Abstract
Objective: Paraquat (N,N0-dimethyl-4,40-bipyridinium dichloride;PQ) is a highly toxic pesticide, which usually leads to acute lung injury and subsequent development of pulmonary fibrosis. The exact mechanism underlying PQ-induced lung fibrosis remain largely unclear and as yet, no specific treatment drugs have been approved. Our study aimed to identify its potential mechanisms of PQ-induced fibrosis through a modeling study in vitro studies and bioinformatics analysis.Methods: Gene expression datasets associated with PQ-induced lung fibrosis were obtained from the Gene Expression Omnibus, wherefrom differentially expressed genes (DEGs) were identified using GEO2R. Functional enrichment analyses were performed using the Database for Annotation Visualization and Integrated Discovery. The DEGs analyzed by a protein–protein interaction network was constructed with the Search Tool for the Retrieval of Interacting Genes database. MCODE, a Cytoscape plugin, was subsequently used to identify the most significant modules. The expression of the key genes in PQ-induced pulmonary fibrotic tissues was verified by reverse transcription-quantitative PCR (RT-qPCR).Results: Two datasets were analyzed and revealed 92 overlapping DEGs. Functional analysis demonstrated that these 92 DEGs were enriched in the ‘TNF signaling pathway’, ‘CXCR chemokine receptor binding’, and ‘core promoter binding’. Moreover, nine hub genes were identified from the protein–protein interaction network formed from the DEGs. These results suggested that the TNF signaling pathway and nine hub genes are possibly involved in PQ-induced lung fibrosis progression.Conclusions: This integrative analysis identified candidate genes and pathways potentially involved in PQ-induced lung fibrosis, and could benefit future development of novel approaches for controlling and treating this disease.
Highlights
Paraquat (PQ) has become a widely used herbicide in agriculture for its ability to rapidly kill leaf weeds with non-selective characteristics [1, 2]
The analysis by western blot demonstrated that PQ treatment induced a pronounced increase in the levels of α-SMA protein, with a peak of expression at 200 μmol/L of PQ lasting for 48 h. These results are indicative of a differentiation of the lung fibroblasts into myofibroblasts
This is the first study to report the development of a preclinical in vitro model of PQinduced pulmonary fibrosis and explore the potential mechanism of development of this disease through bioinformatics analysis
Summary
Paraquat (PQ) has become a widely used herbicide in agriculture for its ability to rapidly kill leaf weeds with non-selective characteristics [1, 2]. As a harmful substance to humans and livestock, PQ poisoning has become a common cause of deaths by pesticide poisoning and has a fatality rate of 38.08% [2]. PQ intoxication leads to health damage in human health and causes multiple serious diseases, such as severe pulmonary inflammation, edema, and pulmonary fibrosis, which have high mortality rate and lack effective therapeutic strategies [3, 4]. The extremely high toxicity and lethality of PQ impedes effective research, and the identification of the mechanisms underlying PQ-induced pulmonary fibrosis remains challenging. The accurate determination and control of the highest nonlethal concentration of PQ is a crucial prerequisite for further research on PQ-induced pulmonary fibrosis. Microarray technology helps determine mRNA profiles and provides a comprehensive and systematic analysis of disease processes, including those involved in pulmonary fibrosis [5]. Integrative analyses of genes and pathways associated with lung fibrosis may provide insights into potential therapeutic targets and diagnostic biomarkers for PQ-induced pulmonary fibrosis
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