Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis.
Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis.
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DOI：
10.1016/j.freeradbiomed.2015.04.031
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发表时间：
2015-09
影响因子：
7.4
通讯作者：
Carter AB
中科院分区：
文献类型：
--
作者：
Osborn-Heaford HL;Murthy S;Gu L;Larson-Casey JL;Ryan AJ;Shi L;Glogauer M;Neighbors JD;Hohl R;Carter AB
肺损伤中的纤维化重构是发病的主要原因。介导持续纤维化的机制尚不清楚，并且没有可用的治疗方法来减轻异常修复。活性氧（ROS）通过调节细胞外基质沉积在诱导纤维化中具有关键作用。具体而言，肺泡巨噬细胞产生的线粒体过氧化氢（H2 O2）与肺纤维化直接相关，因为抑制线粒体H2 O2可减弱小鼠的纤维化反应。先前的研究表明，小GTP结合蛋白，Rac 1，直接介导过氧化氢的产生在线粒体膜间隙。C-末端半胱氨酸残基（Cys 189）的香叶基香叶基化是Rac 1激活和线粒体输入所必需的。我们推测，损伤的香叶基香叶基化将限制线粒体氧化应激，从而消除肺纤维化的进展。通过靶向类异戊二烯途径与一种新的代理，二香叶基二膦酸酯（DGBP），这损害香叶基香叶基化，我们证明，Rac 1线粒体进口，线粒体氧化应激，和肺损伤的纤维化反应的进展显着减弱。这些观察结果表明，靶向类异戊二烯途径以改变Rac 1香叶基香叶基化可以阻止肺损伤后肺纤维化的进展。
Fibrotic remodeling in lung injury is a major cause of morbidity. The mechanism that mediates the ongoing fibrosis is unclear, and there is no available treatment to abate the aberrant repair. Reactive oxygen species (ROS) have a critical role in inducing fibrosis by modulating extracellular matrix deposition. Specifically, mitochondrial hydrogen peroxide (H2O2) production by alveolar macrophages is directly linked to pulmonary fibrosis as inhibition of mitochondrial H2O2 attenuates the fibrotic response in mice. Prior studies indicate that the small GTP-binding protein, Rac1, directly mediates H2O2 generation in the mitochondrial intermembrane space. Geranylgeranylation of the C-terminal cysteine residue (Cys189) is required for the for Rac1 activation and mitochondrial import. We hypothesized that impairment of geranylgeranylation would limit mitochondrial oxidative stress, and, thus, abrogate progression of pulmonary fibrosis. By targeting the isoprenoid pathway with a novel agent, digeranyl bisphosphonate (DGBP), which impairs geranylgeranylation, we demonstrate that Rac1 mitochondrial import, mitochondrial oxidative stress, and progression of the fibrotic response to lung injury are significantly attenuated. These observations reveal that targeting the isoprenoid pathway to alter Rac1 geranylgeranylation halts the progression of pulmonary fibrosis after lung injury.