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Abstract and Background
Abstract
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.
Conclusion: 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.
Background
Pulmonary alveolar proteinosis (PAP; also alveolar proteinosis and alveolar lipoproteinosis) has been classified as a disease entity since 1958. PAP is characterized by the massive accumulation of surfactant in the airspaces of the lower respiratory tract. Pulmonary surfactant is a mixture of phospholipids and proteins essential for lung homeostasis and alveolar stability. The accumulation of surfactant in alveolar proteinosis appears to result from impaired phospholipid clearance rather than over-production by type II pneumocytes. PAP is also characterized by inflammation with accumulation of abnormal alveolar macrophages containing intracellular surfactant-like material, and these phagocytes demonstrate impaired function. Hyperplasia of type II pneumocytes, infiltration of lymphocytes and fibroblasts, and fibrosis can also be observed in PAP.
In most cases, PAP is idiopathic or primary, but secondary PAP can accompany inhalational dust exposures (e.g. silica), infections (especially Mycobacteria, pneumocystis carinii, nocardia, and cryptococci), malignancies, and immunosuppressive disorders. The etiological factors in primary PAP remain unknown, but the development of antibodies to GM-CSF has led to the postulate that it is an auto-immune disorder. Lung damage from infectious agents and inhaled dusts is promoted by the availability of iron and metal-catalyzed oxidative stress. We tested the hypothesis that primary PAP can be associated with altered iron homeostasis in the lung by measuring concentrations of iron and iron-related proteins in lavage from both patients with idiopathic PAP and healthy control subjects.
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