Fourteen-membered ring macrolides inhibit vascular cell adhesion molecule 1 messenger RNA induction and leukocyte migration - Role in preventing lung injury and fibrosis in bleomycin-challenged mice
Fourteen-membered ring macrolides inhibit vascular cell adhesion molecule 1 messenger RNA induction and leukocyte migration - Role in preventing lung injury and fibrosis in bleomycin-challenged mice
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DOI：
10.1378/chest.122.6.2137
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发表时间：
2002-12-01
期刊：
影响因子：
9.6
通讯作者：
Kudoh, S
中科院分区：
文献类型：
--
作者：
Li, YJ;Azuma, A;Kudoh, S
背景与目的：虽然间质性肺炎和肺纤维化的发病机制尚不清楚，但已有报道炎症细胞，特别是中性粒细胞及其产生的有害物质在间质性肺炎的进展和随后的纤维化中发挥重要作用。据报道，红霉素和其他 14 元环大环内酯类药物 (14-MRML) 可通过抗中性粒细胞和其他几种抗炎机制改善弥漫性全细支气管炎患者的生存率。本研究旨在研究 14-MRML 对博来霉素诱导的小鼠急性肺损伤和随后的纤维化实验模型的影响。方法：对 ICR 小鼠静脉注射博莱霉素。注射博来霉素后28天，组织学观察左肺组织中纤维化灶，并对右肺组织中羟脯氨酸含量进行化学分析。通过对照（单独的生理盐水溶液 [NS]）、未治疗组（单独的博莱霉素）和治疗组（博莱霉素加 14-MRML）之间的总体比较来评估 14-MRML 的抑制作用。为了评估早期炎症，在博莱霉素治疗后 0 至 13 天检查了 BAL 液中的细胞群和肺组织中粘附分子（E-选择素、P-选择素、细胞间粘附分子 I [ICAM-1] 和血管细胞粘附分子 1 [VCAM-1]）信使 RNA (mRNA) 的诱导。这些参数也与对照组（单独 NS）、14-MRML 未治疗组（单独博莱霉素）和 14-MRML 预处理组（博来霉素加 14-MRML 预处理）进行了比较。 结果：ICR 小鼠注射博莱霉素后第 28 天，特别是那些用 14-MRML 预处理的小鼠，红霉素和其他 14-MRML 可以抑制博莱霉素诱导的肺纤维化。 14-MRML 预处理组的肺组织中羟脯氨酸含量也有所降低。 BAL液中中性粒细胞数量显着增加，在博莱霉素给药后第1天和第9天（6至11天）出现两个峰值。 14-MRML 显着抑制中性粒细胞浸润到空腔的两个峰值。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迁移到空域相关。 14-MRML 明显抑制 VCAM-1 mRNA 的诱导，并倾向于减弱 ICAM-1 mRNA 的诱导，但既不抑制 E-选择素 mRNA 的诱导，也不抑制 P-选择素 mRNA 的诱导。结论：这些发现表明，14-MRML 减弱炎症细胞迁移到空气空间，特别是中性粒细胞和巨噬细胞，导致抑制肺损伤和随后的纤维化。在博来霉素诱导的肺损伤的早期阶段，14-MRML明显减弱了VCAM-I mRNA的表达，这可能是14-MRML抑制中性粒细胞和巨噬细胞迁移到空腔的机制之一。这可能是 14-MRML 抗炎和抗纤维化作用的机制之一。这些发现表明，14-MRML 的预防性给药可能在临床上有效预防间质性肺炎和急性肺损伤的急性加重。
Background and objective: Although the pathogenesis of interstitial pneumonia and pulmonary fibrosis are not well understood, it has been reported that inflammatory cells, especially neutrophils, and the 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 by antineutrophil and several other anti-inflammatory mechanisms. The present study was undertaken to investigate the effects of 14-MRMLs on an experimental model of bleomycin-induced acute lung injury and subsequent fibrosis in mice.Methods: Bleomycin was administered IV to ICR mice. At 28 days after bleomycin injection, fibrotic foci were histologically observed in left lung tissues, and hydroxyproline content in right lung tissues was chemically analyzed. The inhibitory effects of 14-MRMLs were assessed by overall comparison between control (normal saline solution [NS] alone), untreated (bleomycin alone), and treated (bleomycin plus 14-MRMLs) groups. For evaluation of early-phase inflammation, cell populations in BAL fluid and induction of messenger RNA (mRNA) of adhesion molecules (E-selectin, P-selectin, intercellular adhesion molecule I [ICAM-1], and vascular cell adhesion molecule 1 [VCAM-1]) in lung tissues were examined at 0 to 13 days after bleomycin treatment. These parameters were also compared with those for the control (NS alone), 14-MRML untreated (bleomycin alone), and 14-MRML pretreated (bleomycin plus 14-MRML pretreated) groups.Results: Bleomycin-induced pulmonary fibrosis was inhibited by erythromycin and other 14-MRMLs on day 28 after bleomycin injection in ICR mice, especially those pretreated with 14-MRMLs. Hydroxyproline content in lung tissues was also decreased in the 14-MRML-pretreated groups. The number of neutrophils in BAL fluid significantly increased, with two peaks at I day and 9 days (from 6 to 11 days) after bleomycin 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 leukocyte 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-I mRNA during the early phase of bleomycin-induced lung injury, and this might be one mechanism of inhibition of neutrophil and macrophage migration into the airspace by 14-MRMLs. This may be one mechanism of the anti-inflammatory and antifibrotic 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.