Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium

Liu, Yuan; Fj, Lu; Kang, L.; Wang, Zhihua; Wang, Yongfu

doi:10.1186/s12890-017-0405-7

Cited by 122 publications

(98 citation statements)

References 40 publications

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“…Preclinical models of pulmonary fibrosis indicate that Nrf2 is suppressed as the disease progresses [16, 17] and that haploinsufficiency is sufficient for enhanced susceptibility [8]. Conversely, pirfenidone-mediated inhibition of pulmonary fibrosis does so in part by inducing expression of Nrf2 [18]. Hence, these data support a hypothesis that posits that loss of Nrf2 promotes pulmonary fibrosis.…”

Section: Introductionmentioning

confidence: 68%

Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung

Traver

Mont

Gius

et al. 2017

Free Radical Biology and Medicine

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The development of radiation-induced pulmonary fibrosis represents a critical clinical issue limiting delivery of therapeutic doses of radiation to non-small cell lung cancer. Identification of the cell types whose injury initiates a fibrotic response and the underlying biological factors that govern that response are needed for developing strategies that prevent or mitigate fibrosis. C57BL/6 mice (wild type, Nrf2 null, Nrf2flox/flox, and Nrf2Δ/Δ; SPC-Cre) were administered a thoracic dose of 12 Gy and allowed to recover for 250 days. Whole slide digital and confocal microscopy imaging of H&E, Masson’s trichrome and immunostaining were used to assess tissue remodeling, collagen deposition and cell renewal/mobilization during the regenerative process. Histological assessment of irradiated, fibrotic wild type lung revealed significant loss of alveolar type 2 cells 250 days after irradiation. Type 2 cell loss and the corresponding development of fibrosis were enhanced in the Nrf2 null mouse. Yet, conditional deletion of Nrf2 in alveolar type 2 cells in irradiated lung did not impair type 2 cell survival nor yield an increased fibrotic phenotype. Instead, radiation-induced ΔNp63 stem/progenitor cell mobilization was inhibited in the Nrf2 null mouse while the propensity for radiation-induced myofibroblasts derived from alveolar type 2 cells was magnified. In summary, these results indicate that Nrf2 is an important regulator of irradiated lung’s capacity to maintain alveolar type 2 cells, whose injury can initiate a fibrotic phenotype. Loss of Nrf2 inhibits ΔNp63 stem/progenitor mobilization, a key event for reconstitution of injured lung, while promoting a myofibroblast phenotype that is central for fibrosis.

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Section: Introductionmentioning

confidence: 68%

Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung

Traver

Mont

Gius

et al. 2017

Free Radical Biology and Medicine

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“…Pirfenidone was dosed at 100 mg/kg three times daily (Liu et al. ) and nintedanib was dosed at 100 mg/kg twice daily (Wollin et al. ) by gavage.…”

Section: Methodsmentioning

confidence: 99%

Phosphodiesterase 4 inhibition reduces lung fibrosis following targeted type II alveolar epithelial cell injury

et al. 2018

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Fibrosis of the lung constitutes a major clinical challenge and novel therapies are required to alleviate the associated morbidity and mortality. Investigating the antifibrotic efficacy of drugs that are already in clinical practice offers an efficient strategy to identify new therapies. The phosphodiesterase 4 (PDE4) inhibitors, approved for the treatment of chronic obstructive pulmonary disease, harbor therapeutic potential for pulmonary fibrosis by augmenting the activity of endogenous antifibrotic mediators that signal through cyclic AMP. In this study, we tested the efficacy of several PDE4 inhibitors including a novel compound (Compound 1) in a murine model of lung fibrosis that results from a targeted type II alveolar epithelial cell injury. We also compared the antifibrotic activity of PDE4 inhibition to the two therapies that are FDA‐approved for idiopathic pulmonary fibrosis (pirfenidone and nintedanib). We found that both preventative (day 0–21) and therapeutic (day 11–21) dosing regimens of the PDE4 inhibitors significantly ameliorated the weight loss and lung collagen accumulation that are the sequelae of targeted epithelial cell damage. In a therapeutic protocol, the reduction in lung fibrosis with PDE4 inhibitor administration was equivalent to pirfenidone and nintedanib. Treatment with this class of drugs also resulted in a decrease in plasma surfactant protein D concentration, a reduction in the plasma levels of several chemokines implicated in lung fibrosis, and an in vitro inhibition of fibroblast profibrotic gene expression. These results motivate further investigation of PDE4 inhibition as a treatment for patients with fibrotic lung disease.

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“…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. pirfenidone (Liu, Lu, Kang, Wang, & Wang, 2017;Oku et al, 2008;Wollin et al, 2015), there are several imperfections in this model that could affect future approaches to IPF drug development (Carrington et al, 2018;Degryse & Lawson, 2011;Jenkins et al, 2017;Moore et al, 2013). First and most notably, fibrosis completely resolves over time in these mice, which is in contrast to the progressive and nonresolving nature of fibrosis in IPF.…”

Section: • What Is the Central Question Of This Study?mentioning

confidence: 99%

“…model of BLM‐induced lung fibrosis, a single dose of BLM is instilled and results in an inflammatory response that persists for 7–10 days that ultimately leads to lung fibrosis 14–21 days after BLM administration (Carrington et al., ; Degryse & Lawson, ; Jenkins et al., ; Moore et al., ). Although this experimental model was used to show the effectiveness of both nintedanib and pirfenidone (Liu, Lu, Kang, Wang, & Wang, ; Oku et al., ; Wollin et al., ), there are several imperfections in this model that could affect future approaches to IPF drug development (Carrington et al., ; Degryse & Lawson, ; Jenkins et al., ; Moore et al., ). First and most notably, fibrosis completely resolves over time in these mice, which is in contrast to the progressive and non‐resolving nature of fibrosis in IPF.…”

Section: Introductionmentioning

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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Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium

Cited by 122 publications

References 40 publications

Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung

Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung

Phosphodiesterase 4 inhibition reduces lung fibrosis following targeted type II alveolar epithelial cell injury

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

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