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Pulmonary Fibrosis and Ferruginous Bodies Associated with Exposure to Synthetic Fibers
1 Clinical Research Branch, Human Studies Division, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA Correspondence: Address correspondence to: Andrew J. Ghio, Campus Box 7315, Human Studies Division, US EPA, 104 Mason Farm Road, Chapel Hill, North Carolina 27599-7315, USA; e-mail:ghio.andy{at}epa.gov
Exposure to synthetic fibers with employment in textile mills can be associated with an elevated risk of interstitial lung disease (ILD). A mechanism of injury has not been determined. ILD can follow exposures to inorganic fibers (e.g., asbestos) which are associated with a mobilization of iron and catalysis of an oxidative stress. We describe 2 patients with ILD associated with exposure to synthetic textile fibers who demonstrated carbon-based ferruginous bodies suggesting an in vivo accumulation of iron by synthetic fibers after deposition in the lung. These iron-laden bodies varied from perfectly linear fibers to almost particulate matter. Linear structures were irregularly interrupted by deposition of iron-abundant material. The capacity of these synthetic fibers to complex iron and generate an oxidative stress is confirmed in vitro.
Key Words: Textiles • nylon • Dacron • pulmonary fibrosis • pulmonary diseases • pneumoconiosis
Exposure to synthetic fibers with employment in a textile mill can be associated with an elevated risk of interstitial lung disease (Pimentel et al., 1975; Lougheed et al., 1995; Kern et al., 1998; Eschenbacher et al., 1999). A spectrum of histopathology has been described in textile workers with interstitial injury and this can include findings consistent with diffuse interstitial pneumonitis, diffuse alveolar damage, and bronchiectasis (Pimentel et al., 1975; Lougheed et al., 1995). Workers in the nylon flocking industry have more recently been described to be at an increased risk for chronic interstitial lung disease designated Flock Worker’s Lung (FWL) (Kern et al.,1998, 2000; Boag et al., 1999; Burkhart et al., 1999; Eschenbacher et al., 1999; Kuschner, 2000; Washko et al., 2000; Barroso et al., 2002). Pathologically, FWL was first characterized by bronchiolocentric nodular and diffuse lymphocytic interstitial infiltrates, a lymphocytic bronchiolitis, and variable interstitial fibrosis. Later, any pathologic evidence of interstitial lung disease would be accepted as supporting the diagnosis of FWL (Kern et al., 2000; Kuschner, 2000). Granulomas and giant cells have not been described. A mechanism for these lower respiratory tract injuries associated with textile work has not been determined. Interstitial lung disease can follow chronic exposures to inorganic fibers (e.g., asbestos). Inflammation and fibrosis after asbestos inhalation correlate with a mobilization of iron from either the fiber matrix itself or the host (Lund and Aust, 1991). Some portion of this metal is catalytically active and an oxidative stress is produced, transcription factor activation and release of mediators follow, and inflammation and fibrosis result. Synthetic fibers do not include metals. However, following deposition in the lung, synthetic fibers present an insoluble solid-liquid interface to the surrounding host tissue. Comparable to the inorganic fibers, the surface of the synthetic fiber will include functional groups with a capacity to mobilize metal from endogenous sources. Therefore, the deposition of a synthetic fiber could introduce a metal-catalyzed oxidative stress in the lower respiratory tract similar to that of inorganic fibers. The ferruginous body, with its accumulated iron, functions as an indicator of both metal accumulation and a potential oxidative stress. Ferruginous bodies have not been found in the human lung following exposure to synthetic fibers. We describe 2 patients with interstitial lung disease associated with exposure to synthetic textile fibers who demonstrated ferruginous bodies suggesting an accumulation of iron onto the fiber after its deposition in the lung. The capacity of synthetic fibers to complex iron and generate an oxidative stress is then confirmed in vitro.
Electron microscopy of fibers collected from the textile mill A dust sample was collected by hand from several surfaces in the textile mills by simply acquiring it from the top of factory machinery. Fibers were examined using SEM and EDXA.
In Vitro Iron Uptake by Fibers
In Vitro Oxidant Generation
Case Reports
Patient 2 A 41-year-old African-American female was referred with an interstitial lung disease of unclear etiology. There were complaints of dyspnea with minimal exertion and a nonproductive cough. She had smoked 2 to 1 packs of cigarettes per day for 16 years (she stopped at the time of her first being seen). Employment for 23 years had been a grader in a textile mill (different site of employment relative to patient 1); she reported no occupational exposures to asbestos, silica, or silicates. There were bibasilar crackles on examination. The FVC was 1.07 L (38% predicted), the FEV1 was 0.98 L (42% predicted), and the FEV1/FVC was 92%. The TLC was 1.98 L (41% predicted) and the diffusion capacity was not able to be measured. The chest X-ray showed diffuse interstitial markings throughout both lung fields with areas of honeycombing. The HRCT scan confirmed interstitial lung disease and honeycombing more prominent in the superior portions of the lungs. A transbronchial biopsy showed bronchiolitis with mixed lymphocytic and eosinophilic infiltration of the bronchial walls. Two courses of prednisone (each over several months) were associated with no improvement and were stopped. A thoracoscopic biopsy was obtained which demonstrated end stage fibrotic injury of the lung. No birefringent fibers or particles were observed. Iron staining revealed numerous ferruginous bodies. Positively stained bodies appeared to include both particles and fibers. These bodies varied from perfectly linear fibers, with very small core diameters, to almost particulate matter. Lung tissue was retrieved from the paraffin block, deparaffinized in xylene, and rehydrated to 95% ethanol (wet weight of 0.281 g). This tissue was processed for digestion using the sodium hypochlorite technique (Roggli, 2004). The residue was collected on a 0.4 micron pore-size Nuclepore filter, which was then mounted on a carbon disc with colloidal graphite, sputter coated with gold, and examined by scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDXA) (Roggli et al., 1993). By SEM, there were 35,000 uncoated fibers per gram of wet lung tissue (1300 x magnification, corrected for paraffin block). Twenty consecutive fibers were examined by EDXA, 8 of which consisted of carbon and oxygen without evidence of an inorganic components (Figure 4B). Fibers varied in length, tended to be irregular in shape with knobbed or blunted ends, and had a twisted configuration (Figure 4A). EDXA also confirmed the presence of a ferruginous body associated with a nylon fiber (Figures 5A and 5B). The remaining twelve fibers included five talc, two silica, two aluminum silicates, one rutile, one iron (probably the oxide), and one sodium potassium aluminum silicate.
SEM of synthetics collected at the site of employment demonstrated irregular fibers with a twisted appearance identical to those noted in the lung tissue sample digest (Figure 6A). EDXA spectra yielded a pattern comparable to that obtained from the fibers isolated from the lung tissue digest (Figure 6B). Except for the lack of birefringence, fibers collected from both the textile mill and the lung specimen were comparable in appearance to those previously isolated from individuals with Flock Worker’s Lung and rats instilled with Nylon (Boag et al., 1999).
There was a measurable concentration of iron associated with the synthetic fibers as acquired from the textile mill. This was quantified to be 0.040 µg iron/mg fiber. However, further concentrations of this metal were complexed by the synthetic fibers. It appears that the capacity of the synthetic fibers to complex iron approximated 9.20 µg/mg fiber. Oxidant generation, as measured by TBA reactive products of deoxyribose, by fibers was significantly elevated relative to controls without the additional iron loading (Table 1). This oxidative stress presented by the synthetic fibers was increased further following complexation by iron. Both the radical scavenger DMTU and the metal chelator deferoxamine significantly diminished oxidant generation by the textile fiber measured as absorbance of TBA reactive products of deoxyribose.
The clinical presentations of the patients were consistent with a chronic fibrotic disease of the lung with dyspnea, crackles on examination, restrictive pulmonary function, and radiographic procedures supportive of interstitial disease. While fibroblastic foci were not demonstrated, the trichrome stain showed a significant deposition of collagen. Staining of the resected tissue for iron revealed structures having the appearance of ferruginous bodies. It is proposed that these structures reflect an in vivo accumulation of metal on synthetic fibers sequestered in the lung. Alternatively, there could be additional exposures in these patients which disrupted normal iron homeostasis in the lower respiratory tract and affected an accumulation of this metal. EDXA demonstrated that fibers isolated from the lung were carbonaceous. Again, these may reflect either those structures included in the ferruginous bodies observed or a second exposure. Fibers collected from surfaces at a textile mill were remarkably similar in both appearance (using SEM) and composition (using EDXA) suggesting that the fibers sequestered in the lungs of these patients were synthetics originating from the mill. In vitro investigation demonstrated that synthetic fibers collected from a mill had some concentration of iron comparable to both inorganic (Lund and Aust, 1991) and cellulose (Kongdee and Bechtold, 2004) fibers. There was a capacity of the synthetics to complex further amounts of iron which is also a property shared by all fibers (Lund and Aust, 1991; Kongdee and Bechtold, 2004). The composition of synthetic fibers will vary. Dacron is ethylene glycol-terephthalic acid polyester, Nylon is a polyamide, and Rayon is cellulose acetate. They have carbonyl groups (and Nylon also has -NH groups) which demonstrate a capacity to complex metals particularly iron. As a result of a lack of flexibility of a solid surface, the complexation of a metal by the surface of synthetic fibers will be incomplete with coordination sites away from the surface being either labile or vacant. This allows a participation of the metal in electron transport and catalysis of oxidants including hydroxyl radical, perferryl radical, and superoxide. Generation of TBA reactive products by the synthetic fibers was increased following exposure to iron supporting such complexation and radical production as a potential mechanism of biological effect. Previous investigation has confirmed total dust levels as high as 40 mg/m3 in textile mills suggesting that the burden of dust in the lungs of workers in a textile mill can be considerable (Burkhart et al., 1999). This would result in some sequestration of insoluble fiber in the lower respiratory tract of textile mill workers. After complexation of metal at the surface of the fiber, an oxidative stress in the lower respiratory tract would result. This can correspond with phosphorylation-dependent cell signaling, an activation of specific transcription factors, an increased expression of mediators, and finally an inflammatory injury. This is comparable to instillation of nylon in an animal model, which resulted in an inflammatory response (Burkhart et al., 1999). The metal-catalyzed oxidative stress associated with exposure to synthetic fibers could also affect a fibrotic injury. Exposure to iron with a labile or reactive coordination site, such as the ferrous-bleomycin coordination complex, directly increases, while a metal chelator inhibits, prolyl hydroxylase activity (Hunt et al., 1979; Giri et al., 1983; Franklin et al., 1991). Finally, dietary depletion of iron and metal chelation can inhibit lung fibrosis after exposure to the iron chelate bleomycin (Chandler et al., 1988). It is concluded that textile workers with pulmonary fibrosis can potentially demonstrate evidence of sequestered synthetic fibers with ferruginous body formation. In vitro investigation is provided to support that this accumulation of metal reflects a potential oxidative stress in the lower respiratory tract after exposure to synthetic fibers.
Toxicologic Pathology, Vol. 34, No. 6,
723-729 (2006)
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Abstract
Introduction
