Valerie Chang kept waking up breathless in the middle of the night. As a regular swimmer and non-smoker, she figured it was a fluke, a remnant of her childhood asthma, perhaps. But after a lung test, doctors told her that she had the chronic obstructive pulmonary disease (COPD); her lung function was only 30% and she had done irreversible damage to her lungs. Unfortunately, they said, there was nothing they could do to improve her lung function, and she would likely need a transplant in a year.

To develop novel therapies to treat specific subtypes of COPD, and potentially even to reverse some of the symptoms, scientists at UCSF are taking a medicine approach to the disease. They are also searching for improved biomarkers that will match the patients who will benefit from them the most.

Fighting Inflammation

The first intervention for COPD is usually to get patients to stop smoking cigarettes, since that is the primary cause of the condition in the United States, where 16 million people have been diagnosed with the disease. Chronic exposure to cigarette smoke can trigger inflammation and scarring in the airways. Ordinarily, healthy organs absorbed scar tissue over time and return to normal, but in COPD the damage to the airways remains and lung function can continue to decline even after people quit smoking.

In his search for the source of inflammation, Nishimura turned to TGF-beta, a protein that is critical for immune function and the generation of scar tissue. When TGF-beta is activated in a cell it leads to the production of the inflammatory protein IL-17. Working in mice, Nishimura developed an antibody that was able to prevent the activation of TGF-beta specifically in the lung. By suppressing TGF-beta activation, the anti-body successfully blocked IL-17 inflammation, which in turn prevented scar tissue formation.

Searching the Microbiome

One biomarker that could help to indicate what's happening in the lung and categorize the different subtypes of COPD is the lung's microbiome. "A lot of our work focuses on trying to identify subgroups of patients with different responses in the lung. If we can find subsets of patients that are going to be more responsive to therapies, doctors can tailor their treatment options accordingly," said Stephanie Christenson. 

Changes to the microbiome during an exacerbation and, perhaps even more importantly, how the lung responds may hold the answer. Christenson is analyzing phlegm samples that were collected from patients before, during and after an exacerbation to see if she can subgroup them based on how their microbiome changed. She can track gene expression in the lung to see changes in inflammation, as well as the presence of a virus or bacterial infection.

Looking at the Genes

Over the last decade, genome-wide studies have identified several changes within different parts of the genome that might predict who is at risk for emphysema. One of the cellular pathways that might be genetically modified is called "hedgehog." The hedgehog pathway plays an important role in how stem cells function in the lung. It is typically activated in cells around the airways of the lung but not lower down in the air sacs, or alveoli.

In a recent article in the Journal of Clinical Investigation, Peng reports that abnormal activation of hedgehog in cells in the alveoli causes emphysema in mice by impeding the ability of lung stem cells to regenerate damaged alveoli.

"Stem cells are critical to maintaining the structure of an organism. We show that activation of hedgehog results in fewer stem cells because the cells will not renew, and that may explain the loss of air sac structures in emphysema," Peng says. "This is a new way of thinking about emphysema as a disease of aberrant regeneration or loss of stem cell capacity, rather than simply as a disease of inflammation."