Enhanced endogenous bone morphogenetic protein signaling protects against bleomycin induced pulmonary fibrosis.
Enhanced endogenous bone morphogenetic protein signaling protects against bleomycin induced pulmonary fibrosis.
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DOI：
10.1186/s12931-015-0202-x
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发表时间：
2015-03-15
影响因子：
5.8
通讯作者：
Lories RJ
中科院分区：
文献类型：
--
作者：
De Langhe E;Cailotto F;De Vooght V;Aznar-Lopez C;Vanoirbeek JA;Luyten FP;Lories RJ
很大程度上缺乏针对特发性肺纤维化等纤维化疾病的有效治疗方法。转化生长因子β（TGFβ）在纤维化的病理生理学中发挥着核心作用。我们假设骨形态发生蛋白 (BMP)（生长因子 TGFβ 超家族中的另一个家族）调节 TGFβ 驱动的纤维发生。因此，我们研究了内源性 BMP 信号在博来霉素诱导的肺纤维化中的作用。通过气管内滴注博莱霉素或磷酸盐缓冲盐水作为对照，在野生型或头蛋白单倍体不足（Nog+/LacZ）小鼠中诱导肺纤维化。使用 flexiVent® SCIREQ 系统进行有创肺功能测试。处死小鼠并收集肺组织用于组织病理学、胶原蛋白定量、免疫组织化学和基因表达分析的分析。 Nog+/LacZ 小鼠是已知的 BMP 信号传导增强模型，可部分保护其免遭博莱霉素诱导的肺纤维化，同时减少 Ashcroft 评分、减少胶原蛋白含量并保留肺顺应性。在博来霉素诱导的肺纤维化中，TGFβ和BMP信号传导遵循相反的过程，TGFβ信号传导动态激活并抑制BMP信号传导活性。接触博来霉素后，活性 BMP 信号传导会减少。 Nog+/LacZ 小鼠中 BMP 信号传导的去抑制可防止博莱霉素诱导的肺纤维化。因此，调节 BMP 和 TGFβ 之间的平衡，特别是增加内源性 BMP 信号，可能是纤维化肺病的治疗靶点。
Effective treatments for fibrotic diseases such as idiopathic pulmonary fibrosis are largely lacking. Transforming growth factor beta (TGFβ) plays a central role in the pathophysiology of fibrosis. We hypothesized that bone morphogenetic proteins (BMP), another family within the TGFβ superfamily of growth factors, modulate fibrogenesis driven by TGFβ. We therefore studied the role of endogenous BMP signaling in bleomycin induced lung fibrosis. Lung fibrosis was induced in wild-type or noggin haploinsufficient (Nog+/LacZ) mice by intratracheal instillation of bleomycin, or phosphate buffered saline as a control. Invasive pulmonary function tests were performed using the flexiVent® SCIREQ system. The mice were sacrificed and lung tissue was collected for analysis using histopathology, collagen quantification, immunohistochemistry and gene expression analysis. Nog+/LacZ mice are a known model of increased BMP signaling and were partially protected from bleomycin-induced lung fibrosis with reduced Ashcroft score, reduced collagen content and preservation of pulmonary compliance. In bleomycin-induced lung fibrosis, TGFβ and BMP signaling followed an inverse course, with dynamic activation of TGFβ signaling and repression of BMP signaling activity. Upon bleomycin exposure, active BMP signaling is decreased. Derepression of BMP signaling in Nog+/LacZ mice protects against bleomycin-induced pulmonary fibrosis. Modulating the balance between BMP and TGFβ, in particular increasing endogenous BMP signals, may therefore be a therapeutic target in fibrotic lung disease.
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影响因子：
5.8
作者：
Rodt T;von Falck C;Dettmer S;Halter R;Maus R;Ask K;Kolb M;Gauldie J;Länger F;Hoy L;Welte T;Galanski M;Maus UA;Borlak J
通讯作者：
Borlak J
影响因子：
4.8
作者：
Pannu, Jaspreet;Nakerakanti, Sashidhar;Trojanowska, Maria
通讯作者：
Trojanowska, Maria
DOI：
10.1165/rcmb.2012-0201oc
发表时间：
2013-04-01
影响因子：
6.4
作者：
Lepparanta, Outi;Tikkanen, Jussi M.;Myllarniemi, Marjukka
通讯作者：
Myllarniemi, Marjukka
影响因子：
3.7
作者：
Gao X;Cao Y;Staloch DA;Gonzales MA;Aronson JF;Chao C;Hellmich MR;Ko TC
通讯作者：
Ko TC
影响因子：
3.7
作者：
Gore B;Izikki M;Mercier O;Dewachter L;Fadel E;Humbert M;Dartevelle P;Simonneau G;Naeije R;Lebrin F;Eddahibi S
通讯作者：
Eddahibi S