ROLE OF ALVEOLAR EPITHELIUM AND AIRWAY EPITHELIUM IN ACUTE LUNG INJURY MODEL : CYTOKINES PRODUCTION AND EPITHELIUM INJURY

肺泡上皮和气道上皮在急性肺损伤模型中的作用：细胞因子的产生和上皮损伤

• 批准号: 10671414
• 负责人: OBARA Hidefumi
• 金额: $ 1.22万
• 依托单位: Kobe University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671414/
• 关键词: CULTURED CELL; ALVEOLAR MACROPHAGE; ALVEOLAR EPITHELIUM; OXYGEN TOXICITY; ENDOTOXIN; ADHESION FACTOR; CYTOKINE; GROWTH FACTOR

[Study 1] In acute lung injury, alveolar and airway epithelial cells are target for insult. On the other hand, the epithelium plays an important role in the pathogenesis of acute lung injury by producing various mediators and growth factors. The aim of the current study was to elucidate mediators produced by the epithelium and assess the effects of various drugs on mediators. Acute lung injury was induced by intraperitoneal endotoxin (10 mg/kg) in rats. Protein expression of inducible nitric oxide synthase (iNOS), nitrotyrosine (nTyr), tumor necrosis factor-α (TNF-α), and growth regulated oncogene (GRO/CINC) was immunohistochemically evaluated. Acute lung injury was quantified by lung wet/dry weight ratio and neutrophil counts in bronchoalveolar lavage fluid (BALF). The effects of lidocaine (2 mg/kg/hr), ketamine (10 mg/kg/hr), and propofol (20 mg/kg/hr) were assessed. Protein expression of iNOS, nTyr, and GRO/CINC was observed in alveolar type II pneumocytes 3-6 hr after endotoxin. Li … More docaine, ketamine, and propofol attenuated expression of these proteins. These drugs also attenuated increase in lung wet/dry weight ratio and neutrophils in BALF found in endotoxin-treated rats.[Study 2] In process of recovery from acute lung injury and prevention of pulmonary fibrosis, proliferation of type II pneumocytes is a prerequisite. Keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF) are well known to promote proliferation of the type II cells. The aim of the current study was to assess the effects of various drugs on proliferation of alveolar type II epithelial cells. Type II pneumocytes were isolated from rats' lungs and cultured. We assessed the effects of ketamine, lidocaine, and rolipram, a selective inhibitor of the type IV phosphodiesterase on proliferation of type II cells in the presence and absence of KGF or HGF. Ketamine and lidocaine had no effect. These drugs failed to enhance KGF/HGF-induced promotion of type II cell proliferation. Rolipram successfully enhanced proliferation of type II pneumocytes in the absence of the growth factors, and furthermore increased enhancement of type II cells proliferation by KGF/HGF. Less

[研究1] 在急性肺损伤中，肺泡和气道上皮细胞是损伤的目标。另一方面，上皮通过产生各种介质和生长因子，在急性肺损伤的发病机制中发挥着重要作用。当前研究的目的是阐明上皮产生的介质并评估各种药物对介质的影响。腹腔内注射内毒素（10 mg/kg）引起大鼠急性肺损伤。采用免疫组织化学方法评估诱导型一氧化氮合酶 (iNOS)、硝基酪氨酸 (nTyr)、肿瘤坏死因子-α (TNF-α) 和生长调节癌基因 (GRO/CINC) 的蛋白表达。通过肺湿/干重比和支气管肺泡灌洗液（BALF）中的中性粒细胞计数来量化急性肺损伤。评估了利多卡因（2 mg/kg/hr）、氯胺酮（10 mg/kg/hr）和异丙酚（20 mg/kg/hr）的作用。内毒素处理后 3-6 小时，在肺泡 II 型肺细胞中观察到 iNOS、nTyr 和 GRO/CINC 的蛋白表达。多卡因、氯胺酮和异丙酚减弱了这些蛋白质的表达。这些药物还减弱了内毒素治疗大鼠肺湿/干重比和BALF中中性粒细胞的增加。[研究2]在急性肺损伤的恢复和预防肺纤维化的过程中，II型肺细胞的增殖是先决条件。众所周知，角质细胞生长因子（KGF）和肝细胞生长因子（HGF）可促进 II 型细胞的增殖。本研究的目的是评估各种药物对肺泡 II 型上皮细胞增殖的影响。从大鼠肺部分离并培养II型肺细胞。我们评估了氯胺酮、利多卡因和咯利普兰（IV 型磷酸二酯酶的选择性抑制剂）在存在和不存在 KGF 或 HGF 的情况下对 II 型细胞增殖的影响。氯胺酮和利多卡因没有效果。这些药物未能增强 KGF/HGF 诱导的 II 型细胞增殖促进作用。在缺乏生长因子的情况下，咯利普兰成功地增强了II型肺细胞的增殖，并且进一步增强了KGF/HGF对II型细胞增殖的增强作用。较少的

项目成果

Nishina K,et al.: "The inhibitory effects of thiopental,midazolam,and ketar on human neutrophil functions" Anesth Analg. 86. 159-165 (1998)

Nishina K 等人：“硫喷妥钠、咪达唑仑和酮酮对人类中性粒细胞功能的抑制作用”Anesth Analg。

K.Nishina, K.Mikawa, N.Maekawa, et al.: "Attenuation of hyperoxia-induced diaphragmatic dysfunction with lidocaine in hamsters"Crit Care Med. 28 (in press). (2000)

K.Nishina、K.Mikawa、N.Maekawa 等人：“用利多卡因减轻仓鼠高氧诱导的膈肌功能障碍”Crit Care Med。

Nishina K,etal.: "Attenuation of hyperoxia-induced diaphragmatic dysfunction in hamsters"Crit Care Med.. (印刷中)28. (2000)

Nishina K 等人：“仓鼠高氧诱导的膈肌功能障碍的减弱”Crit Care Med..（出版中）28。

Miakwa K,et al.: "Propofol inhibits human neutrophil functions" Anesth Analg. 87. 695-700 (1998)

Miakwa K 等人：“异丙酚抑制人类中性粒细胞功能”Anesth Analg。

Nishina, K. et al.: "Attenuation of hyperoxia-induced diaphragmatic dysfunction in hamsters"Crit Care Med.. 28 (印刷中). (2000)

Nishina, K. 等人：“仓鼠高氧诱导的膈肌功能障碍的减弱”Crit Care Med. 28（印刷中）。