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

FAS/FAS配体（FASL）相互作用介导的凋亡已在包括肺部疾病在内的人类疾病过程中实施。然而，FAS/FASL系统和其他凋亡因子在急性肺损伤（ALI）和急性呼吸遇险综合征（ARDS）中的作用较差。我们先前已经报道了与细胞毒性淋巴细胞（CTL）相关的凋亡分子的上调，例如来自肥大疗法急性阶段的患者的支气管肺泡灌洗细胞中的FAS，FAS，FASL，穿孔蛋白和颗粒酶。该观察结果强烈表明凋亡在急性肺损伤的发病机理中的作用。这是我们首先研究了气体内灌输LPS的实验性鼠肺损伤模型中促凋亡分子的表达。促凋亡分子及其mRNA的表达依赖性地上调，在LPS灌输肺的早期表达最大，在LPS灌输后24小时最明显。在…更多的抗FAS抗体的T型抗体抗体的抗体抗体，在LPS抑制后抑制了肺损伤，而不会减弱促凋亡分子的mRNA表达和肺中性粒细胞的积累。其次，通过在尸检时从不同的患者尸检中获得的肺组织中的半定量免疫荧光显微镜评估FAS/FASL系统的细胞表达。与没有肺部疾病的患者相比，患有ALI或ARDS的患者对FAS和FASL的免疫定位更大程度。两种蛋白质均由肺泡壁以及位于空气空间中的炎性细胞和炎性细胞和裂缝上皮细胞共表达。半定量免疫组织化学表明，与没有肺部疾病的患者相比，与死于ALI或ARD的患者相比，在死于ALI或ARD的患者的肺泡壁细胞中，细胞凋亡的标志物（Tunel，Caspase 3，Bax和P53）更为普遍。这些结果再次表明，FAS/FASL系统在LPS诱导的ALI的发病机理中可能很重要，并且适当调节FASL/FAS系统对于潜在的ARDS治疗可能很重要。较少的

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）。

Kooguchi K, Kobayashi A, Kitamura Y, Ueno H, Urata Y, Onodera H, Hashimoto S: "Elevated expressions of iNOS and inflammatory cytokines in the alveolar macrophages after esophagectomy."Critical Care Medicine. 30. 71-76 (2002)

Kooguchi K、Kobayashi A、Kitamura Y、Ueno H、Uurata Y、Onodera H、Hashimoto S：“食管切除术后肺泡巨噬细胞中 iNOS 和炎症细胞因子的表达升高。”重症监护医学。