Roflumilast Prevents the Metabolic Effects of Bleomycin-Induced Fibrosis in a Murine Model

Milara, Javier; Morcillo, Esteban J.; Monleón, Daniel; Tenor, Herman; Cortijo, Julio

doi:10.1371/journal.pone.0133453

Cited by 14 publications

(15 citation statements)

References 39 publications

(51 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Specifically, the initiation of roflumilast treatment on day 0 and day 7 following bleomycin injury reduced day 14 and day 21 lung fibrosis, respectively (Cortijo et al 2009). In a separate study, roflumilast also reversed the metabolic alterations of bleomycin injury when administered in a preventative regimen (Milara et al 2015).…”

Section: Introductionmentioning

confidence: 90%

See 1 more Smart Citation

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

et al. 2018

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 90%

“…In a separate study, roflumilast also reversed the metabolic alterations of bleomycin injury when administered in a preventative regimen (Milara et al. ).…”

Section: Introductionmentioning

confidence: 98%

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

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Additionally, IPF fibroblasts have been shown to have aberrant metabolic profiles characterized by increased glycolytic activity. When these metabolic processes were inhibited, it resulted in decreased fibrosis, suggesting at the role of glycolytic reprogramming in fibrogenesis.…”

Section: Introductionmentioning

confidence: 99%

Metabolic variations in normal and fibrotic human laryngotracheal‐derived fibroblasts: A Warburg‐like effect

Samad

Motz

et al. 2016

The Laryngoscope

View full text Add to dashboard Cite

Objective/Purpose Laryngotracheal stenosis (LTS) is a chronic fibrotic disease characterized by fibroblast proliferation, collagen deposition, and matrix remodeling in the lamina propria of the larynx and/or trachea. Current medical therapies are limited by a poor understanding of the effector cell’s (fibroblasts) cellular biology and metabolism. The purpose of this study is to compare cellular proliferation, function, and metabolism between normal and LTS-derived fibroblasts in vitro. Methods Human biopsies of normal and iatrogenic LTS tissue (n=7) were obtained and fibroblasts were isolated and cultured in vitro. Cellular proliferation, cellular histology, gene expression and metabolic analyses were performed. Statistical analyses comparing normal and scar-derived fibroblasts were performed. Results LTS fibroblast proliferation rate, cellular surface area, and collagen-1 expression were increased compared to normal fibroblasts. Cellular metabolic analysis of LTS-derived fibroblasts demonstrated reduced oxidative phosphorylation and increased glycolysis/oxidative phosphorylation ratio compared with normal fibroblasts. Conclusion Human iatrogenic LTS-derived fibroblasts demonstrated aberrant behavior when compared with normal fibroblasts. A Warburg-like effect was revealed suggesting human iatrogenic LTS fibroblasts drive their proliferation with aerobic glycolysis. The distinct metabolism suggests metabolic inhibitors could reduce fibroblast hyperplasia and hypertrophy in LTS and fibrosis in general.

show abstract

“…Within this regard, roflumilast could also normalize most of increased metabolic changes like alterations in oxidative equilibrium, increased collagen, and protein synthesis, resulting in decline in the fibrotic score. Simultaneously, reduced lung tissue pH has been proposed as a risk factor for lung fibrosis development, which was also reported to be corrected by roflumilast in bleomycin model of pulmonary fibrosis ( Milara et al, 2015a ).…”

Section: Pharmacotherapeutic Effects Of Roflumilastmentioning

confidence: 99%

New putative insights into neprilysin (NEP)-dependent pharmacotherapeutic role of roflumilast in treating COVID-19

Tabaa

2020

European Journal of Pharmacology

View full text Add to dashboard Cite

Nowadays, coronavirus disease 2019 (COVID-19) represents the most serious inflammatory respiratory disease worldwide. Despite many proposed therapies, no effective medication has yet been approved. Neutrophils appear to be the key mediator for COVID-19-associated inflammatory immunopathologic, thromboembolic and fibrotic complications. Thus, for any therapeutic agent to be effective, it should greatly block the neutrophilic component of COVID-19. One of the effective therapeutic approaches investigated to reduce neutrophil-associated inflammatory lung diseases with few adverse effects was roflumilast. Being a highly selective phosphodiesterase-4 inhibitors (PDE4i), roflumilast acts by enhancing the level of cyclic adenosine monophosphate (cAMP), that probably potentiates its anti-inflammatory action via increasing neprilysin (NEP) activity. Because activating NEP was previously reported to mitigate several airway inflammatory ailments; this review thoroughly discusses the proposed NEP-based therapeutic properties of roflumilast, which may be of great importance in curing COVID-19. However, further clinical studies are required to confirm this strategy and to evaluate its in vivo preventive and therapeutic efficacy against COVID-19.

show abstract

Roflumilast Prevents the Metabolic Effects of Bleomycin-Induced Fibrosis in a Murine Model

Cited by 14 publications

References 39 publications

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

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

Metabolic variations in normal and fibrotic human laryngotracheal‐derived fibroblasts: A Warburg‐like effect

New putative insights into neprilysin (NEP)-dependent pharmacotherapeutic role of roflumilast in treating COVID-19

Contact Info

Product

Resources

About