Investigation of Inhibition of Inflammatory Cell Migration into Lung Tissue by Ammeriolation of Cell Adhesion on Vascular Endothelial Cell

血管内皮细胞上细胞粘附的氨化作用抑制炎症细胞迁移至肺组织的研究

• 批准号: 12670581
• 负责人: AZUMA Arata
• 金额: $ 1.47万
• 依托单位: Nippon Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670581/
• 关键词: erythromycin; macrolide; lung fibrosis; interstitial pneumonia; neutrophil; adhesion molecule; vascular endothelium; VCAM-1; 血管内皮

Background and objective : Although the pathogeneses of interstitial pneumonia and pulmonary fibrosis are not well understood, it has been reported that inflammatory cells, especially neutrophils, and injurious substances produced by them play important roles in the progression of interstitial pneumonia and subsequent fibrosis. Erythromycin and other 14-membered ring macrolides (14-MRMLs) have been reported to improve the survival of patients with diffuse panbronchiolitis (DPB) by anti-neutrophil and several other anti-inflammatory mechanisms. The present study was undertaken to investigate the effete of 14-MRMLs on an experimental model of bleomycin (BLM)-induced acute lung injury and subsequent fibrosis in mice.Methods : BLM was administered intravenously to ICR mice. At 28 days after BLM injection, fibrotic foci were histologically observed in left lung tissues, and hydroxyproline (HOP) content in right lung tissues was chemically analyzed. The inhibitory effects of 14-MRMLs were as … More sessed by overall comparison between control (NS alone), untreated (BLM alone), and treated (BLM + 14-MRMLs) groups. For evaluation of early-phase inflammation, cell populations in bronchoalveolar lavage fluid (BALF) and induction of mRNA of adhesion molecules (E-selectin, P-selectin, ICAM-1, VCAM-1) in lung tissues were examined at 0 to 13 days after BLM. These parameters were also compared wife those for the control (NS alone), 14-MRML-unteated (BLM alone) and -pre-treated (BLM + pre14-MRMLs) groups.Results : BLM-induced pulmonary fibrosis was inhibited by erythromycin and other 14-MRMLs on day 28 after BLM injection in ICR mice, especially those pre-treated with 14-MRMLs, HOP content in lung tissues was also decreased in the l4-MRML-pre-1reated groups. The number of neutrophils in BALF significantly increased, with two peaks at 1 and 9 (from 6 to 11) days after BLM administration. 14-MRMLs significantly inhibited both peaks of neutrophil infiltration into the airspace. Changes in mRNA expression of adhesion molecules (E-selectin, P-selectin, ICAM-1, VCAM-1) were associated with leucocyte migration into the airspace. 14-MRMLs clearly inhibited the induction of VCAM-1 mRNA and tended to attenuate that of ICAM-1 mRNA, but inhibited the induction of neither E-selectin mRNA nor P-selectin mRNA.Conclusion : These findings indicate that attenuation of inflammatory cell migration into the airspace by 14-MRMLs, especially of neutrophils and macrophages, resulted in inhibition of lung injury and subsequent fibrosis. 14-MRMLs clearly attenuated the expression of VCAM- 1 mRNA during the early phase of BLM-induced lung injury, and this might be one mechanism of inhibition of neutrophil and macrophage migration into the airspace by 14-MRMLs. This might be one potent mechanism of the anti-inflammatory and subsequent fibrotic effects of 14-MRMLs. These findings suggest that prophylactic administration of 14-MRMLs may be clinically efficacious in preventing acute exacerbation of interstitial pneumonia and acute lung injury. Less

背景和目的：尽管间质性肺炎和肺纤维化的发病机制尚不清楚，但据报道，炎症细胞（尤其是中性粒细胞）及其产生的有害物质在间质性肺炎和随后的纤维化的进展中发挥着重要作用。红霉素和其他14元环大环内酯类（14-MRML）已被报道通过抗中性粒细胞和其他几种抗炎机制改善弥漫性泛细支气管炎（DPB）患者的生存率。本研究旨在观察14-MRML对博莱霉素（BLM）诱导的小鼠急性肺损伤及肺纤维化的影响。注射博莱霉素后28天，左肺组织病理学观察纤维化灶，右肺组织羟脯氨酸（HOP）含量进行化学分析。14-MRMLs的抑制作用为 ...更多信息 通过对照组（单独NS）、未处理组（单独BLM）和处理组（BLM + 14-MRML）之间的总体比较来评估。为了评价早期炎症，在BLM后0至13天检测支气管肺泡灌洗液（BALF）中的细胞群和肺组织中粘附分子（E-选择素、P-选择素、ICAM-1、VCAM-1）mRNA的诱导。这些参数也与对照组进行了比较（NS单药），14-MRML-未给药（BLM单独）和-预处理（BLM + pre 14-MRML）组。红霉素和其他14-MRML在BLM注射后第28天抑制了BLM诱导的ICR小鼠肺纤维化，尤其是那些用14-MRML预处理的小鼠，14-MRML预处理组肺组织中HOP含量也降低。BALF中中性粒细胞数量显著增加，在给药后1和9天（6 ~ 11天）出现两个高峰。14-MRML显著抑制了两个中性粒细胞浸润到空气中的峰值。粘附分子（E-选择素、P-选择素、ICAM-1、VCAM-1）mRNA表达的变化与白细胞向气道内的迁移有关。14-MRMLs明显抑制VCAM-1 mRNA的诱导，并有减弱ICAM-1 mRNA的趋势，但不抑制E-选择素mRNA和P-选择素mRNA的诱导。结论：这些结果表明，14-MRMLs减弱炎性细胞，特别是中性粒细胞和巨噬细胞迁移到空气中，导致抑制肺损伤和随后的纤维化。14-MRMLs明显抑制BLM肺损伤早期VCAM- 1 mRNA的表达，这可能是14-MRMLs抑制中性粒细胞和巨噬细胞向肺内迁移的机制之一。这可能是14-MRML的抗炎和随后的纤维化作用的一个有效机制。这些结果表明，预防性给予14-MRML在预防间质性肺炎急性加重和急性肺损伤方面可能具有临床有效性。少

项目成果

李 英姫, 吾妻安良太, 工藤翔二ほか: "ブレオマイシン急性肺傷害に対する14員環マクロライドの抑制作用"J.Nippon Medical School. 69(3)(in press). (2002)

Yinghee Lee、Ryota Azuma、Shoji Kudo 等：“14 元环大环内酯对博莱霉素急性肺损伤的抑制作用”J. Nippon Medical School 69(3)（印刷中）。

Arata, Azuma: "Novel Activity of Erythromycin Derivatives on Inflammatory Lung Diseases"Recent Res.Developments In Respir.& Crit.Care Medicine. 1. 191-207 (2002)

Arata，Azuma：“红霉素衍生物对炎症性肺病的新活性”呼吸领域的最新研究进展。

李 英姫, 吾妻安良太, 工藤翔二ほか: "プレオマイシン肺線維症に対する14員環マクロライドの抑制作用の検討"Jpn. J. Antibiotics. 54 Suppl.A. 87-91 (2001)

Yinghee Lee、Ryota Azuma、Shoji Kudo 等：“14 元环大环内酯对多霉素肺纤维化的抑制作用的研究”J. Antibiotics 54 Suppl.A。

李 英姫, 吾妻安良太, 工藤翔二ほか: "ブレオマイシン肺線維症に対する14員環マクロライドの抑制作用の検討"Jpn.J.Antibiotics. 54 Suppl.A. 87-91 (2001)

Yonghee Lee、Ryota Azuma、Shoji Kudo 等：“14 元环大环内酯对博来霉素肺纤维化的抑制作用的研究”Jpn.J.Antibiotics 54 Suppl.A.

李 英姫, 吾妻安良太, 工藤翔二ほか: "プレオマイシン急性肺傷害に対する14員環マクロライドの抑制作用"J. Nippon Medical School. 69(3)(in press). (2002)

Yonghee Lee、Ryota Azuma、Shoji Kudo 等人：“14 元环大环内酯对普莱霉素急性肺损伤的抑制作用”J. Nippon Medical School 69(3)（印刷中）。