Cystic fibrosis results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), shown above. As a result, the CFTR channel is blocked and ions cannot flow out of the cell, causing mucus buildup in the lungs.
Source: http://upload.wikimedia.org/wikipedia/commons/5/5e/PDB_1r0z_EBI.jpg
On March 28, 2014, Dr. Alex H. Gifford, an assistant professor of medicine at Dartmouth’s Geisel School of Medicine, discussed the schools’s recent studies of the relationship between cystic fibrosis and iron regulation. Patients with cystic fibrosis (CF), a disease caused by a genetic mutation (most commonly F508del), suffer from chronic airway inflammation. This inflammation results in a thickening of the bronchial airways, increased mucus production, and chronic bacterial infections, most commonly by Psuedomonas aeruginosa, which coats the lungs with mucus slime.
In the first study, researchers grew P. aeruginosa in a culture of human airway cells. They discovered that human cells with CF infected with P. aeruginosa had increased extracellular iron in the airway surface liquid, and P. aeruginosa thrives on iron.
In the second study, researchers compared stable CF patients with CF patients whose condition was worsened from cystic fibrosis pulmonary exacerbation (CFPE). Despite similar gender ratios and prevalence of the F508del mutation, the CFPE patients had recently been admitted to the hospital more often, tended to have lower BMIs, had more severe airflow obstruction, and had higher incidence of CF-related diabetes as compared to CF patients without CFPE. The researchers found that the patients with CFPE had twice as much iron in their sputum, and less iron in their blood. They were also less effective at making new red blood cells despite higher quantities of erythropoietin, a hormone that stimulates the production of red blood cell. By comparing the experimental results to national public data that described healthy individuals who are not affected by CF, the researchers were able to concretely define the severity of CF based on iron regulation.
The third study examined how treatment of CFPE affected iron regulation. Although hemoglobin levels were unchanged, researchers found that patients treated for CFPE had better airflow, significant increases in their serum iron levels, lower levels of iron in their sputum, and less inflammation as indicated by lower levels of inflammatory markers interleukin-6 (IL-6) and hepcidin-25.
Inflammation or infection increases the level of IL-6, which stimulates the production of hepcidin. Hepcidin controls iron regulation by blocking ferroportin, an enzyme that allows iron to be absorbed into the bloodstream. When hepcidin increases, iron content in the serum decreases and iron in the sputum and airways increases.
The results of the aforementioned studies suggested a conundrum: all humans rely on iron for processes such as red blood cell production and DNA replication, yet iron accumulating in the lungs facilitates the growth of P. aeruginosa.
In the last study, Gifford and other researchers examined the effects of iron supplementation. To track the CFPE, Gifford used a Pulmonary Exacerbation Score (PES) used by Akron Children’s Hospital, which previously had not been utilized to examine CF markers.
When given a 325 mg iron supplement for six weeks, patients’ serum iron increased, but the level of iron in their sputum did not change. The researchers discovered that the hormones, including hepcidin-25, used to regulate red blood cell production correlated to sputum iron levels. Importantly, hepcidin-25 was also predictive of the patient’s PES score, meaning that researchers were able to use an iron-related biomarker to objectively determine the condition of CF patients. Importantly, Gifford found that supplementing iron in the CF patients did not affect the amount of P. aeruginosa and other bacteria in the lungs.
These studies suggest that hepcidin-25 may be used to predict the worsening of CF patients. This means that researchers may be able to treat patients earlier, which might lead to shorter CF-related hospital stays. In the future, researchers will have to determine whether using chelating agents to remove iron from the lungs will reduce lung infection, allowing CF patients’ condition to improve.