Apoptosis and inflammatory cell in the pathogenesis of acute lung injury

急性肺损伤发病机制中的凋亡和炎症细胞

• 批准号: 13470326
• 负责人: HASHIMOTO Satoru
• 金额: $ 4.74万
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470326/
• 关键词: Acute lung injury; Acute respiratory distress syndrome; Apoptosis; HMGB1; 急性呼吸窮迫症候群ARDS; Fas; HMG-1

Apoptosis mediated by Fas/Fas ligand (FasL) interaction has been implicated in human disease processes, including pulmonary disorders. However, the role of the Fas/FasL system and other apoptotic factors in acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) is poorly defined. We have previously reported upregulation of pro-apoptosis molecules associated with cytotoxic lymphocytes (CTLs) such as Fas, FasL, perforin, and granzymes in bronchoalveolar lavage cells from patients in the acute phase of septic ARDS. This observation strongly suggested a role of apoptosis in the pathogenesis of the acute lung injury. Thus, we first studied the expressions of pro-apoptosis molecules in an experimental murine lung injury model of intratracheally instilled LPS. Expressions of the pro-apoptosis molecules and their mRNAs were dose-dependently upregulated, with maximal expression in the early phase in the LPS instilled lung and most apparent 24 hours after LPS-instillation. In … More tratracheal administration of P2 antibody, which is an anti-Fas blocking antibody, attenuated the lung injury after LPS-instillation without attenuating mRNA expressions of pro-apoptosis molecules and neutrophil accumulation in the lung. Secondly, cellular expression of the Fas/FasL system was assessed by semi-quantitative immunofluorescence microscopy in lung tissue obtained at autopsy from a different set of patients. Both Fas and FasL were immunolocalized to a greater extent in the patients who died with ALI or ARDS than in the patients who died without pulmonary disease. Both proteins were co-expressed by epithelial cells that lined the alveolar walls, as well as by inflammatory cells and sloughed epithelial cells that were located in the air spaces. Semi-quantitative immunohistochemistry showed that markers of apoptosis (TUNEL, caspase 3,Bax and p53) were more prevalent in alveolar wall cells from the patients who died with ALI or ARDS compared to the patients who died without pulmonary disease. These results again indicate that Fas/FasL system could be important in the pathogenesis of LPS induced ALI, and proper regulation of FasL/Fas system might be important for potential ARDS treatment. Less

由FAS/FAS配体（FASL）介导的凋亡一直处于人类疾病过程，FAS/FASL系统的Th th th pas th th pas/fasl系统以及急性肺损伤（ALI）中的其他凋亡因子（ALI）和急性呼吸道差综合征（ARDS）均报道了联盟上升的上调上调与细胞毒性淋巴细胞（CTL）H相关的促毒性分子，如spection菌患者的急性症状的急性症状。在插曲内灌输的LPS的经验鼠肺损伤模型中。从肺部降低的LPS渗透中，肺部的中性粒细胞在肺部的肺泡中的半定量免疫荧光显微镜在尸体上获得了FAS和​​FAS的肺组织，从而评估了FAS的中性粒细胞的mRNA表达。在没有肺部E的情况下，与Ali或Ards死亡的程度更大。在空气空间中，与没有肺部疾病的没有死亡的患者相比，用ALI或ARDS死亡的患者中的肺泡壁细胞更为普遍。 FASL/FAS系统的适当调节对于潜在的ARDS治疗可能很重要

项目成果

Albertire K et al.: "Fas and Fas ligand are upregulated in pulmonary edema fluid and lung tissues of patients with acute lung injury and ARDS"An J Pathology. 161. 1783-1796 (2002)

Albertire K 等人：“急性肺损伤和 ARDS 患者的肺水肿液和肺组织中 Fas 和 Fas 配体上调”《病理学杂志》。

Hashimoto S, Kobayashi A: "Clinical Pharmacokinetics and Pharmacodynamics of Glyceryl Trinitrate and its Metabolites."Clinical Pharmacokinetics. 42. 205-221 (2003)

Hashimoto S、Kobayashi A：“三硝酸甘油酯及其代谢物的临床药代动力学和药效学”。临床药代动力学。

Kitamura Y, Hashimoto S, Mizuta N, Kobayashi A, Kooguchi K, Fujiwara I, Nakajima H: "Fas/FasL Dependent Apoptosis if Alveolar Cells after Lipopolysaccharide-induced lung injury in Mice"American Journal of Respiratory and Critical Care Med. 163. 762-768 (2

Kitamura Y、Hashimoto S、Mizuta N、Kobayashi A、Kooguchi K、Fujiwara I、Nakajima H：“脂多糖诱导小鼠肺损伤后肺泡细胞的 Fas/FasL 依赖性凋亡”美国呼吸与重症监护医学杂志。

Shime N, Ashida H, Hiramatsu N, Kageyama K, Katoh Y: "Arterial ketone body ratio for the assessment of the severity of illness in pediatric patients following cardiac surgery."J Critical Care (Hashimoto S, Tanaka Y). 16. 102-107 (2001)

Shime N、Ashida H、Hiramatsu N、Kageyama K、Katoh Y：“用于评估心脏手术后儿科患者疾病严重程度的动脉酮体比率。”J Critical Care（Hashimoto S、Tanaka Y）。

Kitamura Y, Hashimoto S. et al.: "Fas/FasL Dependent Apoptosis if Alveolar Cells after Lipopolysaccharide-induced lung injury in Mice"American Journal of Respiratory and Critical Care Med. 163. 762-769 (2001)

Kitamura Y、Hashimoto S.等人：“小鼠脂多糖诱导的肺损伤后肺泡细胞的Fas/FasL依赖性细胞凋亡”美国呼吸与重症监护医学杂志。