Suppressor of cytokine signaling 1 inhibits pulmonary inflammation and fibrosis
Suppressor of cytokine signaling 1 inhibits pulmonary inflammation and fibrosis
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DOI：
10.1016/j.jaci.2008.02.003
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发表时间：
2008-05-01
影响因子：
14.2
通讯作者：
Kohno, Nobuoki
中科院分区：
文献类型：
--
作者：
Nakashima, Taku;Yokoyama, Akihito;Kohno, Nobuoki
背景：细胞因子信号抑制蛋白（SOCS）是细胞因子信号传导的抑制剂。我们以前的研究表明，SOCS 1调节肺成纤维细胞胶原蛋白的合成，这表明SOCS 1在肺纤维化的病理生理学中的作用。Objectives：我们试图研究SOCS 1在肺部炎症和纤维化中的作用invivo.Methods：SOCS 1-haplodeficient博莱霉素（BLM）治疗的小鼠与野生型小鼠相比，评估肺部炎症和纤维化。人类研究组由18例间质性肺病患者组成。研究通过开放性肺活检获得的肺标本，以确定纤维化的严重程度是否与SOCS 1表达降低相关。最后，我们进一步分析了外源性SOCS 1对BLM诱导的肺损伤的影响，基于腺病毒SOCS 1基因转移到lung.Results：SOCS 1-haplodeficient小鼠与BLM治疗表现出显着增强的肺炎症和纤维化相比，野生型小鼠。使用人肺标本，我们发现SOCS 1 mRNA水平与疾病持续时间呈负相关。与非特发性肺纤维化患者相比，特发性肺纤维化（IPF）患者的肺组织中SOCS 1表达显著减少。此外，SOCS 1表达在严重纤维化病变（下叶）中显著低于纤维化程度较轻的病变（上叶）。腺病毒SOCS 1基因转移到小鼠肺显着降低淋巴细胞炎症，肺纤维化，死亡率，因为BLM诱导的肺损伤。外源性SOCS 1抑制多种细胞因子的表达，包括TNF-α，这可能发挥了关键作用。结论：这些结果表明，SOCS 1可能作为一个抑制肺纤维化。SOCS 1可能是IPF治疗的靶点。
Background: Suppressor of cytokine signaling (SOCS) proteins are inhibitors of cytokine signaling. Our previous study suggested that SOCS1 regulates collagen synthesis by lung fibroblasts, suggesting a role of SOCS1 in the pathophysiology of pulmonary fibrosis.Objectives: We sought to investigate the role of SOCS1 in pulmonary inflammation and fibrosis in vivo.Methods: SOCS1-haplodeficient mice treated with bleomycin (BLM) were evaluated for pulmonary inflammation and fibrosis compared with wild-type mice. The human study group was composed of 18 patients with interstitial lung disease. Lung specimens obtained by means of open lung biopsy were investigated to determine whether the severity of fibrosis was associated with decreased SOCS1 expression. Finally, we further analyzed the effect of exogenous SOCS1 on BLM-induced lung injury based on adenoviral SOCS1 gene transfer to the lung.Results: SOCS1-haplodeficient mice treated with BLM showed markedly enhanced pulmonary inflammation and fibrosis compared with wild-type mice. Using human lung specimens, we found that SOCS1 mRNA levels inversely correlated with duration of the disease. SOCS1 expression was significantly less in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) compared with that in non-IPF patients. Moreover, SOCS1 expression was significantly less in severe fibrotic lesions (lower lobe) than in less fibrotic lesions (upper lobe). Adenoviral SOCS1 gene transfer to murine lungs significantly decreased lymphocytic inflammation, pulmonary fibrosis, and mortality because of BLM-induced lung injury. Exogenous SOCS1 inhibited expression of various cytokines, including TNF-alpha, which might play a key role.Conclusions: These results suggest that SOCS1 might act as a suppressor for pulmonary fibrosis. SOCS1 might be a target of IPF treatment.