Seunghye Han, MD, MPH

Lung fibrosis is a devastating disorder that limits the lungs’ ability to extract oxygen due to progressive scarring. Affected patients eventually die from poor oxygen supply to the body. The few available therapies only slow disease progression without curing the disease. Mitochondria, small organelles responsible for energy generation and cellular signaling, do not function properly in patients with lung fibrosis. We have identified certain aspects of mitochondrial function that regulate the transformation of specific lung cells into oxygen-extracting cells. In a mouse model, we found that without proper mitochondrial functioning, the mice developed lung fibrosis. Their fibrosis was improved by a molecule targeting mitochondrial dysfunction. We will study in detail how lung cells behave with and without proper mitochondrial functioning by obtaining large-scale data on DNA expression and metabolite levels in mice. We will test this molecule in different animal models with a goal of validating mitochondrial function as a target for therapy to treat lung fibrosis.

Update:

The lungs have special stem cells called alveolar epithelial type 2 (AT2) cells. These cells can turn into gas-exchanging cells called alveolar epithelial type 1 (AT1) cells, which help us breathe and get oxygen. During the repair process, these cells sometimes get stuck in between the two types and have features of both AT2 and AT1 cells. We call them “transitional cells.” These cells are more common in patients with lung fibrosis, and in mice with lung injury and scarring. We found that loss of mitochondrial function prevents intermediate transitional cells from properly becoming AT1 cells through deregulation of mitochondrial stress pathways (the integrated stress response, ISR). We also found out that if we block this highly activated stress response, we can help the transitional cells properly become AT1 cells and improve the lung function. The adult mice without mitochondrial function develop lung fibrosis, and we have shown that lung fibrosis is reversed by improving cell differentiation by replacing the regenerating function of mitochondria. Our study will help us to develop a new therapy to treat or prevent the development of pulmonary fibrosis in patients.