Molecular mechanisms of pulmonary response progression in crystalline silica exposed rats

Abstract

An understanding of the mechanisms underlying diseases is critical for their prevention. Excessive exposure to crystalline silica is a risk factor for silicosis, a potentially fatal pulmonary disease. Male Fischer 344 rats were exposed by inhalation to crystalline silica (15 mg/m, six hours/day, five days) and pulmonary response was determined at 44 weeks following termination of silica exposure. Additionally, global gene expression profiling in lungs and BAL cells and bioinformatic analysis of the gene expression data were done to understand the molecular mechanisms underlying the progression of pulmonary response to silica. A significant increase in lactate dehydrogenase activity and albumin content in BAL fluid (BALF) suggested silica-induced pulmonary toxicity in the rats. A significant increase in the number of alveolar macrophages and infiltrating neutrophils in the lungs and elevation in monocyte chemoattractant protein-1 (MCP-1) in BALF suggested the induction of pulmonary inflammation in the silica exposed rats. Histological changes in the lungs included granuloma formation, type II pneumocyte hyperplasia, thickening of alveolar septa and positive response to Masson's trichrome stain. Microarray analysis of global gene expression detected 94 and 225 significantly differentially expressed genes in the lungs and BAL cells, respectively. Bioinformatic analysis of the gene expression data identified significant enrichment of several disease and biological function categories and canonical pathways related to pulmonary toxicity, especially inflammation. Taken together, these data suggested the involvement of chronic inflammation as a mechanism underlying the progression of pulmonary response to exposure of rats to crystalline silica at 44 weeks following termination of exposure.

Silica inhalation altered telomere length and gene expression of telomere regulatory proteins in lung tissue of rats

“… 28 ; c Sellamuthu et al . 29 ; *significantly different from corresponding air control (p < 0.05); Trichrome: No fibrosis (−), Positive for fibrosis (+).…”

“…Inhalation of silica is a known occupational hazard characterized by the progression from pulmonary inflammation and cellular injury to fibrosis, and the possible development of lung cancer 1 , 4 . Previously, it was reported that silica inhalation (15 mg/m 3 × 6 h/d × 5 d) resulted in lung injury (elevated LDH response) and inflammation (increased number of BALF PMNs) in rats that progressed up to 44 wk after exposure as determined by histopathological analysis and assessment of recovered BALF from exposed rats (Table 1 ; 11 , 28 , 29 ). Silica inhalation increased molecular markers of inflammation (e.g., MCP-1) at all time points post-exposure (Table 1 ).…”

“…However, lung fibrosis was more severe at 44 wk compared to 32 wk, and no histological changes was noticed at 4 wk post-exposure (Table 1 ). In the current investigation, banked lung tissue and blood samples collected from rats exposed to silica by inhalation from these previous studies 11 , 28 , 29 were analyzed for effects on telomere length and the regulation of different genes involved in telomere maintenance.…”

“…The goal of the current study was to assess the effect of silica inhalation exposure on telomere length and the regulation of RTEL1 and TERT gene expression involved in telomere maintenance in the blood and lung tissue in vivo . Banked tissue samples from previous studies were collected from male Fischer 344 rats that had been exposed by inhalation to 15 mg/m 3 of silica for 6 h/d for 5 d 11 , 28 , 29 . Rats were sacrificed at 4, 32, and 44 wk after the 5-d exposure.…”

Dendritic cells trigger imbalance of Th1/Th2 cells in silica dust exposure rat model via MHC-II, CD80, CD86 and IL-12

“…[6][7][8][9] The immune hypothesis has been conrmed with high consensus in silicosis research. 10 Silicosis is a complex immune process including the identi-cation, uptake and presentation of silica dust, which triggers and regulates the immune response through mechanisms that have not been established. The Si-OH complex of silica and H 2 O is similar to pathogen-associated molecular patterns (PAMPs) and therefore, it is recognized and bound by pattern recognition receptors (PRRs) on AMs;…”