Research & Innovation
Pulmonary Fibrosis: The Search for Novel Therapies
By Ross Summer, MD
Idiopathic pulmonary fibrosis (IPF) is a relatively uncommon respiratory condition that develops almost exclusively in older individuals (rare before the fifth decade of life) and causes respiratory failure by progressively scarring the lung. It is estimated that 50,000 people in the U.S. are diagnosed with IPF each year, and despite newly approved treatments, the prognosis for this condition remains worse than many aggressive cancers.
Although the mechanisms leading to development of IPF remain poorly understood, it is now generally believed that repetitive insults to the cells lining the airways, called the lung epithelium, play an important role in the disease. As a consequence to breathing 20,000 times a day, which is the average for most individuals, the lung epithelium is continuously exposed to environmental pollutants, cigarette smoke, inorganic dusts (coal or silica) and viruses. Over a lifetime, these cumulative insults take a toll, and in some people the effects are too much, leading to scarring of the lung. This repetitive-injury hypothesis is believed to explain why IPF is more common in older individuals and why many people with this condition have a long history of being exposed to various environmental insults (such as cigarettes).
From an evolutionary standpoint, scar tissue serves an important function: it restores the barrier after a breach to any epithelial surface. This is best exemplified in the skin, where scar tissue formation is essential to sealing cuts. However, scar tissue also has detrimental consequences, which manifest as disfigurement in the skin and, in the case of repeated insult and scarring in the lung, respiratory failure. While current strategies to treat IPF aim to inhibit scar tissue formation, we believe this strategy will ultimately prove ineffective if one does not stop the process that ultimately causes barrier disruption.
One major focus of my laboratory is to develop novel therapies to help patients with IPF. (My lab also aims to develop therapies for other rare lung diseases.) Related to IPF, my goal is to understand the mechanisms by which the aged lung epithelium becomes more vulnerable to insults. Currently, our hypothesis, which is grounded in strong animal and human data, is that IPF results from age-related changes in lung metabolism. We believe that IPF occurs when the lung epithelium can no longer metabolically adapt to chronic insults and fails to effectively divert nutrients to parts of the cell in greatest need after being injured. Our data indicate that this failed mechanism leaves the epithelium more vulnerable to injury.
Ongoing studies in my laboratory are testing ways to enhance metabolic responses to make the lung epithelium more fit. By upregulating metabolic responses—increasing cellular activity in response to injury—we hope to enhance the viability of the epithelial cells and allow them to adapt better to the continuous assault that comes from breathing ambient air. In young and old mice, we have already uncovered several therapies that halt and even reverse fibrotic remodeling or scarring to diverse types of pulmonary insults. Our goal is to use this work as a foundation for testing our hypotheses in humans.
By making the cells more metabolically fit, we could stop or even heal fibrotic lung disease. The idea that we could make a major impact like that, and help our patients, is what fuels our passion.