Abnormal Stem Cells Underlie COPD’s Persistence

Even after they quit smoking, some people can’t breathe easy. The chronic bronchitis and emphysema that can afflict long-term smokers, called chronic obstructive pulmonary disease COPD, never goes away and may even progress despite the smoker quitting. Now, researchers from UConn Health and the University of Houston report the reason in the May 14 issue of Cell: the lungs of people with COPD are filled with abnormal stem cells.

COPD, a progressive inflammatory disease of the lungs, affects 16 million Americans and costs about $49 billion each year, according to the Centers for Disease Control and Prevention. Half the people with severe cases of the disease will die within five years. COPD is most commonly seen in longtime smokers, but people with asthma, viral pneumonia, and other inflammatory lung diseases who are chronically exposed to air pollution are also at risk.

COPD eventually damages airways and the alveoli, the tiny air sacs in the lungs that exchange carbon dioxide in the blood for oxygen. The Global Burden of Disease Study reports 251 million cases of the disease globally in 2016. But despite it accounting for more deaths than any single disease on the planet, relatively little has been written or understood about the root cause of COPD.

“It’s a frustrating disease to care for. We can try and improve the symptoms, but we don’t have anything that can cure the disease or prevent death,” says UConn Health pulmonologist and critical care doctor Mark Metersky.

Dr. Mark Metersky in an examination room at UConn Health
Dr. Mark Metersky (Lanny Nagler for UConn Health)

Metersky and colleagues Frank McKeon, director of the Stem Cell Center at the University of Houston, and Wa Xian, a research associate professor at the same institution, examined stem cells from fluid Metersky and another UConn Health pulmonologist, Omar Ibrahim, obtained from the lungs of patients undergoing bronchoscopies. Some of the patients had COPD, and some did not. The stem cells the researchers found in the lung fluid of patients with COPD were quite different than those from patients without the condition.

The stem cells from healthy lungs tended to look like the normal cells you’d find lining the lungs’ air sacs. No surprise there. But the stem cells from COPD lungs looked very different. They fell into three major types: one grew mucus glands, and the other two developed into precancerous cells and caused extreme inflammation.

“We actually found that three variant cells in all COPD patients drive all the key features of the disease. One produces tremendous amounts of mucins which block the small airways, while the other two drive fibrosis and inflammation which together degrade the function of the lung,” Xian says. “These patients have normal stem cells, though not many of them, but they are dominated by the three variant cells that together make up the disease.”

Mucus, inflammation, and precancerous lesions are hallmarks of COPD, but doctors had thought they were symptoms caused directly by smoking and environmental pollutants, and that removing the toxic smoke and pollutants would allow the lungs to heal. Instead, it seems as though the stem cells that are supposed to regenerate healthy tissue to heal the lungs have themselves been permanently altered in patients with COPD.

“It’s quite remarkable,” says McKeon. “In the deep lung, the distal airway stem cells gave rise to both the distal tubes and the alveoli and our research indicates those are the stem cells that make it possible for lungs to regenerate on their own.”

Xian and McKeon discovered lung regeneration in 2011 in their studies of subjects recovering from infections by a flu virus that was nearly identical to that which sparked the 1918 pandemic. But in the lungs of people with COPD, that regeneration process goes awry.

Now that they know why COPD persists even after people quit smoking, researchers hope to learn how to fix it. The team is hard at work screening these cells against libraries of drug-like molecules to discover new therapeutics that could potentially turn off, or decrease, the abnormal stem cells’ activity and allow healthy cells to regenerate the lung.

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