Epithelial Protective Effects of Thyroid Hormone Signaling in Fibrosis

项目总结 肺纤维化(PF)描述了一种情况，即正常的肺解剖被一种 两种成纤维细胞的活性重塑、细胞外基质沉积和表型的显著变化 和肺泡上皮细胞，这是伤口愈合过程异常的结果。这种情况可能是特发性的， 如在特发性肺纤维化(IPF)中，或继发于遗传性疾病，肺实质受累于 自身免疫性疾病，或暴露于环境毒素、化学战、药物、外来抗原或 辐射。IPF是最常见的特发性肺纤维化形式，影响约120,000人 美国患者的发病率和死亡率都在稳步上升。每年有4万名患者死于IPF。 最近有人提出，衰老的许多特征包括基因组不稳定、端粒 磨耗、表观遗传学改变和线粒体功能障碍可被认为是纤维化的特征。 阿龙。具体地说，肺泡II型细胞表现出线粒体变形，能量产生减少和 线粒体活性氧增加。我们最近发现，服用甲状腺激素 博莱霉素性肺损伤后期显著提高博莱霉素性肺损伤小鼠肺组织的分辨率 纤维化症。我们发现，这些效应与PPARGC1A的诱导有关，PPARGC1A是一种转录 对代谢、线粒体重塑和线粒体有重要调节作用的辅活化子 生物发生学。伴随这一效应的是细胞凋亡减少和线粒体形态正常化 在肺泡II型细胞中的功能，并依赖于完整的有丝分裂生成和有丝分裂吞噬途径。最后， 在从IPF患者的大的、特征良好的纵向队列中获得的银行血浆样本中，我们 发现循环中线粒体DNA水平的增加与显著增加有关 这些患者的死亡率。考虑到甲状腺激素对损伤后的修复至关重要，通过 促生存和抗氧化信号通路的激活及其对线粒体动态平衡的调节 代谢和甲状腺功能减退与多种慢性疾病的不良预后有关 包括IPF在内，我们假设通过增加甲状腺激素来恢复线粒体的动态平衡 信号转导可以建立一种可行的治疗策略，以保护和解决肺上皮细胞 纤维化症。我们将通过以下具体目标来解决这一假说：目标1：确定甲状腺激素 信号通过诱导有丝分裂生成和有丝分裂吞噬来逆转细胞损伤。目标2：确定如何 甲状腺激素信号转导导致线粒体生物学改变，导致器官纤维化减轻。目标3： 为了确定Sobetirome的潜在用途，Sobetirome是一种相对缺乏甲状腺心脏和甲状腺功能的类似甲状腺的药物 骨骼毒性，作为一种抗纤维化药物。这些实验将共同确立这些机制和原理。 用于在人类中使用增强甲状腺激素信号作为抗纤维化策略。

PROJECT SUMMARY Pulmonary fibrosis (PF) describes a condition in which the normal lung anatomy is replaced by a process of active remodeling, deposition of extracellular matrix and dramatic changes in the phenotype of both fibroblasts and alveolar epithelial cells, as a result of an abnormal wound healing process. This condition can be idiopathic, as in idiopathic pulmonary fibrosis (IPF), or secondary to genetic disorders, lung parenchyma involvement in autoimmune disorders, or to exposure to environmental toxins, chemical warfare, drugs, foreign antigens, or radiation. IPF is the most common idiopathic form of pulmonary fibrosis that affects approximately 120,000 patients in the US with a steady increase in both incidence and mortality. 40,000 patients die from IPF each year. More recently it has been proposed that many of the hallmarks of aging including genomic instability, telomere attrition, epigenetic alterations, and mitochondrial dysfunction can be considered characteristic of the fibrotic lung. Specifically, alveolar type II cells exhibit dysmorphic mitochondria, reduced energy production and increased mitochondrial reactive oxygen species. We recently discovered that administration of thyroid hormone late after bleomycin induced lung injury significantly enhanced the resolution of murine bleomycin-induced lung fibrosis. We discovered that these effects were associated with induction of PPARGC1A, a transcriptional coactivator with significant roles in regulation of metabolism, mitochondrial remodeling and mitochondrial biogenesis. This effect was accompanied by reduced apoptosis and normalized mitochondrial morphology and function in alveolar type II cells and was dependent on intact mitogeneration and mitophagy pathways. Finally, in banked plasma specimens obtained from a large, well characterized longitudinal cohort of IPF patients, we identified increased levels of circulating mitochondrial DNA that were associated with significantly increased mortality in these patients. Considering that thyroid hormone is critically important for repair after injury through activation of pro-survival and anti-oxidant signaling pathways and regulation of mitochondrial homeostasis and metabolism and that hypothyroidism is associated with unfavorable prognosis in multiple chronic conditions including IPF, we hypothesize that restoration of mitochondrial homeostasis by augmented thyroid hormone signaling could establish a viable therapeutic strategy for epithelial protection and resolution of pulmonary fibrosis. We will address this hypothesis by the following specific aims: Aim 1: To determine that thyroid hormone signaling reverses cellular injury by inducing both mitogeneration and mitophagy. Aim 2: To determine how thyroid hormone signaling induced changes in mitochondrial biology result in reduction of organ fibrosis. Aim 3: To establish the potential utility of Sobetirome, a thyromimetic drug relatively devoid of thyroid cardiac and skeletal toxicity, as an antifibrotic agent. Together these experiments will establish the mechanisms and rationale for the use of augmenting thyroid hormone signaling as an antifibrotic strategy in humans.