Mechanism of cell damage and repair in acute lung injury

急性肺损伤的细胞损伤与修复机制

• 批准号: 16390457
• 负责人: HASHIMOTO Satoru
• 金额: $ 8.53万
• 依托单位: Kyoto Prefectural University of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390457/
• 关键词: Acute lung injury; HMGB1; Microsampling; Ventilator induced lung iniury; Fas; FasL; アポトーシス; ラミニン; ATP; モエシン; ARDS; 急性肺障害

The first study was performed to examine the putative role of high-mobility group box (HMGB) protein in the pathogenesis of acute lung injury. Observations were made 1) in 21 septic patients with acute lung injury and 15 patients with normal lung function, and 2) in a mouse model, 24 h after intratracheal instillation of lipopolysaccharide. The concentrations of HMGB 1 were increased in plasma and lung epithelial lining fluid of patients with acute lung injury and mice instilled with lipopolysaccharide. Lipopolysaccharide-induced acute lung injury was mitigated by anti-HMGB1 antibody. Although this protein was not detected in the plasma of control humans or mice, the concentrations of HMGB 1 in lung epithelial lining fluid or in bronchoalveolar lavage fluid were unexpectedly high. The nuclear expression of HMGB 1 was apparent in epithelial cells surrounding terminal bronchioles in normal mice, while its nuclear and cytoplasmic expression was observed in alveolar macrophages in lipopoly … More saccharide-instilled mice. Lung instillation of HMGB2 did not cause as much inflammation as HMGB 1. Extracellular HMGB 1 may play a key role in the pathogenesis of clinical and experimental acute lung injury. However, its expression in normal airways is noteworthy, and suggests that it also plays a physiologic role in the lung. And the second study was about Fas/FasL system. Alveolar epithelial cell death plays a crucial role in the progression of acute lung injury. We have demonstrated up-regulation of Fas expression on alveolar epithelial cells, and soluble Fas ligand secretion from inflammatory cells upon acute lung injury. Here we show that the lipopolysaccharide-stimulated human monocyte cell line THP-1 releases Fas ligand, and that conditioned medium from lipopolysaccharide-stimulated THP-1 cells induces apoptosis of the human pulmonary adenocarcinoma cell line A549. Activation of caspase-3 and -8 is associated with the apoptosis. Gene targeting on Fas in A549 cells by specific small interfering RNA impairs apoptosis induced by conditioned medium from activated THP-1, while that on Fas ligand in THP-1 cells impairs the apoptosis-inducing activity of the conditioned medium produced by lipopolysaccharide-stimulated cells. These results suggest that Fas ligand released by monocytes causes alveolar epithelial cell death through a Fas-dependent apoptotic mechanism in the development of acute lung injury. Less

第一项研究旨在研究高迁移率族蛋白（HMGB）在急性肺损伤发病机制中的作用。观察1）21例脓毒症急性肺损伤患者和15例肺功能正常的患者，2）在小鼠模型中，内滴注脂多糖后24小时。急性肺损伤患者血浆和肺上皮细胞衬里液中HMGB 1浓度升高，脂多糖滴注小鼠血浆和肺上皮细胞衬里液中HMGB 1浓度升高。抗HMGB 1抗体可减轻脂多糖诱导的急性肺损伤。尽管在对照人或小鼠的血浆中未检测到该蛋白，但肺上皮衬里液或支气管肺泡灌洗液中的HMGB 1浓度出乎意料地高。HMGB 1在正常小鼠终末细支气管周围的上皮细胞中有明显的核表达，而在脂多糖组肺泡巨噬细胞中有核和胞浆表达 ...更多信息 糖灌注小鼠。HMGB 2的肺滴注没有引起HMGB 1那么多的炎症。细胞外HMGB 1可能在临床和实验性急性肺损伤的发病机制中起重要作用。然而，其在正常气道中的表达是值得注意的，并且表明其在肺中也起生理作用。Fas/FasL系统的研究。肺泡上皮细胞的死亡在急性肺损伤的发展过程中起着至关重要的作用。我们已经证实了急性肺损伤时肺泡上皮细胞Fas表达上调，炎性细胞分泌可溶性Fas配体。在这里，我们表明，脂多糖刺激的人单核细胞系THP-1释放Fas配体，从脂多糖刺激的THP-1细胞的条件培养基诱导人肺腺癌细胞系A549的凋亡。caspase-3和caspase-8的激活与细胞凋亡有关。特异性小分子干扰RNA（siRNA）靶向A549细胞中Fas基因可减弱活化THP-1条件培养液诱导细胞凋亡的作用，而靶向THP-1细胞中Fas配体基因可减弱脂多糖刺激细胞产生的条件培养液诱导细胞凋亡的作用。这些结果表明，在急性肺损伤的发展过程中，单核细胞释放的Fas配体通过Fas依赖的凋亡机制引起肺泡上皮细胞死亡。少

项目成果

High mobility group protein (HMGB1) as a possible mediator of acute exacerbation in idiopathic pulmonary fibrosis

高迁移率族蛋白（HMGB1）作为特发性肺纤维化急性加重的可能介质

• 发表时间: 2005
• 作者: Ebina;M.;Kimura;Y.;Shibata;N.;Konishi;K.;Ishizaka;A.;Hashimoto;S.;MaruyamaI;Nukiwa;T
• 通讯作者: T

Contribution of high-mobility group box-1 to the development of ventilator-induced lung injury

• DOI: 10.1164/rccm.200605-699oc
• 发表时间: 2006-08-15
• 期刊: AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
• 影响因子: 24.7
• 作者: Ogawa, Eileen N.;Ishizaka, Akitoshi;Takeda, Junzo
• 通讯作者: Takeda, Junzo

Pharmacokinetics of clarithromycin in bronchial epithelial lining fluid

• DOI: 10.1111/j.1440-1843.2007.01208.x
• 发表时间: 2008-03-01
• 期刊: RESPIROLOGY
• 影响因子: 6.9
• 作者: Kikuchi, Eiki;Yamazaki, Koichi;Nishimura, Masaharu
• 通讯作者: Nishimura, Masaharu

Endothelin-1 levels of serum and epithelial lining fluid in ALI/ARDS

ALI/ARDS 患者血清和上皮衬里液的内皮素-1 水平

• 发表时间: 2006
• 作者: Nakano;Y.;S.;Tasaka;Hashimoto;S.;Ogawa;Y.;Kurihara;A.;Saito;F.;Yamada;W.;Shimizu;M.;Koh;H.;Nakamura;M.;Hasegawa;N.;Fujishima;S.;Ishizaka;A
• 通讯作者: A

Measurement of neutrophil elastase activity in ARDS patients treated with neutrophil elastase inhibitor

中性粒细胞弹性蛋白酶抑制剂治疗的 ARDS 患者中性粒细胞弹性蛋白酶活性的测定

• 发表时间: 2005
• 作者: Hashimoto;S.;Okayama;Y.;Shime;N.;Amaya;F.;Ishizaka;A
• 通讯作者: A