Time Course of Pulmonary Response of Rats to Inhalation of Crystalline Silica: Histological Results and Biochemical Indices of Damage, Lipidosis, and Fibrosis

Porter, Dale W.; Ramsey, Dawn; Hubbs, Ann F.; Battelli, Lori; Ma, Jane; Barger, Mark; Landsittel, Douglas; Robinson, Victor A.; McLaurin, Jeff; Khan, Amir; Jones, William G.; Teass, Alexander W.; Castranova, Vincent

doi:10.1615/jenvironpatholtoxicoloncol.v20.isuppl.1.10

Cited by 54 publications

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“…In this study, we demonstrated that pulmonary administration of Survanta is associated with an increase in lung cell apoptosis, pulmonary macrophage infiltration and a decrease in lung clearance function when used at high doses (6.25 and 12.5 mg/rat lung). The level of alveolar surfactant in rat is approximately 1.2 mg/lung 31,32 and about 6-53 times higher in silicaexposed rats, 9,31,32 which is comparable to the doses of surfactant used in our in vivo instillation study. Thus, our findings provide useful information concerning the role of elevated surfactant in pulmonary disorders with associated surfactant accumulation.…”

Section: Discussionsupporting

confidence: 77%

“…In animals, pulmonary exposure to inflammatory and fibrogenic agents causes a sustained increase in lung phospholipids. 31 Although the role of surfactant in the maintenance of normal lung function and in pathologic conditions has been intensively studied, its role in the clearance of apoptotic cells has not been well demonstrated. In this study, we demonstrated that pulmonary administration of Survanta is associated with an increase in lung cell apoptosis, pulmonary macrophage infiltration and a decrease in lung clearance function when used at high doses (6.25 and 12.5 mg/rat lung).…”

Section: Discussionmentioning

confidence: 99%

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Role of lung surfactant in phagocytic clearance of apoptotic cells by macrophages in rats

Wang

Scabilloni

Antonini

et al. 2006

Laboratory Investigation

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Two of the common features of inflammatory lung diseases are the increased production of pulmonary surfactant and the induction of lung cell apoptosis. However, the relationship between these two events has not been addressed. To investigate the role of surfactant in pulmonary inflammation and apoptosis, we instilled natural lung surfactant (Survanta) (1.6-12.5 mg) into the rat lungs and determined the number of alveolar macrophages (AMs) and apoptotic lung cells. High-dose treatments of Survanta (46.25 mg/rat) caused an increase in macrophage cell influx and lung cell apoptosis at 4 weeks post-treatment. In vitro studies using lavaged macrophages showed Survanta did not cause apoptosis. We then examined the role of Survanta on ability of macrophages phagocytizing apoptotic cells. This study demonstrated that macrophages were able to eliminate apoptotic cells more efficiently in the absence of surfactant than in its presence. Keywords: Survanta; rat lung; apoptosis; clearance; alveolar macrophage Lung surfactant is synthesized by alveolar epithelial type II cells and is composed of approximately 80% phospholipids, 10% proteins and 10% neutral lipids. Pulmonary surfactant exists in two major compartments in the lung: the intracellular or storage compartment in the cytoplasm of alveolar type II cells and the extracellular compartment in the alveoli and distal airways. Under normal circumstances, these two pools of surfactant are maintained relatively constant. Alveolar macrophages (AMs) and type II cells are responsible for degradation of the surfactant 1,2 and exhibit increased lipid uptake and degradation in inflamed animal lungs. 3 Many toxicants, both chemical and particulate, appear to interfere with this balance. 4

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Role of lung surfactant in phagocytic clearance of apoptotic cells by macrophages in rats

Wang

Scabilloni

Antonini

et al. 2006

Laboratory Investigation

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“…By comparison, lung burden by inhalation can occur over a time period of minutes, hours, days, weeks, and even months. The lung burden for the present study was examined by our colleagues (25) who found that from 10 to 116 days of exposure, there was a steady increase in lung silica burden to a maximum of ϳ7 mg at 116 days. Also, inhalation results in a relatively homogeneous distribution of silica throughout the lungs as opposed to gravitational distribution by IT (2).…”

Section: Discussionmentioning

confidence: 83%

“…Particle size was measured with an Andersen eight-stage cascade impactor. The average value of chamber concentration ranged from 14.9 to 15.5 mg/m 3 with a mass median aerodynamic diameter of Ͻ2 m. Additional details of the exposure system, characterization of the aerosol, as well as particle deposition, and clearance results from these exposures have been previously published (25). Lung tissue harvesting.…”

Section: Methodsmentioning

confidence: 99%

Matrix metalloproteinase induction in fibrosis and fibrotic nodule formation due to silica inhalation

Scabilloni

Wang

Antonini

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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. Matrix metalloproteinase induction in fibrosis and fibrotic nodule formation due to silica inhalation. Am J Physiol Lung Cell Mol Physiol 288: L709 -L717, 2005. First published December 17, 2004 doi:10.1152/ ajplung.00034.2004 are the principle enzymes that initiate degradation of collagen. We examined the role of MMPs during alveolar wall fibrosis and fibrotic nodule formation from silica exposure. Rats were exposed to filtered air or 15 mg/m 3 silica by inhalation for 5 days/wk, 6 h/day. Lungs were preserved by intratracheal instillation of fixative at 20, 40, 60, 79, and 116 days of exposure. Additional groups were fixed after 20, 40, and 60 days of exposure followed by 36 days of recovery. The number of nodules, defined by a collagenous core and a bounding cell layer detached from the alveolar wall, was determined by morphometry. Lungs showed increased alveolar wall collagen and fibrotic nodules at 79 and 116 days of exposure with increased collagenase and gelatinase activity. The number of nodules per lung in exposed groups increased from 619 Ϯ 447 at 40 days to 13,221 Ϯ 1,096 at 116 days (means Ϯ SE, n ϭ 5). No nodules were seen in control lungs. Silica-exposed rats with a 36-day recovery in filtered air showed enhanced MMP activity over exposure to silica for the same duration with no recovery. MMP-2 and MMP-9 were significantly elevated in alveolar macrophages after 40-day exposure. Stromelysin expression was demonstrated in alveolar macrophages and cells within fibrotic nodules. TIMP-1 expression was not significantly altered. In summary, MMP activity was upregulated at 40 days of silica exposure and progressively increased during ensuing fibrotic responses. Early expression of stromelysin was found in fibrosing alveolar walls and fibrotic nodules.

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“…injection of sodium pentobarbital (>100 mg/kg BW). After exsanguination by cutting the abdominal vena cava/ abdominal aorta, a tracheal cannula was inserted and BAL was performed as described previously (Porter et al, 2001). Briefly, the first lavage (6 ml) was kept separate from the rest of the lavage fluid.…”

Section: Bronchoalveolar Lavagementioning

confidence: 99%

Cell- and Isoform-Specific Increases in Arginase Expression in Acute Silica-Induced Pulmonary Inflammation

Poljakovic

Porter

Millecchia

et al. 2007

Journal of Toxicology and Environmental Health, Part A

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Arginase induction was reported in several inflammatory lung diseases, suggesting that this may be a common feature underlying the pathophysiology of such diseases. As little is known regarding arginase expression in silicosis, the induction and cellular localization of arginase was elucidated in lungs of Sprague-Dawley rats 24 hr following exposure to varying doses of silica by intratracheal instillation. Arginase expression was evaluated by activity assay, quantification of arginase I and arginase II mRNA levels using real-time PCR, and immunohistochemistry. Analyses of cells and fluid obtained by bronchoalveolar lavage (BAL) showed that markers of pulmonary inflammation, tissue damage, activation of alveolar macrophages (AM) and NO production were significantly increased by all silica doses. Arginase activity was increased also in AMs isolated from BAL fluid of silica-treated rats. Silica produced 2-and 3-fold increases in arginase activity of whole lung at doses of 1 and 5 mg/100g body weight, respectively. Levels of arginase I mRNA, but not of arginase II mRNA, were similarly elevated. In control lungs, arginase I immunoreactivity was observed only in AMs sparsely dispersed throughout the lung; no iNOS immunoreactivity was detected. In silicatreated lungs, arginase I and iNOS were co-expressed in most AMs that were abundantly clustered at inflammatory foci. The rapid induction of arginase I expression in inflammatory lung cells, similar to induction of arginase in other inflammatory lung diseases, implicates elevated arginase activity as a factor in the development of lung damage following exposure to silica.

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Time Course of Pulmonary Response of Rats to Inhalation of Crystalline Silica: Histological Results and Biochemical Indices of Damage, Lipidosis, and Fibrosis

Cited by 54 publications

References 0 publications

Role of lung surfactant in phagocytic clearance of apoptotic cells by macrophages in rats

Role of lung surfactant in phagocytic clearance of apoptotic cells by macrophages in rats

Matrix metalloproteinase induction in fibrosis and fibrotic nodule formation due to silica inhalation

Cell- and Isoform-Specific Increases in Arginase Expression in Acute Silica-Induced Pulmonary Inflammation

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