Iron is an element esential for the synthesis of hemoglobin, the major red blood cell protein that binds oxygen and carries it around the body to be used by cells. The absorption of iron is a process that is strictly regulated at multiple levels, to prevent deficiency as well as excessive storage, while keeping circulating iron levels normal. The over-absorption of iron can cause the accumulation of iron within the cells. However, children born to iron-deficient mothers are more likely to have wheezing and reduced lung function in childhood, and a higher risk of atopy. A new study published in the European Respiratory Journal in March 2020 reports that the accumulation of iron in the cells of the lung exacerbates asthma symptoms and reduces lung function. As researcher Jeff Horvat explains: “Our organs and tissues need iron to support oxygen flow and normal enzyme activity, but infections in the body also need iron to thrive. Because of this, our immune system has ways of hiding iron minerals within cells where infections cannot access the iron. This can result in a build-up of iron in the cells and tissues of nearby organs. It is not clear whether iron build-up in the lungs contributes to disease development. We sought to build on this by investigating the link between iron and asthma, to understand better whether increased or decreased iron levels in the lung cells makes the disease worse”.
The study was motivated by the need to know whether iron levels in the lungs participate in the development of asthma. The authors point out that both high and low iron levels are found in asthmatic patients. This may indicate the contribution of uneven iron absorption patterns as well as abnormal iron levels to lung disease. The researchers used data from samples taken from asthma patients as well as experimental models to detect irregular iron absorption into the lung cells and to find out how the iron levels within lung cells are related to the severity of the disease. The first step was to analyze iron levels within the airway cells in 23 patients, of whom 12 had mild to moderate asthma, and 11 had severe asthma. The severity of asthma was determined by the amount of air that could be exhaled in one second, as well as how frequently the individual experienced asthma symptoms. To measure iron levels within airway cells, the researchers took a biopsy from each of the patients, and also did a bronchoscope wash. This procedure involves the insertion of a tube into the lungs through the nose or mouth, through which saline solution is passed in small amounts, into the part of the lung that is being tested. The solution is then gently sucked back up and examined for cells and other findings. In addition, the investigators took bronchial brushing samples to obtain high-quality cell samples.
Such samples were collected from 97 patients, 39 with severe asthma, 29 with mild to moderate asthma, and 29 healthy individuals. The sample collection was part of the U-BIOPRED project that covers the whole of Europe. The researchers now analyzed all the samples using multiple tests for iron. The levels of iron outside the lung cells were lower in asthma patients than in healthy people, and the reduction was proportional to the severity of asthma (lower volume of air exhaled in the first second). However, the levels inside the lung cells obtained by bronchoscope wash were significantly higher in patients with asthma than in healthy people. There was no marked difference in the level of lung cell iron with the severity of asthma. However, the ratio of iron inside and outside the cell increased with the degree of airflow obstruction. Altogether, the results indicate that finding lower iron outside the cells and higher iron levels inside the cells are linked to worse asthmatic status and more reduced lung function. Dr Horvat explained: “We showed that lung function was lowest among patients with the highest levels of iron build-up in their airway cells and tissues. We think that the immune system’s role in ‘hiding’ iron minerals within the lung cells may be contributing to asthma severity. However, data from the patient samples are not able to confirm this relationship, and the symptoms of increased iron in lung cells were not clear”.
The researchers now set up a mouse experiment to find out what would happen to the asthmatic mice if the levels of iron in the lung cell went up. In the first model, one group of mice was fed excessively iron-rich foods to induce iron overload, over eight weeks. The other group was fed a normal diet. At the end of the study, both lung and liver tissues were taken for analysis and inflammation in the airway was measured as well. In the second model, the researchers switched on a gene that causes iron overload, even when on a normal diet, to find out how the lungs would be affected. The findings showed that higher iron levels in lung cells were linked to inflammation, high mucus secretion, and airway scarring, all of which are associated with airway obstruction and asthmatic exacerbations, according to the authors. Macrophages are the cells primarily involved in this iron sequestration. They also found that high iron levels increase inflammation in the airway smooth muscle cells and fibroblasts. This gives rise to the characteristic features of asthma, including hyper-responsiveness, fibrosis, and inflammation. The team was careful to make sure there were no germs or other factors that could contribute to asthma. Hence, they say, “We are confident that the data clearly demonstrates the link between increasing lung cell and tissue iron levels and these immune system responses”.
They are confident that these findings could point towards new avenues for the treatment of asthma, such as preventing irregular iron absorption in lung cells and tissues. For instance, they are looking into ways to change the way iron is stored inside lung cells, and how to modulate the cells that cause iron absorption by lung cells.
Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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