Attenuation of bleomycin-induced pulmonary fibrosis by follistatin
Attenuation of bleomycin-induced pulmonary fibrosis by follistatin
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DOI：
10.1164/rccm.200412-1620oc
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发表时间：
2005-09-15
影响因子：
24.7
通讯作者：
Kojima, I
中科院分区：
文献类型：
--
作者：
Aoki, F;Kurabayashi, M;Kojima, I
理由。激活素是转化生长因子β超家族的成员，被认为参与组织损伤后的修复过程。目的：本研究的目的是阐明激活素及其拮抗剂卵泡抑素是否在肺损伤和纤维化中发挥重要作用。方法和结果：在博来霉素（BLM）处理的大鼠肺中，激活素β（A）亚基的mRNA在第3天和第7天上调，此后逐渐下降。免疫反应性激活素A在肺中浸润的巨噬细胞中大量表达，并且在第28天在纤维化区域中积累的成纤维细胞中检测到。然后，我们给予卵泡抑素，激活素拮抗剂，BLM治疗的大鼠。卵泡抑素可显著减少支气管肺泡灌洗液中巨噬细胞和中性粒细胞的数量，并降低蛋白质含量。在组织学上，卵泡抑素显著减少浸润细胞的数量，在第7天改善肺结构的破坏，并在第28天减弱肺纤维化。羟脯氨酸含量显着降低卵泡抑素治疗的大鼠。在培养的肺成纤维细胞中，激活素A的产生被转化生长因子-β增强，激活素拮抗剂卵泡抑素显著抑制转化生长因子-β诱导的成纤维细胞活化。这些结果表明，激活素A在BLM治疗后在肺中产生，并促进急性炎症和随后的纤维化。结论：卵泡抑素通过阻断激活素和转化生长因子β的作用，有效治疗急性肺损伤和BLM诱导的纤维化。
Rationale. Activins are members of the transforming growth factor-beta superfamily thought to be involved in repair processes after tissue injury. Objectives:The aim of this study was to clarify whether activin and its antagonist, follistatin, played a significant role in lung injury and fibrosis. Methods and Results: In bleomycin (BLM)-treated rat lung, mRNA for the beta(A) subunit of activin was upregulated on Days 3 and 7 and decreased gradually thereafter. Immunoreactive activin A was abundantly expressed in macrophages infiltrated in the lung, and was detected in fibroblasts accumulated in the fibrotic area on Day 28. We then administered follistatin, an activin antagonist, to BLM-treated rats. Follistatin significantly reduced the number of macrophages and neutrophils in bronchoalveolar lavage and reduced the protein content. Histologically, follistatin markedly reduced the number of infiltrating cells, ameliorated the destruction of lung architecture on Day 7, and attenuated lung fibrosis on Day 28. The hydroxyproline content was significantly lower in follistatin-treated rats. In cultured lung fibroblasts, production of activin A was augmented by transforming growth factor-beta, and activin antagonist follistatin significantly inhibited transforming growth factor-beta-induced fibroblast activation. These results suggest that activin A was produced in the lung after BLM treatment and promoted acute inflammation and subsequent fibrosis. Conclusions: Follistatin is effective in treating acute lung injury and BLM-induced fibrosis by blocking the actions of activin and transforming growth factor-beta.