A new study sheds light on how smoking causes COPD to be worse in some patients than others.
Protein levels and an immune response in a person’s lung cells that react to cigarette smoke have a lot to do with whether someone develops chronic obstructive pulmonary disease (COPD).
In human observations and mouse model studies, the researchers found that suppressing a protein can encourage the development of emphysema (also known as lung destruction) in COPD patients. The study was published inThe Journal of Clinical Investigation.
“What we observed in this study is a new explanation of how lung damage in COPD is occurring. We found it has a lot to do with the mitochondria in lung cells,” said Min-Jong Kang, a researcher at both Yale and Brown universities. He is the lead author of the study.
In the paper, researchers examined the NLRX1 protein, which protects the pathway in normal patients. But in people with COPD, cigarette smoke impairs the protein and thus leaves the pathway vulnerable to lung destruction.
“When that pathway is unleashed by the lack of NLRX1 due to cigarette smoke, it ends up damaging lung tissues,” Kang explained.
Altering Protein Affected Results in Mice
In one of the mouse experiments, the scientists found that boosting the NLRX1 protein restored the proper function of the immune response pathway. This stopped the development of disease.
The researchers also found that mice exposed to smoke had lower levels of NLRX1 protein expression than unexposed rodents.
Mice missing the gene for NLRX1 came down with severe emphysema (and exaggerated levels of lung cell death) when they were exposed to smoke. However, smoke-exposed mice lacking both the NLRX1 gene and the MAVS gene — a central integrator of the MAVS/RIG-like helicase pathway — had much less lung damage. In other words, if mice lacked the pathway that the protein suppresses, they didn’t suffer as much damage.
In another experiment, the researchers used a virus to prompt mice exposed to cigarette smoke to overexpress the protein. Meanwhile, they left other smoke-exposed mice without that boost.
After six months, the mice with higher levels of protein expression had significantly less lung damage than the mice without that advantage.
“We now have a common denominator that seems to bring all these hypotheses together,” said Dr. Jack A. Elias, dean of medicine and biological sciences at Brown University and corresponding author of the study.
Lung Tissue Samples Used in Human Tests
The researchers also looked at lung tissue samples from healthy patients and those with COPD.
They noticed the protein levels were lower in COPD patients. They also found the protein levels were lower in COPD patients with worsening conditions. Those with lower levels of the protein had greater breathing difficulty, reduced quality of life, and poorer prognosis.
“We observed that the levels of this molecule could explain diverse aspects of disease severity and patient’s symptoms,” Kang said.
Researchers say their study could change the way patients are assessed for COPD. It could possibly help doctors predict its severity as well.
Connecting the Dots
How does cigarette smoke suppress NLRX1 in people?
The researches still want to know why inflammation slows down when smoke exposure ends in mice — and why the same isn’t true in humans. Additionally, they want to know if variations in the protein’s gene can affect a patient’s susceptibility to COPD.
“Our hope is that our insights may lead to NLRX1 serving as a biomarker of COPD and to a possible therapy based on our new understanding of this mitochondrial pathway’s role,” Kang said.
Dr. Michael Steinberg, director of the Rutgers Tobacco Dependence Program, said the data suggests that certain genetic factors can predispose some people to suffer worse lung damage when they smoke than others.
“Tobacco smoke is not safe at any level for anyone, but some of us may be at particularly high risk based on our genetic makeup,” he said.
Steinberg said we are years away from being able to tell who is at an especially high risk of developing COPD.
He notes that the authors were not sure how cigarette smoke subdues NLRX1 in people. Therefore, the only sensible recommendation to avoid COPD is not to smoke.
“Taking steps to become tobacco-free is the only definitively proven way to significantly reduce your risk of COPD and other health consequences,” Steinberg said.
