Abstract B20: Repurposing of fenofibrate to prevent and treat PM-induced pulmonary fibroblast-mediated inflammation: Mechanism involved in SIRT1-SREBP1-PIR/NLRP3 inflammasome axis

Abstract

Abstract Particulate matter (PM) has been shown to have strong link with a variety of human morbidity and mortality. World Health Organization (WHO) recognizes air pollution as an invisible killer responsible for around 7 million global deaths per year, including 43% from chronic obstructive pulmonary disease (COPD), 29% from lung cancer, 25% from heart diseases, 24% from stroke, and 24% from pneumonia. Cardiopulmonary disease is considered as the leading PM-induced complication. The main mechanism involved in PM-induced cardiopulmonary disease is through upregulation of redox-sensitive signaling pathways, mediated by nuclear factor kappa B (NF-κB). We analyzed transcriptomics data by microarray chips in human pulmonary fibroblasts (HPF) after being treated by different doses of PM, and our result identified sterol regulatory element-binding protein 1 (SREBP1) as the top 1 transcription factor activated after PM exposure in HPF. Our analysis showed that Pirin (PIR), an iron-dependent redox regulator of NF-κB, was the most significantly and plausible transcriptional targets of SREBP1. Additionally, SREBP1, directly deacetylated and inhibited by Sirtuin 1 (SIRT1), increased the expression of inflammasome markers, e.g., NACHT, LRR and PYD domains containing protein 3 (NLPR3), Apoptosis-Associated Speck-Like Protein Containing CARD (ASC), and interleukin-1β (IL-1β), were documented. Our results further showed PM-induced inflammation could be reversed by inhibitors of SIRT1, SREBF1, and PIR. We concluded that SIRT1-SREBP1-PIR/NLRP3 inflammasome axis may play a key role in PM-induced sequel and may present new targets. Fenofibrate, clinically prescribed for dyslipidemia, prevented atrial fibrillation rabbits from atrial metabolic remodeling through the SIRT1-SREBP1 pathway. Moreover, in vivo fenofibrate was reported to regulate hyperglycemia-induced metabolic memory and reduce the inflammatory response via SIRT1-dependent suppression of NF-κB. On the basis of previous work and this study, we may repurpose fenofibrate as an anti-PM drug to prevent and treat PM-induced cardiopulmonary disease, which can be used in combination with COPD, heart disease, or anticancer medicines in future research. Citation Format: Chia-Ping Tien, Yu-Chan Chang, Shih-Chieh Hung, Michael Hsiao. Repurposing of fenofibrate to prevent and treat PM-induced pulmonary fibroblast-mediated inflammation: Mechanism involved in SIRT1-SREBP1-PIR/NLRP3 inflammasome axis [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B20.