Pirfenidone ameliorates silica-induced lung inflammation and fibrosis in mice by inhibiting the secretion of interleukin-17A

Cao, Zhujie; Liu, Ying; Zhang, Zhe; Yang, Peiran; Li, Zhaoguo; Song, Meiyue; Qi, Xianmei; Han, Zhifa; Pang, Junling; Li, Bai-Cun; Zhang, Xinri; Dai, Huaping; Wang, Jing; Wang, Chen

doi:10.1038/s41401-021-00706-4

Cited by 38 publications

(16 citation statements)

References 29 publications

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“…Pirfenidone (PFD) is a pyridine derivative that has been approved by the FDA for the treatment of idiopathic pulmonary fibrosis and has been shown to exert anti-inflammatory and anti-fibrotic effects in multiple fibrosis models. Accumulating in vivo and in vitro evidence has confirmed that PFD could attenuate the development of silicosis ( Cao et al, 2021 ; Guo et al, 2019 ). Nevertheless, PFD has significant side effects and other tolerability and half-life (T1/2) issues, which limits its clinical application.…”

Section: Introductionmentioning

confidence: 99%

A Novel N-Arylpyridone Compound Alleviates the Inflammatory and Fibrotic Reaction of Silicosis by Inhibiting the ASK1-p38 Pathway and Regulating Macrophage Polarization

et al. 2022

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Silicosis is one of the potentially fatal occupational diseases characterized by respiratory dysfunction, chronic interstitial inflammation, and fibrosis, for which treatment options are limited. Previous studies showed that a novel N-arylpyridone compound named AKEX0011 exhibited anti-inflammatory and anti-fibrotic effects in bleomycin-induced pulmonary fibrosis; however, it is unknown whether it could also be effective against silicosis. Therefore, we sought to investigate the preventive and therapeutic roles of AKEX0011 in a silicosis rodent model and in a silica-stimulated macrophage cell line. In vivo, our results showed that AKEX0011 ameliorated silica-induced imaging lung damages, respiratory dysfunction, reduced the secretion of inflammatory and fibrotic factors (TNF-α, IL-1β, IL-6, TGF-β, IL-4, and IL-10), and the deposition of fibrosis-related proteins (collagen I, fibronectin, and α-SMA), regardless of early or advanced therapy. Specifically, we found that AKEX0011 attenuated silicosis by inhibiting apoptosis, blocking the ASK1-p38 MAPK signaling pathway, and regulating polarization of macrophages. In vitro, AKEX0011 inhibited macrophages from secreting inflammatory cytokines and inhibited apoptosis of macrophages in pre-treated and post-treated models, concurrent with blocking the ASK1-p38 pathway and inhibiting M1 polarization. Collectively, AKEX0011, as a novel N-arylpyridone compound, exerted protective effects for silica-induced pulmonary inflammation and fibrosis both in vivo and in vitro, and hence, it could be a strong drug candidate for the treatment of silicosis.

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Section: Introductionmentioning

confidence: 99%

A Novel N-Arylpyridone Compound Alleviates the Inflammatory and Fibrotic Reaction of Silicosis by Inhibiting the ASK1-p38 Pathway and Regulating Macrophage Polarization

et al. 2022

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“…Next, we investigated the mechanisms by which impaired IFN-γ signaling promotes pulmonary interstitial fibrosis and respiratory dysfunction in our model of silicosis. Because IL-1α、IL-1β、IL-17A、IL-23, IL-27, MCP-1, and IL-10 as important proinflammatory cytokines that significantly associated with the progression of silicosis( Liu et al., 2015 ; Cao et al., 2021 ; Chen et al., 2017 ; Luna-Gomes et al., 2015 ; Slavov et al., 2010 ), we measured these cytokine levels in the BALF using a Cytometric Bead Array. Inhalation of silica crystals increased the release of IL-1β, and to a lesser extent, IL-1ɑ, whereas the BALF levels of IL-17A, IL-23, IL-27, MCP-1 and IL-10 were not altered ( Figure 4 A).…”

Section: Resultsmentioning

confidence: 99%

Impaired interferon-γ signaling promotes the development of silicosis

et al. 2022

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“…However, the combination of VX-765 and pirfenidone robustly decreased silica crystal-induced inflammation and fibrosis (Figure 9B). Pirfenidone has also been shown to ameliorate silica inflammation and fibrosis in rodent models of silicosis (Cao et al, 2022; Guo et al, 2019). As pirferidone is approved for the treatment of idiopathic pulmonary fibrosis and a clinical trial with VX-765 has shown good tolerance and pharmacokinetic properties in patients (EudraCT Numbers 2004-000283-27 and 2011-004156-19), the combination therapy used here is seems to show promise for treating silicosis and other devastating pneumoconiosis.…”

Section: Discussionmentioning

confidence: 99%

Combination therapy targeting inflammasome and fibrogenesis alleviates inflammation and fibrosis in a zebrafish model of silicosis

Tyrkalska

Pedoto

Martínez‐López

et al. 2022

Preprint

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Silicosis is a long-term lung disease caused by the inhalation of large amounts of crystalline silica dust. As there is no effective treatment available, patients are provided with supportive care, and some may be considered for lung transplantation. There is therefore an evident need for a better understanding of the disease’s biology and for identifying new therapeutic targets and therapies. In this context, our group has developed a larval zebrafish model of silicosis by injecting silica crystals into the hindbrain ventricle, a cavity into which immune cells can be recruited and that mimics the alveolar environment of the human lung. The injection of silica crystals into this cavity led to the initiation of local and systemic immune responses driven through both TLR- and inflammasome-dependent signaling pathways, followed by fibrosis, as happens in human patients. The combination of the inflammasome inhibitor VX-765 and the antifibrotic agent pirfenidone was found to be the best therapy to alleviate both inflammation and fibrosis. The zebrafish model of silicosis developed here is a unique tool that will shed light onto the molecular mechanisms involved in the progression of this devastating disease and for identifying novel drugs that improve the quality of life of silicosis patients.

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Pirfenidone ameliorates silica-induced lung inflammation and fibrosis in mice by inhibiting the secretion of interleukin-17A

Cited by 38 publications

References 29 publications

A Novel N-Arylpyridone Compound Alleviates the Inflammatory and Fibrotic Reaction of Silicosis by Inhibiting the ASK1-p38 Pathway and Regulating Macrophage Polarization

A Novel N-Arylpyridone Compound Alleviates the Inflammatory and Fibrotic Reaction of Silicosis by Inhibiting the ASK1-p38 Pathway and Regulating Macrophage Polarization

Impaired interferon-γ signaling promotes the development of silicosis

Combination therapy targeting inflammasome and fibrogenesis alleviates inflammation and fibrosis in a zebrafish model of silicosis

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