Posttreatment with Protectin DX ameliorates bleomycin-induced pulmonary fibrosis and lung dysfunction in mice

Li, Hui; Yu, Hao; Zhang, Huawei; Ying, Weiyang; Li, Dan; Ge, Yahe; Bin-yu, Ying; Cheng, Bihuan; Lian, Qingquan; Jin, Shudong

doi:10.1038/srep46754

Cited by 40 publications

(40 citation statements)

References 33 publications

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“…Additionally, we observed statistically significant increases in collagen content in the lung, accompanied by increased lung weight and lung index in treated animals compared to untreated mice. Analysis of biomarkers in BALf showed significant increases in TGF-β1, IL-6, VEGF, TIMP1, and CRP levels, all of which are consistent with previous reports [12][13][14][15][16][17].…”

Section: Discussionsupporting

confidence: 92%

Bleomycin mouse model with active-phase pulmonary fibrosis and no acute mortality

Kadam¹,

Faix²,

Schnitzer³

2020

Preprint

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Background The bleomycin mouse model is the most prevalent animal model used to study idiopathic pulmonary fibrosis (IPF), ranging from basic pathophysiological mechanisms to therapeutic modalities. High mortality rates, inconsistencies in disease induction, and great severity of the disease phenotype have limited its utility and clinical relevance. In this study, we identify conditions in the mouse bleomycin model that maintain the desired IPF phenotype found in patients while avoiding the usual, associated rapid mouse mortality. Methods In two independent studies, we analyzed the effects of incremental intratracheal (IT) high (1-3 U/kg) and low (0.05-0.5 U/kg) bleomycin doses on pulmonary fibrosis in mice. We observed dose effects on weight loss, morbidity and mortality, inflammation, lung collagen content, presence of various biomarkers in bronchoalveolar lavage fluid (BALf), and histology 14 days post-treatment, when the animals were in the active phase of fibrosis. Results We characterize the fibrotic effects of various bleomycin doses in mice on pulmonary inflammation, myofibroblast activation, vascular leakiness, angiogenesis, and extracellular tissue remodeling. Higher bleomycin doses induced acute disease with severe and saturated responses, extreme and progressive weight loss, and high morbidity and mortality rates. In contrast, lower doses of bleomycin induced a milder and chronic response, featuring robust, active-phase fibrosis with mild weight loss and no mortality. Conclusion Here we demonstrate that the bleomycin mouse model can be used to reproduce symptoms of IPF patients in an animal by using low doses of bleomycin. Low concentrations of bleomycin induce chronic and progressive fibrosis with no mortality.

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Section: Discussionsupporting

confidence: 92%

Bleomycin mouse model with active-phase pulmonary fibrosis and no acute mortality

Kadam¹,

Faix²,

Schnitzer³

2020

Preprint

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“…and i.p . BLM treatment (De Langhe et al., ; Devos et al., ; Li et al., ). Interestingly, we report changes in A , an estimate of inspiratory capacity, as early as day 7 of BLM treatment.…”

Section: Discussionmentioning

confidence: 99%

Low‐dose administration of bleomycin leads to early alterations in lung mechanics

Headley

Wilson

et al. 2018

Experimental Physiology

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New Findings What is the central question of this study?When do alterations in pulmonary mechanics occur following chronic low‐dose administration of bleomycin? What is the main finding and its importance?Remarkably, we report changes in lung mechanics as early as day 7 that corresponded to parameters determined from single‐frequency forced oscillation manoeuvres and pressure–volume loops. These changes preceded substantial histological changes or changes in gene expression levels. These findings are significant to refine drug discovery in idiopathic pulmonary fibrosis, where preclinical studies using lung function parameters would enhance the translational potential of drug candidates where lung function readouts are routinely performed in the clinic. Abstract Idiopathic pulmonary fibrosis (IPF) is the most widespread form of interstitial lung disease and, currently, there are only limited treatment options available. In preclinical animal models of lung fibrosis, the effectiveness of experimental therapeutics is often deemed successful via reductions in collagen deposition and expression of profibrotic genes in the lung. However, in clinical studies, improvements in lung function are primarily used to gauge the success of therapeutics directed towards IPF. Therefore, we examined whether changes in respiratory system mechanics in the early stages of an experimental model of lung fibrosis can be used to refine drug discovery approaches for IPF. C57BL/6J mice were administered bleomycin (BLM) or a vehicle control i.p. twice a week for 4 weeks. At 7, 14, 21, 28 and 33 days into the BLM treatment regimen, indices of respiratory system mechanics and pressure–volume relationships were measured. Concomitant with these measurements, histological and gene analyses relevant to lung fibrosis were performed. Alterations in respiratory system mechanics and pressure–volume relationships were observed as early as 7 days after the start of BLM administration. Changes in respiratory system mechanics preceded the appearance of histological and molecular indices of lung fibrosis. Administration of BLM leads to early changes in respiratory system mechanics that coincide with the appearance of representative histological and molecular indices of lung fibrosis. Consequently, these data suggest that dampening the early changes in respiratory system mechanics might be used to assess the effectiveness of experimental therapeutics in preclinical animal models of lung fibrosis.

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“…PD1 has anti-inflammatory and survival effects on neuronal diseases such as Alzheimer's disease and retinal degenerations [305]. PDX (1-100 nM), one of PD1 derivatives, can suppress bleomycin-induced lung fibrosis through blocking EMT [6,306]. However, it is hard to find reports about the effect of PDs on the EMT of cancer cells [6,306].…”

Section: Reversal Of Emt By Natural Pro-resolving Lipidsmentioning

confidence: 99%

“…PDX (1-100 nM), one of PD1 derivatives, can suppress bleomycin-induced lung fibrosis through blocking EMT [6,306]. However, it is hard to find reports about the effect of PDs on the EMT of cancer cells [6,306]. However, it is hard to find reports about the effect of PDs on the EMT of cancer cells.…”

Section: Reversal Of Emt By Natural Pro-resolving Lipidsmentioning

confidence: 99%

Reversal of Epithelial–Mesenchymal Transition by Natural Anti-Inflammatory and Pro-Resolving Lipids

Lee

2019

Cancers

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Epithelial mesenchymal transition (EMT) is a key process in the progression of malignant cancer. Therefore, blocking the EMT can be a critical fast track for the development of anticancer drugs. In this paper, we update recent research output of EMT and we explore suppression of EMT by natural anti-inflammatory compounds and pro-resolving lipids.A typical signaling pathway of EMT is the transforming growth factor-β1 (TGF-β1) pathway. TGF-β1 induces EMT via SMAD-dependent or non-SMAD signaling pathway [7]. Growth factors including FGF, HGF, IGF1, EGF, and PDGF via receptor tyrosine kinase can induce EMT via signaling pathway of PI3K-AKT and ERK MAPK [8][9][10][11]. Wnt signaling, hedgehog signaling, Notch signaling, hypoxia, and inflammatory tumor microenvironment also involves in EMT [5]. Recently, it has been shown that hippo signaling is also involved in EMT [12]. YAP and TAZ can enhance EMT through upregulation of EMT transcription factors such as forkhead box C2 (FOXC2), snail family zinc finger 1/2 (SNAIL1, SLUG), twist-related protein 1 (TWIST1), and ZEB1 [12-15]. Transcription Factors Involved in EMTNovel players are newly recognized as regulatory transcription factor in the EMT. Brachyury, the T-box transcription factor, is a novel transcription factor implicated in the EMT of cancer cells [16]. Brachyury is known as the target gene of WNT, one of the m ajor signaling pathways of EMT [17]. Foxq1, one of forkhead transcription factor, has also regarded as a novel transcription factor mediating the EMT of gastric cancer [6,18]. Runt-related transcription factor 2 (Runx2) belongs to the runt-related transcription factor family [19]. Runx2 plays a key role in EMT of hepatocellular carcinoma (HCC) [20]. GATA transcription factors are also implicated in the EMT of cancer cells [21].A typical signaling pathway of EMT is the transforming growth factor-β1 (TGF-β1) pathway. TGF-β1 induces EMT via SMAD-dependent or non-SMAD signaling pathway [7]. Growth factors including FGF, HGF, IGF1, EGF, and PDGF via receptor tyrosine kinase can induce EMT via signaling pathway of PI3K-AKT and ERK MAPK [8][9][10][11]. Wnt signaling, hedgehog signaling, Notch signaling, hypoxia, and inflammatory tumor microenvironment also involves in EMT [5]. Recently, it has been shown that hippo signaling is also involved in EMT [12]. YAP and TAZ can enhance EMT through upregulation of EMT transcription factors such as forkhead box C2 (FOXC2), snail family zinc finger 1/2 (SNAIL1, SLUG), twist-related protein 1 (TWIST1), and ZEB1 [12-15]. Transcription Factors Involved in EMTNovel players are newly recognized as regulatory transcription factor in the EMT. Brachyury, the T-box transcription factor, is a novel transcription factor implicated in the EMT of cancer cells [16]. Brachyury is known as the target gene of WNT, one of the major signaling pathways of EMT [17]. Foxq1, one of forkhead transcription factor, has also regarded as a novel transcription factor mediating the EMT of gastric cancer [6,18]. Runt-related transcription factor 2 (Runx2...

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Posttreatment with Protectin DX ameliorates bleomycin-induced pulmonary fibrosis and lung dysfunction in mice

Cited by 40 publications

References 33 publications

Bleomycin mouse model with active-phase pulmonary fibrosis and no acute mortality

Bleomycin mouse model with active-phase pulmonary fibrosis and no acute mortality

Low‐dose administration of bleomycin leads to early alterations in lung mechanics

Reversal of Epithelial–Mesenchymal Transition by Natural Anti-Inflammatory and Pro-Resolving Lipids

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