“Although we know that COPD largely arises from smoking-induced airway inflammation, we do not fully understand the physiologic pathways that lead to airway disease and damage,” explains Charles R. Esther Jr., MD, PhD. “A better understanding of these pathways may help us predict which patients are at greatest risk of worsening disease and identify new treatment strategies.”

For a paper published in CHEST, Dr. Esther and colleagues aimed to explore which physiologic pathways are changed in the airways of patients with COPD and how physicians can predict pulmonary exacerbations. The research was a collaborative effort with SPIROMICS, a large, multicenter, observational study of patients with COPD. Nearly 1,000 sputum samples from patients with COPD, as well as from non-smoking and smoking controls, were collected and sent to his lab for analysis. “We analyzed these samples using an existing mass spectrometric-based biomarker panel that included metabolites representative of many physiological pathways, including mucus hydration, adenosine metabolism, methionine salvage, and others that we have previously found to be altered in the airways of patients with other respiratory diseases,” Dr. Esther says.

Metabolites Linked With Markers of COPD

The study team found that metabolites associated with mucus hydration and adenosine metabolism were strongly linked with markers of COPD severity, including lung function, symptoms of bronchitis, and pulmonary exacerbation. “Subjects with higher levels of these metabolites—sialic acid and hypoxanthine—were more likely to have later pulmonary exacerbations,” Dr. Esther notes. “We also observed that metabolites within other pathways, including methionine salvage and oxidative stress, were also associated with COPD severity, though not as strongly.”


The key takeaway, he adds, is that the most significant elevations in COPD sputa were with six metabolites: sialic acid, hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione. “These metabolites are part of pathways involved in mucus hydration, adenosine metabolism, methionine salvage, and oxidative stress,” Dr. Esther says. “Many of these metabolites were also correlated with sputum neutrophil counts. We were not surprised by these relationships since this panel was developed to measure metabolites associated with airway inflammation, which is prominent in COPD (Table).”

Mucus Hydration Is Critical in COPD Pathology

These findings emphasize the importance of mucus hydration in the pathology of COPD, Dr. Esther concludes. “Our study confirms a similar evaluation of SPIROMICS samples using different techniques and provides some new insights into mechanism,” he says. “Normally, mucus and adenosine are secreted together since adenosine signals cells to increase hydration to flush out mucus. The increased adenosine metabolism in COPD interferes with this mechanism and contributes to thicker mucus that is harder to clear, triggering inflammation and infection. While these findings need to be validated before they can be utilized in clinical practice, they do support a role for existing treatments that target mucus hydration, such as hypertonic saline.”

As with any biomarker study, a critical next step is to see if these findings can be validated in another study of patients with COPD, according to Dr. Esther and colleagues. “In our study, we used the advanced technology of mass spectrometry, but it would be good to show if sialic acid and hypoxanthine measured using more conventional methods are also useful as clinical markers,” he says. “Eventually, simple measurements of these metabolites could help guide clinical practice by identifying patients at higher risk for more severe disease progression. The study also indicates that drugs targeting adenosine metabolites or the methionine salvage pathway may be useful therapeutics. There are existing drugs targeting these pathways that have been developed for other diseases that we would like to see future studies test whether they are effective for COPD.”