In vivo IL-10 gene delivery attenuates bleomycin induced pulmonary fibrosis by inhibiting the production and activation of TGF-β in the lung
In vivo IL-10 gene delivery attenuates bleomycin induced pulmonary fibrosis by inhibiting the production and activation of TGF-β in the lung
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DOI：
10.1136/thx.2005.056317
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发表时间：
2006-10-01
期刊：
影响因子：
10
通讯作者：
Yamamoto, K.
中科院分区：
文献类型：
--
作者：
Nakagome, K.;Dohi, M.;Yamamoto, K.
背景：特发性肺纤维化是一种破坏性疾病，目前尚无有效的治疗方法。转化生长因子 (TGF)-β 在引发纤维化方面发挥着关键作用。白细胞介素 (IL)-10 是一种有效的免疫抑制细胞因子，但其对纤维化过程的影响尚不清楚。进行了一项研究来检查IL-10是否影响TGF-β的产生和激活，从而减轻纤维化。方法：给小鼠气管内注射博莱霉素。在第1天或第14天，通过快速静脉注射含有质粒的林格氏溶液来递送IL-10基因。质粒注射两周后，检查小鼠的纤维化情况。评估了 IL-10 对肺泡巨噬细胞生成 TGF-β 的影响。 结果：即使在纤维化阶段递送，IL-10 基因也能显着抑制肺中的病理结果、羟脯氨酸含量以及活性和总形式 TGF-β(1) 的生成。免疫组织化学分析表明，肺泡巨噬细胞是 TGF-β(1) 的主要来源之一，而 IL-10 降低了染色强度。 IL-10 还抑制肺上皮细胞上 α(V)β(6) 整合素的表达，这是一种在 TGF-β 激活中发挥重要作用的分子。注射博莱霉素的小鼠的肺泡巨噬细胞在离体条件下自发产生 TGF-β(1)，通过体内处理小鼠或用 IL-10 离体处理移植的巨噬细胞可显着抑制 TGF-β(1)。结论：IL-10 抑制肺中 TGF-β 的产生和激活，从而减轻肺纤维化，即使在慢性期也是如此。
Backgroud: Idiopathic pulmonary fibrosis is a devastating disorder for which there is no effective treatment. Transforming growth factor (TGF)-beta plays a critical role in provoking fibrosis. Interleukin (IL)-10 is a potent immunosuppressive cytokine but its effect on the fibrosing process is unclear. A study was undertaken to examine whether IL-10 affects the production and activation of TGF-beta and thus can attenuate the fibrosis.Methods: Mice were given an intratracheal injection of bleomycin. On day 1 or 14, IL-10 gene was delivered by rapid intravenous injection of Ringer's solution containing plasmid. Two weeks after the plasmid injection the mice were examined for fibrosis. The effect of IL-10 on TGF-beta production by alveolar macrophages was assessed.Results: Even when delivered during the fibrosing phase, IL-10 gene significantly suppressed the pathological findings, hydroxyproline content, and production of both active and total forms of TGF-beta(1) in the lung. Immunohistochemical analyses showed that alveolar macrophages were one of the major sources of TGF-beta(1) and IL-10 diminished the intensity of the staining. IL-10 also suppressed the expression of alpha(V)beta(6) integrin, a molecule that plays an important role in TGF-beta activation, on lung epithelial cells. Alveolar macrophages from bleomycin injected mice produced TGF-beta(1) spontaneously ex vivo, which was significantly suppressed by treatment of the mice in vivo or by treatment of the explanted macrophages ex vivo with IL-10.Conclusion: IL-10 suppresses the production and activation of TGF-beta in the lung and thus attenuates pulmonary fibrosis, even when delivered in the chronic phase.