Iron levels in the lung play a crucial role in regulation of asthma severity, Australian research suggests.
Scientists at Newcastle University, NSW say their data from asthma patient samples and mouse models is the first to definitively show a relationship between iron build-up in the lung cells and tissues and the severity of asthma.
Published in the European Respiratory Journal, their experimental work showed that cell-free iron levels were reduced in the bronchoalveolar lavage (BAL) supernatant of 39 severe asthma and 29 mild-to-moderate asthma patients and correlated with lung function (FEV1).
Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV1/forced vital capacity (FEV1/FVC).
The researcher also showed that airway tissue expression of the iron sequestration molecules DMT1 and TFR1 were increased in asthma, with TFR1 expression correlating with reduced lung function and increased type 2 (T2) inflammatory responses in the airways.
And in a house dust mite-induced animal model of experimental asthma, pulmonary iron levels were increased in association with augmented Tfr1 expression in airway tissue, similar to human disease.
The researchers, led by Associate Professor Jay Horvat of the Hunter Medical Research Institute, said they showed that macrophages were the predominant source of increased Tfr1 – and that Tfr1+ macrophages increased Il13 expression.
“We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma, including airway hyper-responsiveness and fibrosis and T2 inflammatory responses, in vivo,” they wrote.
The study authors said that if confirmed, the findings pointed to potential therapeutic targeting of iron in the pathogenesis and severity of asthma.
“There is evidence that irregular iron absorption and abnormal iron levels are linked to lung disease. We know that both high and low iron levels are reported in asthma, but it is not clear whether iron build-up in the lungs contributes to disease development,” said Dr Horvat.
“We showed that lung function was lowest among patients with the highest levels of iron build-up in their airway cells and tissues. As lower iron levels outside of cells and higher iron levels within cells were both associated with worse lung function, we think that the immune system’s role in ‘hiding’ iron minerals within the lung cells may be contributing to asthma severity.”
The researchers said the findings showed the potential for development of asthma treatments that target irregular iron absorption in the lung cells and tissues, although more research is needed to determine why there is increased absorption in the lungs of asthmatics.
And Professor Horvat emphasised that the study should not be interpreted as high lung iron levels being related to iron intake from diet or use of supplements.
The research team are now investigating ways to modify the iron storage process in lung cells, and whether it is possible to alter the number of the cells that are responsible for iron absorption into the lung cells. They hope to develop these approaches into therapies for not only asthma, but also for other lung diseases such as idiopathic pulmonary fibrosis.