Airway Proteins Found to Be More Pro-inflammatory in CF Patients
Novel findings highlight link between proteins and lung disease severity
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The overall protein profile in the airway is altered toward a more pro-inflammatory state in people with cystic fibrosis (CF), and this difference is more pronounced in those with poorer lung function, a new study reports.
“Some of these proteins might have value as markers of CF lung disease severity,” the researchers wrote.
The study, “The relationship between lung disease severity and the sputum proteome in cystic fibrosis,” was published in the journal Respiratory Medicine.
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Proteomics is the study of all of the proteins in a given biological sample, referred to as the proteome. Given that proteins have so many important and diverse functions, analyzing the proteome can give important clues about biological and disease processes.
Investigating proteins in CF
Here, a team of scientists in the U.K. conducted proteomic analysis on samples of sputum — also known as phlegm, a thick type of mucus — which builds up in various organs in CF patients.
The goal was see how the proteome relates to lung function in CF.
“The novelty of this study is showing the relationship between lung disease severity and the global proteome i.e., the pattern of changes in the entire set of proteins, which has not been previously demonstrated,” they wrote.
“This goes beyond existing studies,” the team noted.
Sputum samples were collected from 38 adults with CF and 32 people without the disease (controls). Both groups were similar in mean age, from early to mid-30s. Three patients each were on treatment with Kalydeco (ivacaftor) or Orkambi (lumacaftor/ivacaftor).
Comparisons between the proteomes of the CF patients and the controls identified 108 proteins present at significantly higher levels in CF sputum. Another 202 proteins were present at significantly lower levels in the CF samples.
Most of these proteins were related to immune or inflammatory functions, the researchers noted. Specifically, most of the proteins present at high levels in CF are made by activated neutrophils — a type of inflammatory immune cell. Meanwhile, many of the proteins present in CF patients at low levels have anti-inflammatory or immune-regulating properties. Several of these proteins have been previously linked with lung disease in CF.
“That we can replicate existing findings, such as increased neutrophil activity … validates our novel findings and supports the utility of a global proteomics in early translational work for understanding disease mechanisms and identifying biomarkers,” the scientists wrote.
The researchers next compared the protein content among CF patients with different extents, or levels of severity, of lung disease. Severity was determined by a standard function of lung measure called forced expiratory volume in one second (FEV1). Based on these measures, four of the CF patients had mild disease, nine had severe disease, and the remaining 25 had moderate disease.
Results showed gradient differences in protein profiles based on disease severity — the changes seen in patients with mild disease overlapped partially with changes seen in patients with moderate disease, which in turn overlapped in part with severe disease.
“Most CF [patients] with mild lung disease had proteomes closely resembling healthy controls,” the researchers noted.
Patients taking Kalydeco also tended to have proteomes similar to those of controls, which was not seen in the Orkambi group. However, the researchers said this group was “too small a cohort to make any firm conclusions.”
Statistical analyses showed that levels of 87 proteins in the sputum samples were significantly associated with FEV1 measures. Specifically, high levels of 20 proteins were linked with better FEV1, while for the other 67 proteins, higher levels were tied to poorer lung function.
“Many of the proteins that increased with severity were also those that showed the greatest discrimination between CF and healthy control samples,” the researchers wrote, noting that several of the FEV1-associated proteins also are related to immune response and neutrophil function.
“We describe, for the first time, differences across the sputum proteome that become more pronounced with worsening CF lung disease,” the researchers concluded.