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Fluorofenidone attenuates pulmonary inflammation and fibrosis via inhibiting the activation of NALP3 inflammasome and IL-1β/IL-1R1/MyD88/NF-κB pathway
Journal article   Open access

Fluorofenidone attenuates pulmonary inflammation and fibrosis via inhibiting the activation of NALP3 inflammasome and IL-1β/IL-1R1/MyD88/NF-κB pathway

Cheng Song, Lujuan He, Jin Zhang, Hong Ma, Xiangning Yuan, Gaoyun Hu, Lijian Tao, Jian Zhang and Jie Meng
Journal of cellular and molecular medicine, Vol.20(11), pp.2064-2077
11/2016
DOI: 10.1111/jcmm.12898
PMCID: PMC5082399
PMID: 27306439
url
https://doi.org/10.1111/jcmm.12898View
Published (Version of record) Open Access

Abstract

Interleukin (IL)-1β plays an important role in the pathogenesis of idiopathic pulmonary fibrosis. The production of IL-1β is dependent upon caspase-1-containing multiprotein complexes called inflammasomes and IL-1R1/MyD88/NF-κB pathway. In this study, we explored whether a potential anti-fibrotic agent fluorofenidone (FD) exerts its anti-inflammatory and anti-fibrotic effects through suppressing activation of NACHT, LRR and PYD domains-containing protein 3 (NALP3) inflammasome and the IL-1β/IL-1R1/MyD88/NF-κB pathway in vivo and in vitro. Male C57BL/6J mice were intratracheally injected with Bleomycin (BLM) or saline. Fluorofenidone was administered throughout the course of the experiment. Lung tissue sections were stained with haemotoxylin and eosin and Masson's trichrome. Cytokines were measured by ELISA, and α-smooth muscle actin (α-SMA), fibronectin, collagen I, caspase-1, IL-1R1, MyD88 were measured by Western blot and/or RT-PCR. The human actue monocytic leukaemia cell line (THP-1) were incubated with monosodium urate (MSU), with or without FD pre-treatment. The expression of caspase-1, IL-1β, NALP3, apoptosis-associated speck-like protein containing (ASC) and pro-caspase-1 were measured by Western blot, the reactive oxygen species (ROS) generation was detected using the Flow Cytometry, and the interaction of NALP3 inflammasome-associated molecules were measured by Co-immunoprecipitation. RLE-6TN (rat lung epithelial-T-antigen negative) cells were incubated with IL-1β, with or without FD pre-treatment. The expression of nuclear protein p65 was measured by Western blot. Results showed that FD markedly reduced the expressions of IL-1β, IL-6, monocyte chemotactic protein-1 (MCP-1), myeloperoxidase (MPO), α-SMA, fibronectin, collagen I, caspase-1, IL-1R1 and MyD88 in mice lung tissues. And FD inhibited MSU-induced the accumulation of ROS, blocked the interaction of NALP3 inflammasome-associated molecules, decreased the level of caspase-1 and IL-1β in THP-1 cells. Besides, FD inhibited IL-1β-induced the expression of nuclear protein p65. This study demonstrated that FD, attenuates BLM-induced pulmonary inflammation and fibrosis in mice via inhibiting the activation of NALP3 inflammasome and the IL-1β/IL-1R1/MyD88/ NF-κB pathway.
 Inflammasomes - metabolism Reactive Oxygen Species - metabolism Humans Actins - metabolism Caspase 1 - metabolism Male NF-kappa B - metabolism Receptors, Interleukin - metabolism Bleomycin Interleukin-1beta - metabolism Pneumonia - chemically induced Chemokine CCL2 - metabolism Lung - metabolism Pulmonary Fibrosis - metabolism Interleukin-6 - metabolism Lung - pathology Collagen Type I - metabolism NLR Family, Pyrin Domain-Containing 3 Protein - metabolism Pulmonary Fibrosis - complications Mice, Inbred C57BL Pulmonary Fibrosis - pathology Myeloid Differentiation Factor 88 Down-Regulation - drug effects Fibronectins - metabolism Animals Pneumonia - drug therapy Signal Transduction - drug effects Uric Acid - pharmacology Lung - drug effects Pneumonia - complications Pyridones - therapeutic use Pulmonary Fibrosis - drug therapy Pneumonia - metabolism Pyridones - pharmacology Peroxidase - metabolism

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