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.
The most common form of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease characterized by epithelial injury, fibroblast accumulation and extensive remodeling in the lung. IPF affects approximately 5 million people worldwide and, despite extensive research efforts and two FDA approved drugs, remains a significant health burden and an unmet therapeutic need. In this proposal we aim to use thyroid hormone signaling to improve mitochondrial function and enhance epithelial cell survival as an antifibrotic strategy.
