Molecular insights into the progression of crystalline silica‐induced pulmonary toxicity in rats

Abstract

Identification of molecular target(s) and mechanism(s) of silica‐induced pulmonary toxicity is important for the intervention and/or prevention of diseases associated with exposure to silica. Rats were exposed to crystalline silica by inhalation (15 mg m−3, 6 h per day, 5 days) and global gene expression profile was determined in the lungs by microarray analysis at 1, 2, 4, 8 and 16 weeks following termination of silica exposure. The number of significantly differentially expressed genes (>1.5‐fold change and <0.01 false discovery rate P‐value) detected in the lungs during the post‐exposure time intervals analyzed exhibited a steady increase in parallel with the progression of silica‐induced pulmonary toxicity noticed in the rats. Quantitative real‐time PCR analysis of a representative set of 10 genes confirmed the microarray findings. The number of biological functions, canonical pathways and molecular networks significantly affected by silica exposure, as identified by the bioinformatics analysis of the significantly differentially expressed genes detected during the post‐exposure time intervals, also exhibited a steady increase similar to the silica‐induced pulmonary toxicity. Genes involved in oxidative stress, inflammation, respiratory diseases, cancer, and tissue remodeling and fibrosis were significantly differentially expressed in the rat lungs; however, unresolved inflammation was the single most significant biological response to pulmonary exposure to silica. Excessive mucus production, as implicated by significant overexpression of the pendrin coding gene, SLC26A4, was identified as a potential novel mechanism for silica‐induced pulmonary toxicity. Collectively, the findings of our study provided insights into the molecular mechanisms underlying the progression of crystalline silica‐induced pulmonary toxicity in the rat. Published 2012. This article is a US Government work and is in the public domain in the USA.

Inflammatory and oxidative stress biomarkers induced by silica exposure in crystal craftsmen

“…diseases and even future treatment options. 15,61 The use of biomarkers, together with more sensitive imaging methods, may allow the design of algorithms that can be implemented to benefit early diagnosis of silicosis.…”

Ceramics manufacturing contributes to ambient silica air pollution and burden of lung disease

“…Furthermore, setting scientifically based limit values is complicated, owing to the difficulties in interpreting heterogeneous experimental and epidemiological findings (Chen et al 2001a;OEHHA 2005;Zhuang et al 2001). Despite much recent progress in our understanding of source attribution, emission factors, and regulation of silica (Chen et al 2012;Rong et al 2013;Sellamuthu et al 2013), current risk assessment models based on parameterization of laboratory experiments cannot fully explain the magnitude of silica-induced pulmonary disease risk. Furthermore, the silicosis is rated the most prevalent occupational disease among all industries in Taiwan (Shih et al 2008).…”

“…Rong et al (2013) and Sellamuthu et al (2013) indicated that the biological effects of silica included direct ones on several pathways such as inflammatory responses, cell-tocell signaling and interaction, cellular movement that lead to inflammatory and respiratory diseases, and finally cancer. Porter et al (2006) and Shen et al (2001) indicated that silica could produce reactive oxygen species (ROS) and lipid peroxidation to disrupt lipid rafts and active protein tyrosine kinase, resulting in the subsequent translocation of transcription factors.…”

“…It is estimated that at least two to three million workers worldwide are occupationally exposed to silica annually (Jutzi and Schubert 2003;Sellamuthu et al 2013). Inhalation of silica in occupational exposures can cause pulmonary fibrosis (silicosis), lung function deficits, pulmonary inflammation, and lung cancer and has been associated with glomerulonephritis and disorders of the liver, spleen, and immune systems (Başaran et al 2002;Brown and Rushton 2005;Calvert et al 2003;Chen et al 2005;Meijers et al 1996;Möhner et al 2013;Sellamuthu et al 2013).…”

Ex vivo perfusion induces a time- and perfusate-dependent molecular repair response in explanted porcine lungs

“…Genome‐wide microarray studies have previously demonstrated that ALI induces coordinated changes in the expression of hundreds of genes . We hypothesized that analyzing a representative subset of these previously described ALI‐related transcripts would allow for more precise, objective, and mechanistic evaluation of lung tissue injury and repair before, during, and after EVLP.…”