic down-regulation of phospho-NF-kappaB. PHC significantly attenuated LPS-induced phospho-NF-kappaB expression in dose-dependent and time-dependent manners.
Conclusions These results suggest that NF-kappaB participates in the signal transduction in LPS induced acute lung injury. PHC relieves the inflammation in acute lung injury rats possibly through the inhibition of NF-kappaB activation.Part IIProtective effect of penehyclidine hydrochloride on ALI rats induced by lipopolysaccharide via inhibition of p38 mitogen-activated protein kinase-* c-Jun N-Terminal kinase and extracellular signal-regulated kinase activation Objective We aimed to investigate whether the therapeutic effect of PHC in the treatment of ALI could~at least in part—be brought about by its direct interference with the LPS-induced activation of p38 mitogen-activated protein kinase > c-Jun N-Terminal kinase and extracellular signal-regulated kinase activation. Methods ALI was induced by intravenous injection of lipopolysaccharide (LPS). It is projected that PHC at dose of 3.0 mg/kg will be administered at 0.5h before injection of LPS or saline and lung tissues at Oh, 2h, 4h, 6h, and 12h were taken for measurement of the levels of phosphorylated p38 mitogen-activated protein kinase % c-Jun N-Terminal kinase and extracellular signal-regulated kinase by western blot analysis to examine the effects of PHC on activation of p38 mitogen-activated protein kinase > c-Jun N-Terminal kinase and extracellular signal-regulated kinase in time-dependent manners. PHC at doses of 3.0 mg/kg, 1.0 mg/kg, and 0.3 mg/kg were administered at 0.5h before injection of LPS or saline and lung tissues at 6 hours were taken for measurement of the levels of phosphorylated p38 mitogen-activated protein kinase, c-Jun N-Terminal kinase and extracellular signal-regulated kinase by western blot analysis to examine the effects of PHC on activation of p38 mitogen-activated protein kinase ^ c-Jun N-Terminal kinase and extracellular signal-regulated kinase in dose-dependent manners. Results Compared to controls, LPS-challenged rats had significantly increased
the levels of phosphorylated p38 mitogen-activated protein kinase ^ c-Jun N-Terminal kinase and extracellular signal-regulated kinase activation in lung tissues. A high level dose of PHC pretreatment resulted in a drastic down-regulation of phospho-p38 mitogen-activated protein kinase and phosphor -extracellular signal-regulated kinase. PHC attenuated LPS-induced phospho-p38 mitogen-activated protein kinase > phospho-extracellular signal-regulated kinase expression in dose-dependent and time-dependent manners. The expression of phospho-c-Jun N-Terminal kinase was not significantly down-regulated in PHC pretreatment group. Conclusions These results suggest that p38 mitogen-activated protein kinase and extracellular signal-regulated kinase participate in the signal transduction in LPS induced acute lung injury. PHC relieves the inflammation in acute lung injury rats possibly through the inhibition of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase activation.In conclusion, our data suggest that PHC pretreatment attenuated LPS-induced lung injury in rats. This beneficial effect of PHC may involve, in part, inhibition of lung neutrophil sequestration and oxygen free radicals injury, possibly through inhibition of lung NF-kappaB,p38 mitogen-activated protein kinase and extracellular signal-regulated kinase activation. If these findings are confirmed in additional models, PHC may become a candidate for clinical testing in critical care.
引文
[1] Xu Xing-xiang, Qian Gui-sheng(徐兴祥,钱桂生). Changes of polymorphonuclear leukocytes sequestration in lungs and influence of anisodamine on it in rats with acute lung injury [J]. Acta Academiae Medicine Militaris Tertiae(第三军医大学学报),2001, 23(8):999-1000 (in Chinese).
[2] Sun Geng-yun, Xiao Zhen-liang, Fang Chuan-biao(孙耕耘,肖贞良,方传彪).Effects of anisodamine on the change of cytoskeleton of rat pulmonary microvascular endothelial cells induced by endotoxin[J]. Chinese Pharmacological Bulletin (中国药理学通报),2001,17(2):197-199. (in Chinese).
[3] Han XY, Liu H, Liu CH, et al. Synthesis of the optical isomers of a new anticholinergic drug, penehyclidine hydrochloride (8018) [J]. Bioorg Med Chem Lett, 2005,15(8):1979-1982.
[4] Han Ji-huan, Chao Feng-sheng, Wang Yi-tang, et al (韩继媛,曹锋生,王一镗,等). Application of penehyclidine hydrochloride in clinic [J]. Chinese Journal of Emergency Medicine (中华急诊医学杂志), 2005, 14(2): 173-174(in Chinese).
[5] Yang J, Li W, Duan M, et al. Large dose ketamine inhibits lipopolysaccharide-induced acute lung injury in rats [J]. Inflamm Res, 2005, 54(3): 133-137.
[6] Feng Xin-wei(冯新为). Pathophysiology (病理生理学) [M], Beijing: People's Medical Publishing House,1993.269-273.
[7] Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial [J]. JAMA, 1998,280(2): 159-65.
[8] EI-Khatib MF, Jamaleddine GW. A new oxygenation index for reflecting intrapulmonary shunting in patients undergoing open-heart surgery [J]. Chest, 2004, 125(2):592-596.
[9] Jian Wen, Qi Hao-wen, Li Zhi-chao(简文,戚好文,李志超). Therapeutic effect of anisodamine, ANP and CGRP on oleic acid induced acute lung injury in rabbits [J]. Journal of The Fourth Military Medical University(第四军医大学学报), 2002, 23(1):19-22(in Chinese).
[10] Lee WL, Downey GE Neutrophil activation and acute lung injury [J]. Curr Opin Crit Care, 2001,7(1): 1-7.
[11] Suttorp N, Nolte A, Wilke A, et al. Human neutrophil elastase increases permeability of cultured pulmonary endothelial cell monolayers [J]. Int J Microcirc Clin Exp, 1993, 13(3):187-203.
[12] Novick RJ, Gehman KE, Ali IS, et al Lung Preservation: The Importance of Endothelial and Alveolar Type II Cell Integrity Richard [J]. Ann Thorac Surg, 1996, 62(1): 302-314.
[13] Silliman CC, Kelher M. The role of endothelial activation in the pathogenesis of transfusion-related acute lung injury [J]. Transfusion, 2005, 45 (2 Suppl):109S-116S.
[14] Ulevitch RJ, Tobias PS. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin [J]. Annu Rev Immunol, 1995,13: 437-457.
[15] Pugin J, Schurer MC, Leturcq D, et al. Lipopolysechride-binding protein and soluble CD14 [J] .Proc Natl Acad Sci USA, 1993,90(7):2744-2748.
[16] Arditi M, Zhou J, Tores M, et al. Lipopolysaecharide stimulates the tyrosine phosphorylation of mitogen-activated protein kinases p44, p42, and p41 in vascular endothelial cells I a soluble CD14-dependent marmer[J].J Immunol, 1995, 155 (8):3994-4003.
[17] Schumann RR, pfeil D, Lamping N, et al. Lipopolysaecharide induces the rapid tyrosine phosphorylation of the mitogen-activated protein kinases erk-1 and p38 in cultured human vascular endothelial cells requiring the presence of soluble CD14 [J].Blood, 1996, 87(7):2805-2814
[18] Han J, Lee .JD, Bibbs L, et al. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells [J].Science, 1994,265(5173): 808-811.
[19] Goeckeler ZM, Wysolmerski RB. Myosin light chain kinase-regulated endothelial cell contraction: the relationship between isometric tension, actin polymerization, and myosin phosphorylation [J]. J Cell Biol, 1995,130 (3): 613-627.
[20] Garcia JG, Schaphorst KM. Regulation of endothelial cell gap formation and paracellular permeability [J]. J Invest Med, 1995, 43(2): 117-126.
[21] Banneman DD, Goldblum SE. Endotoxin induces endothelial barrier dysfunction through protein tyrosine phosphorylation [J]. Am J Physiol, 1997, 273 (1pt1): L217-L226.
[22] Abraham E, Carmody A, Shenkar R, et al. Neutrophils as early immunologic effectors in hemorrhage or endotoxemia-induced acute lung injury [J].Am Physiol Lung Cell Mol Physiol, 2000, 279(6):L1137-L1145.
[23] Chignard M, Balloy V. Neutrophil recruitment and increased permeability during acute lung injury induced by lipopolysaccharide [J]. Am J Physiol, 2000, 279(6): L1083-L1090.
[24] Mason RJ, Walker SR, Shields BA, et al. Identification of rat alveola type Ⅱ epithelial cells with a tannic acid and polychrome stain. [J].Am Rev Respir Dis, 1985,131 (5):786—788.
[25] Brown MA, Lantz RC, Sobonya R, et al. Aerosolized lipopolysaccharide increase Pulmonary clearance of 99m Tc-DTPA in rabbits [J].Am Rev Respir Dis, 1992,146(6): 1462-1468.
[26] Hirano S. Interaction of rat alveola macrophages with pulmonary epithelia cells following exposure to lipopolysaccharide [J]. Arch Toxicol, 1996,70(34): 230-236.
[27] Sunil VR, Connor AJ, Guo Y, et al. Activation of type Ⅱ alveolar epithelial cells during acute endotoxemia [J]. Am J Physiol Lung Cell Mol Physiol, 2002, 282 (4):L872-880.
[28] Rose F, Guthmann B, Tenenbaum T, et al. Apical, but not basolateral endotoxin preincubation protects alveolar epithelial cells against hydrogen peroxide-induced loss of barrier function: the role of nitric oxide synthesis[J]. J Immunol, 2002, 169(3):1474-1481.
[29] Fan J, Ye RD, Malik AB. Transcriptional mechanisms of acute lung injury [J]. Am J Physiol Lung Cell Mol Physiol, 2001,281(5):L1037-L1050.
[30] Li Yong-wang;Zhang De-ming;Qian Gui-sheng, et al(李永旺,张德明,钱桂生,等). TLR4 expression in the activation of alveolar type Ⅱ cells induced by lipopolysaccharide [J]. Acta Academiae Medicinae Militaris Tertiae (第三军医在学学报),2004,26(10):863-866 (in Chinese).
[31] Schulz C, Farkas L, Wolf K, et al. Differences in LPS induced activation of bronchial epithelial cells(BEAS 2B) and type Ⅱ like pneumocytes (A 549)[J]. Scand J Immunol, 2002, 56(3):294-302.
[32] Toga H, Tobe T, Ueda Y, et al. Inducible nitric oxide synthase expression and nuclear factor kappaB activation in alveolar type cells in lung injury [J]. Exp Lung Res, 2001,27(6):485-504.
[33] Li XY, Donaldson K, MacNee W. Lipopolysaccharide induced alveolar epithelial permeability: the role of nitric oxide [J].Am J Respir Crit Care Med, 1998, 157(4Pt1):1027-1033.
[34] Emura M. Stem cells of the respiratory epithelium and their in vitro cultivation. In Vitro Cell [J].Dev Biol, 1997, 33(1):314.
[35] Uhal BD. Cell cycle kinetics in the alveolar epithelium [J].Am J Physiol, 1997, 272 (6Pt1) : L1031-L1045.
[36] Kinnard W, Tuder R, Papst P, et al. Regulation of alveolar type cell differentiation and proliferation in adult rat lung explants [J]. Am J Respir Cell Mol Biol, 1994, 11(4):416-425.
[37] Holm B, Matalon S, Finkelstein J, et al. Type pneumoeyte changes during hyperoxic lung injury and recovery [J]. Appl Physiol, 1988,65(6):2673-2678.
[38] Lewis JF, Jobe AH. Surfactant and the adult respiratory distress syndrome [J]. Am Rev Respir Dis,1993,147(1):218-233.
[39] Yang Qiu, Cui He-qin, Li Ya-ping, et al(杨秋,崔和勤,李亚平,等). Influence of anisodamine (654-2) on plasma fibronectin content in rabbits with pulmonary edema [J]. Chinese pharmacological bulletin(中国药理学通报),1996,12(6): 557-559(in Chinese).
[40] Wright JR. Clearance and recycling of pulmonary surfaetant [J].Am J Physiol, 1990, 259 (2 Pt1):L1-L12.
[41] Jeffrey G, Ramasubbareddy D, Anil B Mukherfee. Surfactant-producing rabbit pulmonare alveolar type Ⅱ cells synthesize and secret an antiinflammatory protein, uteroglobin [J].Binche Biophy Res Commu, 1992,189(2):662-669.
[1] Abraham E, Carmody A, Shenkar R, et al. Neutrophils as early immunologic effectors in hemorrhage or endotoxemia-induced acute lung injury [J].Am Physiol Lung Cell Mol Physiol, 2000, 279(6):L1137-L1145.
[2] Abraham E. Neutrophils and acute lung injury [J]. Clin Care Med, 2003, 31(4 Suppl):S195-S 199.
[3] Gibbs LS, Lai L, Malik AB. Tumor necrosis factor enhances the neutrophil-dependent increase in endothelial permeability [J]. J Cell Physiol, 1990, 145 (3): 496-500.
[4] Rosengren S, Olofsson AM, von Anddan UH, et al. Leukotrien B4-induced neutrophil-mediated endothelial leakage in vitro and in vivo [J].J Physiol,1991, 71(4):1322-1330.
[5] Carden D, Xiao F, Moak C, et al. Neutrophil elastase promotes lung microvascular injury and proteolysis of endothelial cadherins [J].Am J Physiol, 1998, 275(2Pt2): H385-H392.
[6] Chignard M, Balloy V. Neutrophil recruitment and increased permeability during acute lung injury induced by lipopolysaccharide [J].Am J Physiol 2000, 279(6): L1083-L1090.
[7] Brown MA, Lantz RC, Sobonya R, et al. Aerosolized lipopolysaccharide increase Pulmonary clearance of 99m TcoDTPA in rabbits [J]. Am Rev Respir Dis, 1992, 146(6):1462-1468.
[8] Hirano S. Interaction of rat alveola macrophages with pulmonary epithelia cells following exposure to lipopolysaecharide [J]. Arch Toxicol, 1996,70(34):230-236.
[9] S Wan, JL LeClerc, JL Vincent. Inflammatory response to cardiopulmonary bypass: mechanisms involved and possible therapeutic strategies [J].Chest, 1997, 112(3): 676-692
[10] Asimakopoulos G, Smith PL, Ratnatunga CP, et al. Lung injury and acute respiratory distress syndrome after cardiopulmonary bypass [J].Ann Thorac Surg 1999, 68(3): 1107-1115.
[11] John ML. Acute lung injury and acute respiratory distress syndrome [J]. Crit Care Med, 1998, 19(3):533-536.
[12] Nicholson DW, Ali A, Thornberry NA, et al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis [J]. Nature, 1995, 376(6535):37-43.
[13] Reutershan J, Basit A, Galkina EV, et al. Sequential recruitment of neutrophils into lung and bronchoalveolar lavage fluid in LPS-induced acute lung injury[J]. Am J Physiol Lung Cell Mol Physiol, 2005, 289(5): L807- L815.
[14] Fujishima S, AikawaN. Neutrophil mediated tissue injury and its modulation [J]. Intensive Care Med, 1995,21(3):277-285.
[15] Chow CW, Herrera, Abreu MT, et al. Oxidative stress and acute lung injury [J]. Am J Respir Cell Mol Biol, 2003,29(4):427-431.
[16] William MN. Oxidants/Antioxidants and COPD [J].Chest, 2000, 117(5Suppll): 303-317.
[17] Compton CN, Franko AP, Murray MT, et al. Signaling of apoptotic lung injury by lipid hydroperoxides [J]. J Trauma, 1998,44(5):783-788.
[18] Wang T, Zhang X, Li JJ. The role of NF-kappaB in the regulation of cell stress responses. [J]. Int Immunopharmacol, 2002,2(11): 1509 1520.
[19] Spragg RG.. Acute lung injury in 2003 [J]. Acta Pharmacol Sin, 2003, 24(12):1288.
[20] Doerschuk CM, Mizgerd JP, Kubo H, et al. Adhesion molecules and cellular biomechanical changes in acute lung injury [J].Chest,1999,166(1Suppl):37s-43s.
[21] Fein AM, Calalang-Colucci MG. Acute lung injury and acute respiratory distress syndrome in sepsis and septic shock [J].Crit Care Clin 2000;16(2):289-317.
[22] Hiroshi Kubo, Lori Graham, Nicholas A, et al. Complement fragment-induced release of neutrophils from bone marrow and sequestration within pulmonary capillaries in Rabbits [J].Blood, 1998, 92(1): 283-290.
[23] Xu Xing-xiang, Qian Gui-sheng(徐兴祥,钱桂生). Changes of polymorphonuclear leukocytes sequestration in lungs and influence of anisodamine on it in rats with acute lung injury [J]. Acta Academiae Medicine Militaris Tertiae(第三军医大学学报),2001,23(8):999-1000. (in Chinese)
[24] Lee WL, Downey GP. Neutrophil activation and acute lung injury [J].Curr Opin Crit Care, 2001,7(1): 1-7.
[25] Ware LB, Matthay MA. Medical progress: the acute respiratory distress syndrome [J]. N Engl J Med, 2000, 342:1334-1339.
[26] Donnelly SC, Haslett C. Cellular mechanism of acute lung injury [J].Thorax, 1992, 47 (4): 260-263.
[27] Tsuji C, Shioya S, Hirota Y, et al. Increaced production of nitro tyrosine in lung tissue of rats with radiation induced acute lung injury [J].Am J Physiol lung Cell Mol Physiol, 2000, 278(4): L719-L725.
[28] F Chabot, JA Mitchell, JM Gutteridge, et al. Reactive oxygen species in acute lung injury[J].Eur Respir J, 1998,11(3):745-757.
[29] Costa B, Conti S, Giagnoni G, et al. Therapeutic effect of the endogenous fatty acid amide, palmitoylethanolamide, in rat acute inflammation: inhibition of nitric oxide and cyclo-oxygenase systems [J].Br J Pharmacol, 2002, 137(4):413-420.
[30] Metnitz PG, Battens C, Fischer M, et al. Antioxidant statuts in patients with acute respiratory distress syndrome [J].Intensive Care Med, 1999,25(2): 180-185.
[31] Lenz AG, Jorens PG, Meyer B, et al. Oxidatively modified proteins in bronchoalveolar lavage fluid of patients with ARDS and patients at-risk for ARDS [J]. Eur Respir J, 1999,13(1):169-174.
[1] Jang-Ik Lee, Burckart GJ. Nuclear factor kappa B: important transcription factor and therapeutic target [J]. J Clin Pharmacol, 1998;38(11):981-993.
[2] Baldwin AS Jr. The NF-κB and IκB protein: new discoveries and insights [J]. Annu Rev Immunol, 1996,14:649-683.
[3] Moine P, Mclntyre R, Schwartz MD, et al. NF-kappaB regulatory mechanisms in alveolar macrophages from patients with acute respiratory distress syndrome [J]. Shock, 2000, 13(2):85-91.
[4] Amalich F, Garcia-Palomero E, Lopez J, et al. Predictive value of nuclear factor [kappa]B activity and plasma cytokine levels in patients with sepsis[J]. Infect Immun, 2000, 68(4):1942-1945..
[5] Bohrer H, Qiu F, Zimmerman T, et al. Role of NF-[kappa]B in the mortality of sepsis [J].J Clin Invest, 1997,100(5):972-985.
[6] Schwartz MD, Moore EE, Moore FA, et al. Nuclear factor κB is activated in alveolar macrophages from patients with acute respiratory distress syndrome [J]. Crit Care Med,1996, 24(8): 1285-1292
[7] Blackwell TS, Blackwell TR, Holden EP, et al. In vivo antioxidant treatment suppresses nuclear factor-kappa B activation and neutrophilic lung inflammation [J].J Immunol,1996, 157(4):1630-1637.
[8] Shenkar R, Schwartz MD, Terada LS, et al. Hemorrhage activates NF Kappa B in murine lung mononuclear cells in vivo[J]. Am J Physio, 1996, 270(5 Pt 1):L729-735.
[9] Haddad EB, Salmon M, Koto H, et al. Ozone induction of cytokine induced neutrophil chemoattractant (CINC) and nuclear factor Kappa in rat lung: inhibition by corticosteroids [J]. FIBS Lett, 1996,379(3):265-268.
[10] Tremblay LN, Slutsky AS. Ventilator-induced injury: from barotrauma to biotrauma [J]. Proc Assoc Am Physicians, 1998, 110(6): 482-488.
[11] Yi ES, Remick DG, Lim Y, et al. The intratracheal administration of endotoxin: X. Dexamethasone downregulates neutrophil emigration and cytokine expression in vivo [J]. Inflammation, 1996,20(2): 165-175.
[12] Baeuerle PA, Henkel T. Function and activation of NF-κB in the immune system [J]. Annu Rev Immunol, 1994,12:141-179.
[13] Yum HK, Arcaroli J, Kupfner J, et al Involvement of PI3-K in neutrophil activation and the development of acute lung injury [J]. J Immunol, 2001, 167 (11):6601-6608.
[14] Barnes PJ, Adcock IM. NF-κB: Apivotal role in asthma and a new target for therapy [J].Trends Pharmacol Sci, 1997,18(2):46-50.
[15] Rahman I, MacNee W. Role of transription factors in inflammatory lung diseases [J]. Thorax, 1998,53(7):601-612.
[16] Guo Zhen-hui, Hong Xin, Mao Bao-ling, et al (郭振辉,洪新,毛宝龄,等). Effects of ansodamine on the activation of nuclear factor-kappa B in vitro [J]. Acta Academiae Medicine Militaris Tertiae(第三军医大学学报), 2000,22(6):545-548.
[1] Gardner AM, Lange-Carter CA, Vaillancourt RR, et al. Measuring activation of kinases in mitogen-activated protein kinase regulatory network [J]. Methods Enzymol, 1994,238:258-270.
[2] Nakano H, Shindo M, Sakon S, et al. Differential regulation of IkappaB kinase alpha and beta by two upstream kinases, NF-kappaB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-l.Proc Natl Acad Sci USA, 1998, 95(7):3537-3542.
[3] Baud V, Liu ZG, Bennett B, et al. Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain [J].Genes Dev, 1999,13(10): 1297-1308.
[4] Hale K K, Trollinger D, Rihanek M, et al. Differential expression and activation of p38 mitogen-activated protein kinase alpha, beta, gamma, and beta in inflammatory cell lineages [J]. J Immunol, 1999,162(7):4246-4252.
[5] Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation [J]. Physiol Rev, 2001, 81(2):807-869.
[6] Herlaar E, Z Brown. p38 MAPK signalling cascades in inflammatory disease [J]. Mol Med Today, 1999, 5(10):439-447.
[7] Ono K, Han J. The p38 signal transduction pathway: activation and function [J]. Cell Signal, 2000,12(1):1-13.
[8] Nick JA, Avdi NJ, YoungSK, et al. Selective activation and functional significance of p38alpha mitogen-activated protein kinase in lipopolysaccharide-stimulated neutrophils [J]. J Clin Invest, 1999,103(6): 851-858.
[9] Yan SR, Al-Hertani W, ByersD, et al. Lipopolysaccharide-binding protein and CD14-dependent activation of mitogen-activated protein kinase p38 by lipopolysaccharide in human neutrophilsis associated with priming of respiratory burst [J].Infect Immun, 2002, 70(8): 4068-4074.
[10] Patricia AD, Dahua Z, Elizabeth P, et al. Role of stress-activated mitogen-activated protein kinase (p38) in β2-Integrin-dependent neutrophil adhesion and the adhesion-dependent oxidative burst [J]. J Immunol, 1998, 161(4):1921-1929.
[11] Lee JC, Kumar S, Griswold DE, et al. Inhibition of p38 MAP kinase as a therapeutic strategy [J]. Immuno pharmacology, 47(2-3): 185-201.
[12] Lee J C, Kassis S, Kumar S, et al. p38 mitogen activated protein kinase inhibitor -mechanisms and therapeutic potentials [J]. Pharmacol Ther,1999,82(2-3): 389-397.
[13] Lee JC, Laydon JT, McDonnel, et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis [J]. Nuture,1994, 372(6508): 739-746.
[14] Underwood DC, Osbom RR, Kotzer CJ, et al. SB 239063, a potent p38 MAP kinase inhibitor, reduces inflammatory cytokine production, airways eosinophil infiltration, and persistence [J].J Pharmacol Exp Ther, 2000,293(1):281-288.
[15] Jerry AN, Scott KY, Kevin KB, et al. Role of p38 Mitogen-Activated Protein Kinase in a Murine Model of Pulmonary Inflammation [J].J Immunol, 2000,164(4): 2151-2159.
[16] Nick JA, Avdi NJ, Young SK, et al. An intracellular signaling pathway linhing lipopolysaccaride stimulation to cellular responses of the human neitrophil: the p38 MAP kinase cascade and its functional significance [J]. Chest,1999,116 (lSuppl): 54S-55S.
[17] Foey AD, Parry SL, Williams LM, et al. Regulation of monocyte IL-10 synthesis by endogenous IL-1 and TNF-α: role of the p38 and p42/44 mitogen-activated protein kinases [J]. J Immunol, 1998,160(2):920-928.
[18] Manthey CL, Wang SW, Kinney SD, et al. SB 202190, a selective inhibitor of p38 mitogen- activated protein kinase, is a powerful regulator to LPS-induced mRNAs in monocytes [J]. J Leuko Biol,1998,64(3):409-417.
[19] Chen XL, Xia ZF, Ben DF, et al. Role of p38 mitogen-activated protein kinase in lung injury after burn trauma. [J].Shock, 2003,19(5):475-479.
[20] Han J, Lee JD, Bibbs L, et al. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science, 1994,265 (5173): 808-811.
[21] Madhani HD, Fink GR. The riddle of MAP kinase signaling specificity [J].Trends Genet, 1998,14(4):151-155.
[22] Jiang Y, Chen C, Li Z, et al. Characterization of the structure and function of a new mitogen-activated protein kinase (p38|3) [J]. J Biol Chem, 1996, 271 (30): 17920-17926.
[23] Han J, Jiang Y, Li Z, et al. Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation [J].Nature, 1997, 386(6622): 296-299.
[24] Bonizzi G, Karin M. The two NF-kB activation pathways and their role in innate and adaptive immunity [J].Trends Immunol,2004, 25(6):280-288.
[25] ChenCC,WandJK. p38 but not p44/42 mitogen-activated protein kinase is required for nitric oxide synthase induction mediated by Hpopolysaccharide in RAW 264.7 macrophages [J]. Mol Pharmacol, 1999,55(3):481-488.
[26] Liu HS, Pan CE, Liu QG, et al. Effect of NF-kappaB and p38 MAPK in activated monocytes/macrophages on pro-inflammatory cytokines of rats with acute pancreatitis [J].World J Gastroenterol, 2003,9(11):2513-2518.
[27] Murr MM, Yang J, Fier A, et al. Regulation of Kupffer cell TNF gene expression during experimental acute pancreatitis: the role of p38-MAPK, ERK1/2, SAPK /JNK, and NF-kappaB [J]. J Gastrointest Surg, 2003,
7(1):20-25.
[28] Tamura DY, Moore EE, Johnson JL, et al. p38 mitogen-activated protein kinase inhibition attenuates intercellular adhesion molecule-1 up-regulation on human pulmonary microvascular endothelial cells [J]. Surgery, 1998, 124(2):403-408.
[29] Zu YL, Qi J, Gilchrist A, et al. p38 mitogen-activated protein kinase activation is required for human neutrophil function triggered by TNF-alpha or FMLP stimulation [J]. J Immunol, 1998,160(4): 1982-1989.
[30] El Benna J, Han J, Park JW, et al. Activation of p38 in stimulated human neutrophils: phosphorylation of the oxidase component p47phox by p38 and ERK but not by JNK [J]. Arch Biochem Biophys, 1996,334 (2):395-400.
[31] Yang J, Murphy C, Denham W, et al. Evidence of a central role for p38 map kinase induction of tumor necrosis factor alpha in pancreatitis-associated pulmonary injury [J]. Surgery, 1999, 126(2):216-222.
[1] Kolch W. The regulation of the Ras/Raf/MEK/ERK pathway by protein interactions [J]. Biochem J,2000,351 (Pt 2):289-305.
[2] Yao Yong-ming, Cheng Ming-hua, Yao Sheng, et al(姚咏明,程明华,姚胜,等). Effects of extracellular signal-regulated kinase inhibition by AG126 on tissue tumor necrosis factor-α expression and multiple organ dysfunction in rats with postburn Staphylococcus aureus sepsis[J]. Chinese Journal of Surgery(中华外科杂志), 2004 (7):391-395(in Chinese).
[3] Guha M, O'Connell MA, Pawlinski R, et al. Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human monocytic cells mediates tissue factor and tumor necrosis factor alpha expression by inducing Elk-1 phosphorylation and Egr-1 expression [J].Blood, 2001,98(5): 1429-1439.
[4] Kim SH, Kim J, Sharma RP. Inhibition of p38 and ERK MAP kinases blocks endotoxin-induced nitric oxide production and differentially modulates cytokine expression [J]. Pharmacol Res,2004,49(5):433-439.
[5] Zhang Yu, Jiang Jian-xin, Wang Zheng-guo, et al(张宇,蒋建新,王正国,等).A study on activation and role of ERK1/2 signal cascade in LPS-induced response of mice Kupffer cells [J]. Chinese Journal of Traumatology(中华创 伤杂志), 2002,18 (6):364-366(in Chinese).
[6] Weinstein SL, Gold MR, DeFranco AL. Bacterial lipopolysaccharide stimulates protein tyrosine phosphorylation in macrophages. Proc Natl Acad Sci USA, 1991, 88(10): 4148-4152.
[7] Geppert TD, Whitehurst CE, Thompson P, et al. Lipopolysaccharide signals activation of tumor necrosis factor biosynthesis through the Ras/Raf-1/ MEK/ MAPK pathway. Mol Med, 1994, l(l):93-103.
[8] Jacrar D, Kuebler JF, Rue LW, et al. Alveolar macmphage activation after trauma-hemorrhage and sepsis is dependent on NF-kappaB and MAPK/ERK mechanisms [J].Am J Physiol Lung Mol Physiol, 2002,283(4):L799- L 805.
[9] Lahti A, Lahde M, Kankaanranta H, et al. Inhibition of extracellular signal -regulated kinase suppresses endotoxin-induced nitric oxide synthesis in mouse macrophages and in human colon epithelial cells [J]. J Pharmacol Exp Ther, 2000,294(3):1188-1194.
[10] Carter AB, Monick MM, Hunninghake GW. Both Erk and p38 kinases are necessary for cytokine gene transcription [J]. Am J Respir Cell Mol Biol, 1999, 20(4):751-758.
[11] Capodici C, Pillinger MH, Han G, et al. Integrin-dependent homotypic adhesion of neutrophils arachidonic acid activates Raf-1/Mek/Erk via a 5-lipoxygenase- dependent pathway [J]. J Clin Invest,1998,102(l):165-175.
[12] Zouki C, Zhang SL, Chan JS, et al. Peroxynitrite induces integrin-dependent adhesion of human neutrophils to endothelial cells via activation of the Raf-1 /MEK/Erk pathway [J]. FASEB J, 2001,15(l):25-27.
[1] Yaffe MB ,Fink ME Cellular signaling in critical care Putting the pieces together [J]. Crit Care Med, 2000, 28 (Suppl):N1-N2.
[2] Ip YT, Davis RJ. Signal transduction by the c-Jun N-terminal kinase (JNK) from inflammation to development [J]. Curr Opin Cell Biol, 1998, 10(2): 205-219.
[3] Eynott PR, Nath P, Leung SY, et al. Allergen induced inflammation and airway epithelial and smooth muscle cell proliferation: role of c-Jun N-terminal kinase [J].Br J Pharmacol, 2003, 140 (8):1373-1380.
[4] Paola DC, Donatella S, Giuseppe S, et al. Activation of Jun N-terminal Kinase/ Stress-activated Protein Kinase Pathway by Tumor Necrosis Factor-α Leads to Intercellular Adhesion Molecule-1 Expression [J].J Biol Chem, 1999, 274(41): 28978-28982.
[5] Tetsuya M, Akio M, Kenji S, et al. JNK-interacting protein 3 associates with Toll-like receptor 4 and is involved in LPS-mediated JNK activation [J]. EMBO J, 2003, 22(17):4455-4464.
[6] Hambleton J, Weinstein SL, Lem L, et al. Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide-stimulated macrophages. Proc Natl Acad Sci USA, 1996, 93(7):2774-2778.
[7] Davis RJ. Signal transduction by the JNK group of MAP kinases [J]. Cell, 2000, 103 (2) :239-252.
[8] Dong C, Yang DD, Wysk M, et al. Defective T cell differentiation in the absence of Jnkl [J]. Science,1998,282(5396):2092-2095.
[9] Zhou X, Gao XP, Fan J et al. LPS activation of Toll-like receptor 4 signals CD11b/CD18 expression in neutrophils [J].Am J Physiol Lung Cell Mol Physiol, 2005, 288 (4): L655-L662.
[10] Hallsworth MP, Moir LM, Lai D, et al. Inhibitors of mitogen activated protein kinases differentially regulate eosinophil activating cytokine release from human airway smooth muscle [J].Am J Respir Crit Care Med, 2001,164(4) :688-697.
[11] Zhonghong G, ShaAvhree YB, Lisa D, et al. Both p38αMAPK and JNK/SAPK pathways are important for Induction of nitric-oxide synthase by interleukin-1 βin rat glomerular mesangial cells [J]. J Biol Chem,1999 274(51):36200-36206.
[2] Sun Geng-yun, Xiao Zhen-liang, Fang Chuan-biao(孙耕耘,肖贞良,方传彪).Effects of anisodamine on the change of cytoskeleton of rat pulmonary microvascular endothelial cells induced by endotoxin[J]. Chinese Pharmacological Bulletin (中国药理学通报),2001,17(2):197-199. (in Chinese).
[3] Han XY, Liu H, Liu CH, et al. Synthesis of the optical isomers of a new anticholinergic drug, penehyclidine hydrochloride (8018) [J]. Bioorg Med Chem Lett, 2005,15(8):1979-1982.
[4] Han Ji-huan, Chao Feng-sheng, Wang Yi-tang, et al (韩继媛,曹锋生,王一镗,等). Application of penehyclidine hydrochloride in clinic [J]. Chinese Journal of Emergency Medicine (中华急诊医学杂志), 2005, 14(2): 173-174(in Chinese).
[5] Yang J, Li W, Duan M, et al. Large dose ketamine inhibits lipopolysaccharide-induced acute lung injury in rats [J]. Inflamm Res, 2005, 54(3): 133-137.
[6] Feng Xin-wei(冯新为). Pathophysiology (病理生理学) [M], Beijing: People's Medical Publishing House,1993.269-273.
[7] Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial [J]. JAMA, 1998,280(2): 159-65.
[8] EI-Khatib MF, Jamaleddine GW. A new oxygenation index for reflecting intrapulmonary shunting in patients undergoing open-heart surgery [J]. Chest, 2004, 125(2):592-596.
[9] Jian Wen, Qi Hao-wen, Li Zhi-chao(简文,戚好文,李志超). Therapeutic effect of anisodamine, ANP and CGRP on oleic acid induced acute lung injury in rabbits [J]. Journal of The Fourth Military Medical University(第四军医大学学报), 2002, 23(1):19-22(in Chinese).
[10] Lee WL, Downey GE Neutrophil activation and acute lung injury [J]. Curr Opin Crit Care, 2001,7(1): 1-7.
[11] Suttorp N, Nolte A, Wilke A, et al. Human neutrophil elastase increases permeability of cultured pulmonary endothelial cell monolayers [J]. Int J Microcirc Clin Exp, 1993, 13(3):187-203.
[12] Novick RJ, Gehman KE, Ali IS, et al Lung Preservation: The Importance of Endothelial and Alveolar Type II Cell Integrity Richard [J]. Ann Thorac Surg, 1996, 62(1): 302-314.
[13] Silliman CC, Kelher M. The role of endothelial activation in the pathogenesis of transfusion-related acute lung injury [J]. Transfusion, 2005, 45 (2 Suppl):109S-116S.
[14] Ulevitch RJ, Tobias PS. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin [J]. Annu Rev Immunol, 1995,13: 437-457.
[15] Pugin J, Schurer MC, Leturcq D, et al. Lipopolysechride-binding protein and soluble CD14 [J] .Proc Natl Acad Sci USA, 1993,90(7):2744-2748.
[16] Arditi M, Zhou J, Tores M, et al. Lipopolysaecharide stimulates the tyrosine phosphorylation of mitogen-activated protein kinases p44, p42, and p41 in vascular endothelial cells I a soluble CD14-dependent marmer[J].J Immunol, 1995, 155 (8):3994-4003.
[17] Schumann RR, pfeil D, Lamping N, et al. Lipopolysaecharide induces the rapid tyrosine phosphorylation of the mitogen-activated protein kinases erk-1 and p38 in cultured human vascular endothelial cells requiring the presence of soluble CD14 [J].Blood, 1996, 87(7):2805-2814
[18] Han J, Lee .JD, Bibbs L, et al. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells [J].Science, 1994,265(5173): 808-811.
[19] Goeckeler ZM, Wysolmerski RB. Myosin light chain kinase-regulated endothelial cell contraction: the relationship between isometric tension, actin polymerization, and myosin phosphorylation [J]. J Cell Biol, 1995,130 (3): 613-627.
[20] Garcia JG, Schaphorst KM. Regulation of endothelial cell gap formation and paracellular permeability [J]. J Invest Med, 1995, 43(2): 117-126.
[21] Banneman DD, Goldblum SE. Endotoxin induces endothelial barrier dysfunction through protein tyrosine phosphorylation [J]. Am J Physiol, 1997, 273 (1pt1): L217-L226.
[22] Abraham E, Carmody A, Shenkar R, et al. Neutrophils as early immunologic effectors in hemorrhage or endotoxemia-induced acute lung injury [J].Am Physiol Lung Cell Mol Physiol, 2000, 279(6):L1137-L1145.
[23] Chignard M, Balloy V. Neutrophil recruitment and increased permeability during acute lung injury induced by lipopolysaccharide [J]. Am J Physiol, 2000, 279(6): L1083-L1090.
[24] Mason RJ, Walker SR, Shields BA, et al. Identification of rat alveola type Ⅱ epithelial cells with a tannic acid and polychrome stain. [J].Am Rev Respir Dis, 1985,131 (5):786—788.
[25] Brown MA, Lantz RC, Sobonya R, et al. Aerosolized lipopolysaccharide increase Pulmonary clearance of 99m Tc-DTPA in rabbits [J].Am Rev Respir Dis, 1992,146(6): 1462-1468.
[26] Hirano S. Interaction of rat alveola macrophages with pulmonary epithelia cells following exposure to lipopolysaccharide [J]. Arch Toxicol, 1996,70(34): 230-236.
[27] Sunil VR, Connor AJ, Guo Y, et al. Activation of type Ⅱ alveolar epithelial cells during acute endotoxemia [J]. Am J Physiol Lung Cell Mol Physiol, 2002, 282 (4):L872-880.
[28] Rose F, Guthmann B, Tenenbaum T, et al. Apical, but not basolateral endotoxin preincubation protects alveolar epithelial cells against hydrogen peroxide-induced loss of barrier function: the role of nitric oxide synthesis[J]. J Immunol, 2002, 169(3):1474-1481.
[29] Fan J, Ye RD, Malik AB. Transcriptional mechanisms of acute lung injury [J]. Am J Physiol Lung Cell Mol Physiol, 2001,281(5):L1037-L1050.
[30] Li Yong-wang;Zhang De-ming;Qian Gui-sheng, et al(李永旺,张德明,钱桂生,等). TLR4 expression in the activation of alveolar type Ⅱ cells induced by lipopolysaccharide [J]. Acta Academiae Medicinae Militaris Tertiae (第三军医在学学报),2004,26(10):863-866 (in Chinese).
[31] Schulz C, Farkas L, Wolf K, et al. Differences in LPS induced activation of bronchial epithelial cells(BEAS 2B) and type Ⅱ like pneumocytes (A 549)[J]. Scand J Immunol, 2002, 56(3):294-302.
[32] Toga H, Tobe T, Ueda Y, et al. Inducible nitric oxide synthase expression and nuclear factor kappaB activation in alveolar type cells in lung injury [J]. Exp Lung Res, 2001,27(6):485-504.
[33] Li XY, Donaldson K, MacNee W. Lipopolysaccharide induced alveolar epithelial permeability: the role of nitric oxide [J].Am J Respir Crit Care Med, 1998, 157(4Pt1):1027-1033.
[34] Emura M. Stem cells of the respiratory epithelium and their in vitro cultivation. In Vitro Cell [J].Dev Biol, 1997, 33(1):314.
[35] Uhal BD. Cell cycle kinetics in the alveolar epithelium [J].Am J Physiol, 1997, 272 (6Pt1) : L1031-L1045.
[36] Kinnard W, Tuder R, Papst P, et al. Regulation of alveolar type cell differentiation and proliferation in adult rat lung explants [J]. Am J Respir Cell Mol Biol, 1994, 11(4):416-425.
[37] Holm B, Matalon S, Finkelstein J, et al. Type pneumoeyte changes during hyperoxic lung injury and recovery [J]. Appl Physiol, 1988,65(6):2673-2678.
[38] Lewis JF, Jobe AH. Surfactant and the adult respiratory distress syndrome [J]. Am Rev Respir Dis,1993,147(1):218-233.
[39] Yang Qiu, Cui He-qin, Li Ya-ping, et al(杨秋,崔和勤,李亚平,等). Influence of anisodamine (654-2) on plasma fibronectin content in rabbits with pulmonary edema [J]. Chinese pharmacological bulletin(中国药理学通报),1996,12(6): 557-559(in Chinese).
[40] Wright JR. Clearance and recycling of pulmonary surfaetant [J].Am J Physiol, 1990, 259 (2 Pt1):L1-L12.
[41] Jeffrey G, Ramasubbareddy D, Anil B Mukherfee. Surfactant-producing rabbit pulmonare alveolar type Ⅱ cells synthesize and secret an antiinflammatory protein, uteroglobin [J].Binche Biophy Res Commu, 1992,189(2):662-669.
[1] Abraham E, Carmody A, Shenkar R, et al. Neutrophils as early immunologic effectors in hemorrhage or endotoxemia-induced acute lung injury [J].Am Physiol Lung Cell Mol Physiol, 2000, 279(6):L1137-L1145.
[2] Abraham E. Neutrophils and acute lung injury [J]. Clin Care Med, 2003, 31(4 Suppl):S195-S 199.
[3] Gibbs LS, Lai L, Malik AB. Tumor necrosis factor enhances the neutrophil-dependent increase in endothelial permeability [J]. J Cell Physiol, 1990, 145 (3): 496-500.
[4] Rosengren S, Olofsson AM, von Anddan UH, et al. Leukotrien B4-induced neutrophil-mediated endothelial leakage in vitro and in vivo [J].J Physiol,1991, 71(4):1322-1330.
[5] Carden D, Xiao F, Moak C, et al. Neutrophil elastase promotes lung microvascular injury and proteolysis of endothelial cadherins [J].Am J Physiol, 1998, 275(2Pt2): H385-H392.
[6] Chignard M, Balloy V. Neutrophil recruitment and increased permeability during acute lung injury induced by lipopolysaccharide [J].Am J Physiol 2000, 279(6): L1083-L1090.
[7] Brown MA, Lantz RC, Sobonya R, et al. Aerosolized lipopolysaccharide increase Pulmonary clearance of 99m TcoDTPA in rabbits [J]. Am Rev Respir Dis, 1992, 146(6):1462-1468.
[8] Hirano S. Interaction of rat alveola macrophages with pulmonary epithelia cells following exposure to lipopolysaecharide [J]. Arch Toxicol, 1996,70(34):230-236.
[9] S Wan, JL LeClerc, JL Vincent. Inflammatory response to cardiopulmonary bypass: mechanisms involved and possible therapeutic strategies [J].Chest, 1997, 112(3): 676-692
[10] Asimakopoulos G, Smith PL, Ratnatunga CP, et al. Lung injury and acute respiratory distress syndrome after cardiopulmonary bypass [J].Ann Thorac Surg 1999, 68(3): 1107-1115.
[11] John ML. Acute lung injury and acute respiratory distress syndrome [J]. Crit Care Med, 1998, 19(3):533-536.
[12] Nicholson DW, Ali A, Thornberry NA, et al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis [J]. Nature, 1995, 376(6535):37-43.
[13] Reutershan J, Basit A, Galkina EV, et al. Sequential recruitment of neutrophils into lung and bronchoalveolar lavage fluid in LPS-induced acute lung injury[J]. Am J Physiol Lung Cell Mol Physiol, 2005, 289(5): L807- L815.
[14] Fujishima S, AikawaN. Neutrophil mediated tissue injury and its modulation [J]. Intensive Care Med, 1995,21(3):277-285.
[15] Chow CW, Herrera, Abreu MT, et al. Oxidative stress and acute lung injury [J]. Am J Respir Cell Mol Biol, 2003,29(4):427-431.
[16] William MN. Oxidants/Antioxidants and COPD [J].Chest, 2000, 117(5Suppll): 303-317.
[17] Compton CN, Franko AP, Murray MT, et al. Signaling of apoptotic lung injury by lipid hydroperoxides [J]. J Trauma, 1998,44(5):783-788.
[18] Wang T, Zhang X, Li JJ. The role of NF-kappaB in the regulation of cell stress responses. [J]. Int Immunopharmacol, 2002,2(11): 1509 1520.
[19] Spragg RG.. Acute lung injury in 2003 [J]. Acta Pharmacol Sin, 2003, 24(12):1288.
[20] Doerschuk CM, Mizgerd JP, Kubo H, et al. Adhesion molecules and cellular biomechanical changes in acute lung injury [J].Chest,1999,166(1Suppl):37s-43s.
[21] Fein AM, Calalang-Colucci MG. Acute lung injury and acute respiratory distress syndrome in sepsis and septic shock [J].Crit Care Clin 2000;16(2):289-317.
[22] Hiroshi Kubo, Lori Graham, Nicholas A, et al. Complement fragment-induced release of neutrophils from bone marrow and sequestration within pulmonary capillaries in Rabbits [J].Blood, 1998, 92(1): 283-290.
[23] Xu Xing-xiang, Qian Gui-sheng(徐兴祥,钱桂生). Changes of polymorphonuclear leukocytes sequestration in lungs and influence of anisodamine on it in rats with acute lung injury [J]. Acta Academiae Medicine Militaris Tertiae(第三军医大学学报),2001,23(8):999-1000. (in Chinese)
[24] Lee WL, Downey GP. Neutrophil activation and acute lung injury [J].Curr Opin Crit Care, 2001,7(1): 1-7.
[25] Ware LB, Matthay MA. Medical progress: the acute respiratory distress syndrome [J]. N Engl J Med, 2000, 342:1334-1339.
[26] Donnelly SC, Haslett C. Cellular mechanism of acute lung injury [J].Thorax, 1992, 47 (4): 260-263.
[27] Tsuji C, Shioya S, Hirota Y, et al. Increaced production of nitro tyrosine in lung tissue of rats with radiation induced acute lung injury [J].Am J Physiol lung Cell Mol Physiol, 2000, 278(4): L719-L725.
[28] F Chabot, JA Mitchell, JM Gutteridge, et al. Reactive oxygen species in acute lung injury[J].Eur Respir J, 1998,11(3):745-757.
[29] Costa B, Conti S, Giagnoni G, et al. Therapeutic effect of the endogenous fatty acid amide, palmitoylethanolamide, in rat acute inflammation: inhibition of nitric oxide and cyclo-oxygenase systems [J].Br J Pharmacol, 2002, 137(4):413-420.
[30] Metnitz PG, Battens C, Fischer M, et al. Antioxidant statuts in patients with acute respiratory distress syndrome [J].Intensive Care Med, 1999,25(2): 180-185.
[31] Lenz AG, Jorens PG, Meyer B, et al. Oxidatively modified proteins in bronchoalveolar lavage fluid of patients with ARDS and patients at-risk for ARDS [J]. Eur Respir J, 1999,13(1):169-174.
[1] Jang-Ik Lee, Burckart GJ. Nuclear factor kappa B: important transcription factor and therapeutic target [J]. J Clin Pharmacol, 1998;38(11):981-993.
[2] Baldwin AS Jr. The NF-κB and IκB protein: new discoveries and insights [J]. Annu Rev Immunol, 1996,14:649-683.
[3] Moine P, Mclntyre R, Schwartz MD, et al. NF-kappaB regulatory mechanisms in alveolar macrophages from patients with acute respiratory distress syndrome [J]. Shock, 2000, 13(2):85-91.
[4] Amalich F, Garcia-Palomero E, Lopez J, et al. Predictive value of nuclear factor [kappa]B activity and plasma cytokine levels in patients with sepsis[J]. Infect Immun, 2000, 68(4):1942-1945..
[5] Bohrer H, Qiu F, Zimmerman T, et al. Role of NF-[kappa]B in the mortality of sepsis [J].J Clin Invest, 1997,100(5):972-985.
[6] Schwartz MD, Moore EE, Moore FA, et al. Nuclear factor κB is activated in alveolar macrophages from patients with acute respiratory distress syndrome [J]. Crit Care Med,1996, 24(8): 1285-1292
[7] Blackwell TS, Blackwell TR, Holden EP, et al. In vivo antioxidant treatment suppresses nuclear factor-kappa B activation and neutrophilic lung inflammation [J].J Immunol,1996, 157(4):1630-1637.
[8] Shenkar R, Schwartz MD, Terada LS, et al. Hemorrhage activates NF Kappa B in murine lung mononuclear cells in vivo[J]. Am J Physio, 1996, 270(5 Pt 1):L729-735.
[9] Haddad EB, Salmon M, Koto H, et al. Ozone induction of cytokine induced neutrophil chemoattractant (CINC) and nuclear factor Kappa in rat lung: inhibition by corticosteroids [J]. FIBS Lett, 1996,379(3):265-268.
[10] Tremblay LN, Slutsky AS. Ventilator-induced injury: from barotrauma to biotrauma [J]. Proc Assoc Am Physicians, 1998, 110(6): 482-488.
[11] Yi ES, Remick DG, Lim Y, et al. The intratracheal administration of endotoxin: X. Dexamethasone downregulates neutrophil emigration and cytokine expression in vivo [J]. Inflammation, 1996,20(2): 165-175.
[12] Baeuerle PA, Henkel T. Function and activation of NF-κB in the immune system [J]. Annu Rev Immunol, 1994,12:141-179.
[13] Yum HK, Arcaroli J, Kupfner J, et al Involvement of PI3-K in neutrophil activation and the development of acute lung injury [J]. J Immunol, 2001, 167 (11):6601-6608.
[14] Barnes PJ, Adcock IM. NF-κB: Apivotal role in asthma and a new target for therapy [J].Trends Pharmacol Sci, 1997,18(2):46-50.
[15] Rahman I, MacNee W. Role of transription factors in inflammatory lung diseases [J]. Thorax, 1998,53(7):601-612.
[16] Guo Zhen-hui, Hong Xin, Mao Bao-ling, et al (郭振辉,洪新,毛宝龄,等). Effects of ansodamine on the activation of nuclear factor-kappa B in vitro [J]. Acta Academiae Medicine Militaris Tertiae(第三军医大学学报), 2000,22(6):545-548.
[1] Gardner AM, Lange-Carter CA, Vaillancourt RR, et al. Measuring activation of kinases in mitogen-activated protein kinase regulatory network [J]. Methods Enzymol, 1994,238:258-270.
[2] Nakano H, Shindo M, Sakon S, et al. Differential regulation of IkappaB kinase alpha and beta by two upstream kinases, NF-kappaB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-l.Proc Natl Acad Sci USA, 1998, 95(7):3537-3542.
[3] Baud V, Liu ZG, Bennett B, et al. Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain [J].Genes Dev, 1999,13(10): 1297-1308.
[4] Hale K K, Trollinger D, Rihanek M, et al. Differential expression and activation of p38 mitogen-activated protein kinase alpha, beta, gamma, and beta in inflammatory cell lineages [J]. J Immunol, 1999,162(7):4246-4252.
[5] Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation [J]. Physiol Rev, 2001, 81(2):807-869.
[6] Herlaar E, Z Brown. p38 MAPK signalling cascades in inflammatory disease [J]. Mol Med Today, 1999, 5(10):439-447.
[7] Ono K, Han J. The p38 signal transduction pathway: activation and function [J]. Cell Signal, 2000,12(1):1-13.
[8] Nick JA, Avdi NJ, YoungSK, et al. Selective activation and functional significance of p38alpha mitogen-activated protein kinase in lipopolysaccharide-stimulated neutrophils [J]. J Clin Invest, 1999,103(6): 851-858.
[9] Yan SR, Al-Hertani W, ByersD, et al. Lipopolysaccharide-binding protein and CD14-dependent activation of mitogen-activated protein kinase p38 by lipopolysaccharide in human neutrophilsis associated with priming of respiratory burst [J].Infect Immun, 2002, 70(8): 4068-4074.
[10] Patricia AD, Dahua Z, Elizabeth P, et al. Role of stress-activated mitogen-activated protein kinase (p38) in β2-Integrin-dependent neutrophil adhesion and the adhesion-dependent oxidative burst [J]. J Immunol, 1998, 161(4):1921-1929.
[11] Lee JC, Kumar S, Griswold DE, et al. Inhibition of p38 MAP kinase as a therapeutic strategy [J]. Immuno pharmacology, 47(2-3): 185-201.
[12] Lee J C, Kassis S, Kumar S, et al. p38 mitogen activated protein kinase inhibitor -mechanisms and therapeutic potentials [J]. Pharmacol Ther,1999,82(2-3): 389-397.
[13] Lee JC, Laydon JT, McDonnel, et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis [J]. Nuture,1994, 372(6508): 739-746.
[14] Underwood DC, Osbom RR, Kotzer CJ, et al. SB 239063, a potent p38 MAP kinase inhibitor, reduces inflammatory cytokine production, airways eosinophil infiltration, and persistence [J].J Pharmacol Exp Ther, 2000,293(1):281-288.
[15] Jerry AN, Scott KY, Kevin KB, et al. Role of p38 Mitogen-Activated Protein Kinase in a Murine Model of Pulmonary Inflammation [J].J Immunol, 2000,164(4): 2151-2159.
[16] Nick JA, Avdi NJ, Young SK, et al. An intracellular signaling pathway linhing lipopolysaccaride stimulation to cellular responses of the human neitrophil: the p38 MAP kinase cascade and its functional significance [J]. Chest,1999,116 (lSuppl): 54S-55S.
[17] Foey AD, Parry SL, Williams LM, et al. Regulation of monocyte IL-10 synthesis by endogenous IL-1 and TNF-α: role of the p38 and p42/44 mitogen-activated protein kinases [J]. J Immunol, 1998,160(2):920-928.
[18] Manthey CL, Wang SW, Kinney SD, et al. SB 202190, a selective inhibitor of p38 mitogen- activated protein kinase, is a powerful regulator to LPS-induced mRNAs in monocytes [J]. J Leuko Biol,1998,64(3):409-417.
[19] Chen XL, Xia ZF, Ben DF, et al. Role of p38 mitogen-activated protein kinase in lung injury after burn trauma. [J].Shock, 2003,19(5):475-479.
[20] Han J, Lee JD, Bibbs L, et al. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science, 1994,265 (5173): 808-811.
[21] Madhani HD, Fink GR. The riddle of MAP kinase signaling specificity [J].Trends Genet, 1998,14(4):151-155.
[22] Jiang Y, Chen C, Li Z, et al. Characterization of the structure and function of a new mitogen-activated protein kinase (p38|3) [J]. J Biol Chem, 1996, 271 (30): 17920-17926.
[23] Han J, Jiang Y, Li Z, et al. Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation [J].Nature, 1997, 386(6622): 296-299.
[24] Bonizzi G, Karin M. The two NF-kB activation pathways and their role in innate and adaptive immunity [J].Trends Immunol,2004, 25(6):280-288.
[25] ChenCC,WandJK. p38 but not p44/42 mitogen-activated protein kinase is required for nitric oxide synthase induction mediated by Hpopolysaccharide in RAW 264.7 macrophages [J]. Mol Pharmacol, 1999,55(3):481-488.
[26] Liu HS, Pan CE, Liu QG, et al. Effect of NF-kappaB and p38 MAPK in activated monocytes/macrophages on pro-inflammatory cytokines of rats with acute pancreatitis [J].World J Gastroenterol, 2003,9(11):2513-2518.
[27] Murr MM, Yang J, Fier A, et al. Regulation of Kupffer cell TNF gene expression during experimental acute pancreatitis: the role of p38-MAPK, ERK1/2, SAPK /JNK, and NF-kappaB [J]. J Gastrointest Surg, 2003,
7(1):20-25.
[28] Tamura DY, Moore EE, Johnson JL, et al. p38 mitogen-activated protein kinase inhibition attenuates intercellular adhesion molecule-1 up-regulation on human pulmonary microvascular endothelial cells [J]. Surgery, 1998, 124(2):403-408.
[29] Zu YL, Qi J, Gilchrist A, et al. p38 mitogen-activated protein kinase activation is required for human neutrophil function triggered by TNF-alpha or FMLP stimulation [J]. J Immunol, 1998,160(4): 1982-1989.
[30] El Benna J, Han J, Park JW, et al. Activation of p38 in stimulated human neutrophils: phosphorylation of the oxidase component p47phox by p38 and ERK but not by JNK [J]. Arch Biochem Biophys, 1996,334 (2):395-400.
[31] Yang J, Murphy C, Denham W, et al. Evidence of a central role for p38 map kinase induction of tumor necrosis factor alpha in pancreatitis-associated pulmonary injury [J]. Surgery, 1999, 126(2):216-222.
[1] Kolch W. The regulation of the Ras/Raf/MEK/ERK pathway by protein interactions [J]. Biochem J,2000,351 (Pt 2):289-305.
[2] Yao Yong-ming, Cheng Ming-hua, Yao Sheng, et al(姚咏明,程明华,姚胜,等). Effects of extracellular signal-regulated kinase inhibition by AG126 on tissue tumor necrosis factor-α expression and multiple organ dysfunction in rats with postburn Staphylococcus aureus sepsis[J]. Chinese Journal of Surgery(中华外科杂志), 2004 (7):391-395(in Chinese).
[3] Guha M, O'Connell MA, Pawlinski R, et al. Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human monocytic cells mediates tissue factor and tumor necrosis factor alpha expression by inducing Elk-1 phosphorylation and Egr-1 expression [J].Blood, 2001,98(5): 1429-1439.
[4] Kim SH, Kim J, Sharma RP. Inhibition of p38 and ERK MAP kinases blocks endotoxin-induced nitric oxide production and differentially modulates cytokine expression [J]. Pharmacol Res,2004,49(5):433-439.
[5] Zhang Yu, Jiang Jian-xin, Wang Zheng-guo, et al(张宇,蒋建新,王正国,等).A study on activation and role of ERK1/2 signal cascade in LPS-induced response of mice Kupffer cells [J]. Chinese Journal of Traumatology(中华创 伤杂志), 2002,18 (6):364-366(in Chinese).
[6] Weinstein SL, Gold MR, DeFranco AL. Bacterial lipopolysaccharide stimulates protein tyrosine phosphorylation in macrophages. Proc Natl Acad Sci USA, 1991, 88(10): 4148-4152.
[7] Geppert TD, Whitehurst CE, Thompson P, et al. Lipopolysaccharide signals activation of tumor necrosis factor biosynthesis through the Ras/Raf-1/ MEK/ MAPK pathway. Mol Med, 1994, l(l):93-103.
[8] Jacrar D, Kuebler JF, Rue LW, et al. Alveolar macmphage activation after trauma-hemorrhage and sepsis is dependent on NF-kappaB and MAPK/ERK mechanisms [J].Am J Physiol Lung Mol Physiol, 2002,283(4):L799- L 805.
[9] Lahti A, Lahde M, Kankaanranta H, et al. Inhibition of extracellular signal -regulated kinase suppresses endotoxin-induced nitric oxide synthesis in mouse macrophages and in human colon epithelial cells [J]. J Pharmacol Exp Ther, 2000,294(3):1188-1194.
[10] Carter AB, Monick MM, Hunninghake GW. Both Erk and p38 kinases are necessary for cytokine gene transcription [J]. Am J Respir Cell Mol Biol, 1999, 20(4):751-758.
[11] Capodici C, Pillinger MH, Han G, et al. Integrin-dependent homotypic adhesion of neutrophils arachidonic acid activates Raf-1/Mek/Erk via a 5-lipoxygenase- dependent pathway [J]. J Clin Invest,1998,102(l):165-175.
[12] Zouki C, Zhang SL, Chan JS, et al. Peroxynitrite induces integrin-dependent adhesion of human neutrophils to endothelial cells via activation of the Raf-1 /MEK/Erk pathway [J]. FASEB J, 2001,15(l):25-27.
[1] Yaffe MB ,Fink ME Cellular signaling in critical care Putting the pieces together [J]. Crit Care Med, 2000, 28 (Suppl):N1-N2.
[2] Ip YT, Davis RJ. Signal transduction by the c-Jun N-terminal kinase (JNK) from inflammation to development [J]. Curr Opin Cell Biol, 1998, 10(2): 205-219.
[3] Eynott PR, Nath P, Leung SY, et al. Allergen induced inflammation and airway epithelial and smooth muscle cell proliferation: role of c-Jun N-terminal kinase [J].Br J Pharmacol, 2003, 140 (8):1373-1380.
[4] Paola DC, Donatella S, Giuseppe S, et al. Activation of Jun N-terminal Kinase/ Stress-activated Protein Kinase Pathway by Tumor Necrosis Factor-α Leads to Intercellular Adhesion Molecule-1 Expression [J].J Biol Chem, 1999, 274(41): 28978-28982.
[5] Tetsuya M, Akio M, Kenji S, et al. JNK-interacting protein 3 associates with Toll-like receptor 4 and is involved in LPS-mediated JNK activation [J]. EMBO J, 2003, 22(17):4455-4464.
[6] Hambleton J, Weinstein SL, Lem L, et al. Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide-stimulated macrophages. Proc Natl Acad Sci USA, 1996, 93(7):2774-2778.
[7] Davis RJ. Signal transduction by the JNK group of MAP kinases [J]. Cell, 2000, 103 (2) :239-252.
[8] Dong C, Yang DD, Wysk M, et al. Defective T cell differentiation in the absence of Jnkl [J]. Science,1998,282(5396):2092-2095.
[9] Zhou X, Gao XP, Fan J et al. LPS activation of Toll-like receptor 4 signals CD11b/CD18 expression in neutrophils [J].Am J Physiol Lung Cell Mol Physiol, 2005, 288 (4): L655-L662.
[10] Hallsworth MP, Moir LM, Lai D, et al. Inhibitors of mitogen activated protein kinases differentially regulate eosinophil activating cytokine release from human airway smooth muscle [J].Am J Respir Crit Care Med, 2001,164(4) :688-697.
[11] Zhonghong G, ShaAvhree YB, Lisa D, et al. Both p38αMAPK and JNK/SAPK pathways are important for Induction of nitric-oxide synthase by interleukin-1 βin rat glomerular mesangial cells [J]. J Biol Chem,1999 274(51):36200-36206.