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）相互作用介导的细胞凋亡与包括肺部疾病在内的人类疾病过程有关。然而，Fas/FasL系统和其他凋亡因子在急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）中的作用尚不清楚。我们以前曾报道过脓毒性ARDS急性期患者支气管肺泡灌洗液细胞中与细胞毒性淋巴细胞（CTL）相关的促凋亡分子（如Fas、FasL、穿孔素和颗粒酶）上调。这一观察结果有力地表明了细胞凋亡在急性肺损伤发病机制中的作用。因此，我们首先研究了促凋亡分子在实验性小鼠肺损伤模型中的表达。促凋亡分子及其mRNA的表达呈剂量依赖性上调，在LPS灌注肺的早期阶段表达最大，在LPS灌注后24小时最明显。在 ...更多信息 气管内给予P2抗体（其是一种抗Fas阻断抗体）减轻了LPS滴注后的肺损伤，而不减弱肺中促凋亡分子的mRNA表达和中性粒细胞积聚。其次，Fas/FasL系统的细胞表达进行了评估，通过半定量免疫荧光显微镜在肺组织中获得尸检从一组不同的患者。Fas和FasL在ALI或ARDS死亡患者中的免疫定位程度高于无肺部疾病死亡的患者。这两种蛋白质共同表达的上皮细胞排列的肺泡壁，以及炎症细胞和脱落的上皮细胞位于空气空间。半定量免疫组化显示，凋亡标志物（TUNEL，caspase 3，Bax和p53）更普遍的肺泡壁细胞从谁与ALI或ARDS死亡的患者相比，谁没有肺部疾病死亡的患者。这些结果再次表明，Fas/FasL系统可能在LPS诱导的ALI的发病机制中发挥重要作用，并且适当调节FasL/Fas系统对于潜在的ARDS治疗可能很重要。少

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》。

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。

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. 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。

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）。