Excess Iron Linked With COPD Exacerbation

Evidence suggests higher levels of iron in pulmonary macrophages heightens the risk of infectious exacerbations.

A new report yielded fresh insights into the role of pulmonary iron in chronic obstructive pulmonary disease (COPD), suggesting that excess iron in pulmonary macrophages may increase the risk of recurrent airway infection.

Writing in the journal Respiratory Research, corresponding author Terence Ho, MD, of McMaster University in Canada, and colleagues explained that while iron is an essential nutrient, an overabundance of iron can be harmful.

Some evidence has suggested iron plays a role in the pathogenesis of lung disease, the investigators said, although how exactly that happens has yet to be thoroughly explored.

Ho and colleagues wanted to better understand the mechanisms behind iron sequestration in pulmonary macrophages, and then to analyze how macrophage iron-loading affected immune response. Furthermore, they wondered whether sputum hemosiderin index (SHI) could be predictive of infectious COPD exacerbations.

The authors enrolled 56 patients in their prospective study, of whom 49 completed the 1-year observation period required. The authors took serum and sputum samples from patients and performed real-time quantitative polymerase chain reaction of sputum cells from some of the patients and healthy controls. They conducted experiments on cell line-derived and sputum macrophages. Some of those experiments included the use of exogenous interleukin-6 (IL-6) and hepcidin. Among the responses traced by the researchers were the uptake and killing of bacteria based on iron-loading level.

On the mechanistic front, the authors said IL-6 and hepcidin both appeared to play a role in iron sequestration, although they said the former appears to have a hepcidin-independent mechanism.

While they conducted the mechanistic analysis, the investigators prospectively monitored patients with COPD to track infectious exacerbations. They found that sputum macrophage iron content following an exacerbation was predictive of future infective acute exacerbations of COPD (AECOPD).

“During AECOPD, free sputum iron increased, and after the exacerbation resolved, free sputum iron decreased with a concomitant increase in SHI, suggestive of active pulmonary macrophage iron sequestration,” Ho and colleagues said. “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 SHI detected after the exacerbation event.”

They said the data appeared to suggest that elevated sputum macrophage iron impairs macrophage immune function, making the patient more susceptible to infective acute exacerbations.

The authors said their findings align with previous research suggesting increases in SHI correlated with increased exacerbation risk in COPD. Another study showed that patients with higher levels of iron in bronchoalveolar lavage fluid were associated with an increased incidence of exacerbations.

The authors said their findings were subject to limitations, including the small sample size. They added that less severe exacerbations—those not requiring emergency care or hospitalization—were not captured by the study.

Nonetheless, the investigators said their data suggest excess iron has a relationship with the risk of COPD exacerbation.

“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,” they concluded.


Ho T, Nichols M, Nair G, et al. Iron in airway macrophages and infective exacerbations of chronic obstructive pulmonary disease. Respir Res. Published online January 12, 2022. doi:10.1186/s12931-022-01929-7


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