Excess Iron in Lung Immune Cells May Add to Risk of Recurrent Infections

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by Marta Figueiredo PhD |

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Abnormally high levels of iron inside airway immune cells are associated with more frequent lung infection-related exacerbations in people with chronic obstructive pulmonary disease (COPD), a study shows.

Excess iron was also shown to impair the ability of these cells, called macrophages, to fight COPD-related microbes, and can be used to predict infection-related symptom worsening in people with COPD, the researchers noted.

Further research is needed to confirm these findings and determine if excess iron may be a new therapeutic target for COPD.

The study, “Iron in airway macrophages and infective exacerbations of chronic obstructive pulmonary disease,” was published in the journal Respiratory Research.

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COPD is characterized by excessive airway inflammation, lung tissue remodeling, and progressive destruction of alveoli, the tiny lung air sacs responsible for gas exchange. Lung infections are estimated to cause 50%–70% of acute exacerbations in COPD (AECOPD), which often require hospitalization.

Increasing evidence points to airway iron overload as an important contributor to the severity of emphysema, a severe form of COPD, and COPD exacerbations.

Iron is a micronutrient essential for several biological processes, such as immune responses, but it is toxic at abnormally high levels.

Iron levels are tightly controlled by hepcidin, a molecule that suppresses iron release from liver cells and macrophages by promoting the breakdown of ferroportin, the exporter of iron, at their surface. Macrophages are part of the body’s first line of defense, and help fight against microbes by “engulfing” them.

Hepcidin levels are regulated by several factors, including interleukin-6 (IL-6), a pro-inflammatory molecule, and infections.

While previous rodent studies suggested that iron overload may reduce antibacterial immune responses, no such studies have been conducted in humans, and with lung-specific microbes affecting humans.

Now, a team of researchers in Canada have provided further evidence that excess iron inside macrophages increases the susceptibility to infections and recurrent infectious exacerbations in people with COPD.

Researchers collected blood and thick mucus, called sputum, from 49 adults with COPD or emphysema, who were followed for a year for severe infectious AECOPD, as well as the sputum of individuals who had never smoked and had no known lung or heart disease.

They found the levels of free sputum iron in COPD patients increased during AECOPD and dropped afterwards, while stored iron was increased post-AECOPD, suggesting “active pulmonary macrophage iron sequestration,” the researchers wrote.

Analyses of iron levels inside and outside lab-grown sputum macrophages from healthy donors who were exposed to either IL-6 or hepcidin showed that both factors significantly promoted iron uptake, leading to increased iron levels inside these immune cells.

However, data from COPD patients showed that blood and sputum levels of IL-6, but not of hepcidin, at the time of exacerbation were significantly associated with iron accumulation in the sputum after discharge. This suggests that IL-6 may increase iron uptake through a hepcidin-independent mechanism.

“It is plausible that in those individuals with an increase in IL-6 associated with AECOPD, the iron sequestration process initiates and ultimately leads to elevated [stored iron] detected after the exacerbation event,” they wrote.

In addition, greater amounts of stored iron in lab-grown sputum macrophages from COPD patients were significantly associated with a faster growth of bacteria that commonly affects the lungs of people with COPD. This effect was reversed when macrophages were exposed to an iron-binding agent that sequestrates excess free iron.

Similar results were obtained when comparing lab-grown human macrophages loaded with iron to those with normal iron levels.

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Together, these findings suggest that excess iron inside macrophages impairs their ability to “engulf” bacteria and prevent their growth.

Additionally, after adjusting for potential influencing factors, the team found that sputum levels of stored iron in COPD patients shortly after an exacerbation were a significant predictor of future infection-related acute exacerbations.

This link was weakened when the analysis was also adjusted for blood IL-6 levels, further emphasizing the influence of this pro-inflammatory molecule in iron uptake and overload.

The findings highlight that “excess airway macrophage iron occurs in a subset of patients with COPD, and when present prospectively predicts infectious exacerbation,” the researchers wrote.

The data also suggest a potential mechanism by which “IL-6-dependent iron sequestration by sputum macrophages may result in immune cell dysfunction and ultimately lead to increased frequency of infective exacerbation,” the team added.

“Further research is required to fully understand the mechanisms of pulmonary iron sequestration in health and disease, and to determine if airway iron could be a target for therapeutic intervention,” the researchers concluded.