Iron homeostasis and oxidative stress in idiopathic pulmonary alveolar proteinosis: a case-control study.
BACKGROUND
Lung injury caused by both inhaled dusts and infectious agents depends on increased availability of iron and metal-catalyzed oxidative stress. Because inhaled particles, such as silica, and certain infections can cause secondary pulmonary alveolar proteinosis (PAP), we tested the hypothesis that idiopathic PAP is associated with an altered iron homeostasis in the human lung.


METHODS
Healthy volunteers (n = 20) and patients with idiopathic PAP (n = 20) underwent bronchoalveolar lavage and measurements were made of total protein, iron, tranferrin, transferrin receptor, lactoferrin, and ferritin. Histochemical staining for iron and ferritin was done in the cell pellets from control subjects and PAP patients, and in lung specimens of patients without cardiopulmonary disease and with PAP. Lavage concentrations of urate, glutathione, and ascorbate were also measured as indices of oxidative stress.


RESULTS
Lavage concentrations of iron, transferrin, transferrin receptor, lactoferrin, and ferritin were significantly elevated in PAP patients relative to healthy volunteers. The cells of PAP patients had accumulated significant iron and ferritin, as well as considerable amounts of extracellular ferritin. Immunohistochemistry for ferritin in lung tissue revealed comparable amounts of this metal-storage protein in the lower respiratory tract of PAP patients both intracellularly and extracellularly. Lavage concentrations of ascorbate, glutathione, and urate were significantly lower in the lavage fluid of the PAP patients.


CONCLUSIONS
Iron homeostasis is altered in the lungs of patients with idiopathic PAP, as large amounts of catalytically-active iron and low molecular weight anti-oxidant depletion are present. These findings suggest a metal-catalyzed oxidative stress in the maintenance of this disease.
Ghio
Andrew J
AJ
National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Research Triangle Park, NC 27711, USA. ghio.andy@epa.gov
Stonehuerner
Jacqueline G
JG
Richards
Judy H
JH
Crissman
Kay M
KM
Roggli
Victor L
VL
Piantadosi
Claude A
CA
Carraway
Martha Sue
MS
D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016022:Case-Control Studies; D005293:Ferritins / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007781:Lactoferrin / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D018384:Oxidative Stress; D011506:Proteins / Q000378:metabolism; D011649:Pulmonary Alveolar Proteinosis / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism
D011506:Proteins; D011990:Receptors, Transferrin; D014168:Transferrin; D005293:Ferritins; D007501:Iron; D007781:Lactoferrin