Fluorofenidone Attenuates Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice Via Restoring Caveolin 1 Expression and Inhibiting Mitogen-Activated Protein Kinase Signaling Pathway

Abstract

Idiopathic pulmonary fibrosis is a progressive, life-threatening, interstitial lung disease with no effective therapy. In this study, we evaluated the effects of fluorofenidone (FD), a novel pyridone agent, on a murine model of bleomycin-induced pulmonary inflammation and fibrosis. Institute for Cancer Research mice were intravenously injected with BLM or saline for 14 consecutive days. Fluorofenidone, pirfenidone (500 mg · kg · d, respectively), or vehicle was administered throughout the course of the experiment. Animals were killed on day 28, and various parameters reflecting pulmonary vascular permeability, influx of inflammatory cells, and levels of transforming growth factor β in the bronchoalveolar lavage fluid were assessed. Collagen I, α-smooth muscle actin, and fibronectin were measured by real-time reverse transcriptase-polymerase chain reaction or Western blot. Furthermore, caveolin 1 and activation of P38, extracellular signal-regulated kinase, and c-Jun N-terminal kinase were detected by Western blot. Fluorofenidone treatment significantly attenuated the increased pulmonary damage index score, the levels of proteins, transforming growth factor β, and the influx of cells in bronchoalveolar lavage fluid. Fluorofenidone also markedly reduced the expression of fibronectin, α-smooth muscle actin, and collagen I in mouse lung tissues. Inversely, FD restored caveolin 1 protein and mRNA expression, which was significantly downregulated in BLM-induced lung fibrosis. Fluorofenidone also inhibited phosphorylation of extracellular signal-regulated kinase, P38, and c-Jun N-terminal kinase. These findings collectively suggest that FD is an effective agent with antifibrotic and anti-inflammatory properties, and the mechanisms of its antifibrotic effect include regulating caveolin 1 expression and blocking mitogen-activated protein kinase signaling pathways.

Fluorofenidone attenuates hepatic fibrosis by suppressing the proliferation and activation of hepatic stellate cells

“…Moreover, fluorine compounds also have a high hydrophobicity, which can promote their absorption and transmission speed in vivo. In previous studies, AKF-PD has been proven to be a broad-spectrum antifibrosis drug, which could be used against renal fibrosis (34,45,48), pulmonary fibrosis (29), and myocardial fibrosis (8). Intriguingly, it is our…”

“…HSCs were isolated from the liver of normal male Sprague-Dawley rats (400 -450 g) through portal vein perfusion with collagenase-pronase and subsequent density gradient centrifugation as previously described (29). Freshly isolated HSCs were plated on plastic plates and cultured in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% of fetal bovine serum (FBS) at 37°C in a 5% CO 2 atmosphere for the first 48 h. Semiconfluent HSCs with 1-3 passages were used in experiments.…”

All-transretinoic acid ameliorates bleomycin-induced lung fibrosis by downregulating the TGF-β1/Smad3 signaling pathway in rats

“…[27][28][29][30][31] The TGF-b1/ Smad3 signaling pathway promotes fibrotic transformation of lung tissues via activation of EMT. [32][33][34] EMT is a process in which epithelial cells lose their epithelial phenotype, acquire fibroblast-like properties, and display reduced cell adhesion and increased motility. Reduction in expression of adhesion molecules allows the cells to detach from the epithelial layer and migrate towards the site of injury or inflammation where they exercise their profibrotic effects.…”

Fluorofenidone Attenuates Oxidative Stress and Renal Fibrosis in Obstructive Nephropathy via Blocking NOX2 (gp91phox) Expression and Inhibiting ERK/MAPK Signaling Pathway

“…Several studies have reported that it can attenuate fibrosis in kidney, liver, lung and heart [8,9,10,11]. We have reported previously that AKF-PD attenuates collagen I and transforming growth factor-beta1 expression through a Nox4-dependent way in rat proximal tubular epithelial cells (NRK-52E)[9], suggesting its potential anti-oxidative property.…”