Table 2 Studies investigating the role of metals in respiratory diseases and potential treatments targeting metal homeostasis/dysregulation
Disease | Metal | Human studies | Therapy | Animal studies |
|---|---|---|---|---|
Asthma | Iron | Anaemia is associated with asthma [258] Ferritin stores associated with decreased incidence of asthma [257] Lower non-haem iron in BAL, and increased number of iron-loaded cells seen in asthma patients [261] DMT1 and TFR1 expression increased in airway tissue of patients with severe asthma [261] | IV iron administration to correct iron deficiency in asthma patients [567] | Mice: In house dust-mite model, macrophages with highest Tfr1 also upregulate Il13 [261] Mice: Iron supplementation decreased airway eosinophilia and type 2 cytokines in ovalbumin-induced allergic asthma model [149] Rats: Dietary iron supplementation causes increased butyrate [264, 568] |
Zinc | Â | Zinc supplementation in children with asthma [569] | Â | |
COPD | Iron | Iron metabolism altered in COPD [299,300,301,302,303] Current/former smokers have high iron in sputum, exhaled breath condensate, AMs [211, 304,305,306,307,308,309,310,311,312,313] Anaemia and non-anaemic iron deficiency often accompany COPD [314] Anaemia can predict mortality [315,316,317] Iron-deficient patients have more exacerbations [318] COPD AMs do not suppress hepcidin in response to iron deficiency [317] AMs from smokers have higher iron than non-smokers [310] | Iron chelators to reduce lung iron overload [320, 561,562,563] | Rats: Iron accumulates in respiratory epithelial cells after smoke exposure smoke [305] Mice: Smoke exposure reduces hepcidin expression in COPD models [54] Mice: Cigarette smoke increases expression of FPN, ferritin and the TFR1 on AMs and inhibits hepcidin induction by LPS [54] |
Zinc | Zinc lower in COPD patients [77, 324] Low dietary zinc in smokers linked to higher incidence of COPD [325] Chronic smokers have increased ZIP8 expression [326] Zinc deficiency allows cadmium to accumulate to toxic levels in smoker’s AMs [332] |  | Mice: Zinc depletion caused increased lung cadmium burden and permanent lung damage [329] Mice: Zinc deficiency causes increased airway inflammation when exposed to smoke [331] Mice: Zinc supplementation decreases AM numbers after smoke exposure [331] | |
Copper | COPD patients with stable disease have lower copper in EBC than healthy non-smokers [336] Patients with Menkes disease have higher incidence of emphysema [337, 338] | Administration of copper/heparin [337] | Copper deficiency induces emphysema in several animal models [333,334,335] Rats: Copper deficiency reduces AEC integrity [335] | |
Selenium | Selenium responsive genes altered in COPD patients [340] Patients with higher selenium have a higher FEV1 [341] | Â | Â | |
Manganese | Patients with severe COPD have higher manganese levels [343] | Â | Â | |
Cystic Fibrosis | Iron | Systemic iron deficiency common [359,360,361,362,363,364,365] Increased iron in airways and sputum, and within AMs and IMs [366,367,368,369, 383] CF macrophages have altered iron metabolism [370] ΔF508-CFTR expressing AECs have altered iron homeostasis, and release more iron [371, 372] | Gallium administration to CF patients with chronic infection to improve lung function [374] |  |
Zinc | Serum and plasma zinc are decreased [376, 377] Zinc is elevated in CF airway [383, 384] Regions in the lung enriched with calprotectin allow S.aureus to coexist with P. aeruginosa [385] | Â | Â | |
Copper | Increased copper in sputum [383] | Â | Â | |
Selenium | Â | Â | ||
Non-cystic fibrosis bronchiectasis | Iron | Â | Â | |
Zinc | Â | Â | ||
Lung Cancer | Iron | Patients have higher ferritin levels [426] Increased LCN2 and TFR seen [427, 428] Increased miR-20a expression in NSCLC inhibits ferroportin expression [431] | Iron deprivation, iron supplementation to supress tumours [425] Anti-transferrin therapy [425] | Mice: Downregulation of LCN2 or TFR in adenocarcinoma model suppressed tumour growth [427, 428] Mice: Iron given i.v. inhibited tumour growth [437] |
Zinc | Decreased serum zinc is a biomarker of lung cancer [422] Increased plasma zinc correspond with lower risk of lung cancer [424] | Â | Â | |
Copper | Increased copper in serum [422] | Â | Â | |
Manganese | Increased MnSOD activity [438,439,440] Polymorphisms in MnSOD linked to higher risk of lung cancer [441] | Â | Â | |
IPF | Iron | Patients have increased iron deposition [459, 460] Iron is elevated in BAL fluid [458] BAL cells have increased iron-dependent ROS generation [462] | Iron chelators to reduce lung iron overload [320, 561,562,563] | Â |
Zinc | Reduced zinc in BAL fluid [458] | Â | Mice: Cu,Zn-SOD/SOD1 deficient mice are protected from asbestos induced lung injury [470] | |
Copper | Copper is elevated in BAL fluid [458] LOXL2 expression is increased [467] | Â | Mice: LOXL2 expression increased by bleomycin [466] Mice: LOXL2 inhibitory antibody protects against bleomycin induced lung injury [468] | |
Other | Chromium, nickel, manganese lower in BAL fluid [458] | Â | Â | |
PAH | Iron | Iron deficiency and/or anaemia common in PH patients [478, 479] PH is a major cause of mortality in those with chronic haemolytic anaemias [480] Iron accumulation in lungs and AMs of PH patients [482] 70% of those with G208C mutation in NFU1 develop PAH [481] | Iron supplementation in iron deficient patients [322] | Mice: Loss of IRP1 leads to PH [485] Mice: Expression of hepcidin-resistant FPN in smooth muscle causes PAH [483] |
Other | Zinc and copper transport implicated in pulmonary vascular homeostasis [487, 488] Selenium may be elevated in PH [489] | Â | Mice: Low copper diet in PH model has no effect on RV failure [490] Chicken: Dietary supplementation of selenium in PH model prevented RV hypertrophy [491] | |
Mycobacterial infections (TB & NTM) | Iron |  | Gallium compounds to inhibit bacterial iron dependent proteins and siderophores [375, 564, 565] Modulation of iron to support host TB defences [7, 534] Pyrazolopyrimidinone (PZP)—anti mycobacterial compound chelates intracellular iron [570] Synthetic fluorescent iron chelators restrict M.avium within macrophages [571] | Mice: Infected macrophages take up iron and deliver it to phagosomes containing mycobacteria via TFR1 [83] Mice: Nramp1D169 (functionally deficient) expression increases susceptibility to M. avium infection in mice [531] Mice: Expression of functional NRAMP1 had M. avium growth that increased with iron administration [531] Mice: BMDMs infected with M. avium upregulate H-ferritin[533] Mice: M. avium infection induced LCN2, which in turn can limit M. avium growth [536] |
Zinc | Zinc is essential for mycobacteria [546] Neutrophils in necrotic granulomas produce S100 proteins, possibly to sequester zinc and inhibit bacterial growth [551] Zinc deficiency in M. smegmatis causes ribosomal hibernation [552] | Â | Mice: Zinc starvation causing ribosome hibernation in M. tuberculosis may lead to antibiotic tolerance [553] | |
| Â | Copper | Copper responsive transcription factors control genes important for M. tuberculosis virulence [542, 543] | Â | Mice: RicR mutation reduced M. tuberculosis virulence [545] |
| Â | Other | Manganese, nickel and cobalt are essential nutrients for M. tuberculosis [554] | Â | Â |