Myofibroblast-specific inhibition of the Rho kinase-MRTF-SRF pathway using nanotechnology for the prevention of pulmonary fibrosis.
Myofibroblast-specific inhibition of the Rho kinase-MRTF-SRF pathway using nanotechnology for the prevention of pulmonary fibrosis.
复制标题
使用纳米技术对肌成纤维细胞特异性抑制 Rho 激酶-MRTF-SRF 通路来预防肺纤维化。
DOI：
10.1152/ajplung.00086.2022
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
McCarthy,Jason
中科院分区：
文献类型：
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作者：
Knipe,RachelS;Nurunnabi,Md;Probst,ClemensK;Spinney,JillianJ;Abe,Elizabeth;Bose,RajendranJC;Ha,Khanh;Logue,Amanda;Nguyen,Trong;Servis,Rachel;Drummond,Matthew;Haring,Alexis;Brazee,PatriciaL;Medoff,BenjaminD;McCarthy,Jason
肺纤维化的特征在于肺中肌成纤维细胞的积累和进行性组织瘢痕形成。成纤维细胞存在于一系列状态中，从健康状态下的静止到损伤状态下的激活的肌成纤维细胞。高度活化的肌成纤维细胞作为1型胶原和促纤维化介质的主要来源在纤维化的建立中具有关键作用。肌成纤维细胞也是高度收缩的细胞，并且可以通过组织收缩改变肺的生物力学性质。因此，抑制参与肌成纤维细胞活化的信号通路可能具有显著的治疗价值。肌成纤维细胞活化发生的方式之一是通过Rho/肌心蛋白相关转录因子（MRTF）/血清反应因子（SRF）途径的活化，其通过细胞内肌动蛋白聚合发出信号。然而，围绕这些信号通路的多效性和普遍存在的性质的关注限制了抑制性药物的翻译。在此，我们证明了一种新的治疗性抗纤维化策略，使用含有MTRF/SRF通路抑制剂（CCG-1423）的肌成纤维细胞靶向纳米颗粒，该抑制剂已被证明可以在体外阻断肌成纤维细胞活化。肌成纤维细胞优先通过血管紧张素2受体靶向，血管紧张素2受体在动物和人体研究中显示选择性上调。这些纳米颗粒是无毒的，并在博莱霉素诱导的肺纤维化小鼠模型中的肺肌成纤维细胞中积累，减少了这些活化细胞的数量及其促纤维化介质的产生。最终，在肺纤维化的小鼠模型中，与对照小鼠相比，单次注射这些含有靶向纳米剂的药物减少了纤维化。这种方法有可能通过以细胞特异性方式精确靶向信号传导途径来提供个性化治疗，从而提高疗效，减少有害的脱靶效应。
Pulmonary fibrosis is characterized by the accumulation of myofibroblasts in the lung and progressive tissue scarring. Fibroblasts exist across a spectrum of states, from quiescence in health to activated myofibroblasts in the setting of injury. Highly activated myofibroblasts have a critical role in the establishment of fibrosis as the predominant source of type 1 collagen and profibrotic mediators. Myofibroblasts are also highly contractile cells and can alter lung biomechanical properties through tissue contraction. Inhibiting signaling pathways involved in myofibroblast activation could therefore have significant therapeutic value. One of the ways myofibroblast activation occurs is through activation of the Rho/myocardin-related transcription factor (MRTF)/serum response factor (SRF) pathway, which signals through intracellular actin polymerization. However, concerns surrounding the pleiotropic and ubiquitous nature of these signaling pathways have limited the translation of inhibitory drugs. Herein, we demonstrate a novel therapeutic antifibrotic strategy using myofibroblast-targeted nanoparticles containing a MTRF/SRF pathway inhibitor (CCG-1423), which has been shown to block myofibroblast activation in vitro. Myofibroblasts were preferentially targeted via the angiotensin 2 receptor, which has been shown to be selectively upregulated in animal and human studies. These nanoparticles were nontoxic and accumulated in lung myofibroblasts in the bleomycin-induced mouse model of pulmonary fibrosis, reducing the number of these activated cells and their production of profibrotic mediators. Ultimately, in a murine model of lung fibrosis, a single injection of these drugs containing targeted nanoagents reduced fibrosis as compared with control mice. This approach has the potential to deliver personalized therapy by precisely targeting signaling pathways in a cell-specific manner, allowing increased efficacy with reduced deleterious off-target effects.