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.