Abstract
BackgroundLung 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.MethodsHealthy 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.ResultsLavage 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.ConclusionIron 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.
Highlights
Lung injury caused by both inhaled dusts and infectious agents depends on increased availability of iron and metal-catalyzed oxidative stress
The pooled bronchoalveolar lavage (BAL) fluid from healthy volunteers was clear while that collected from patients with pulmonary alveolar proteinosis (PAP) was cloudy and ranged in color from beige to light pink
The amount of protein in the lavage collected from PAP patients was nearly ten-fold higher than that of the healthy volunteers (1,017 +/- 281 vs. 101 +/- 13 μgrams per mL)
Summary
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. PAP is characterized by the massive accumulation of surfactant in the airspaces of the lower respiratory tract [2,3]. 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 [4]. Hyperplasia of type II pneumocytes, infiltration of lymphocytes and fibroblasts, and fibrosis can be observed in PAP [7,8,9]
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