Antifibrotic Agent Pirfenidone Protects against Development of Radiation-Induced Pulmonary Fibrosis in a Murine Model

Abstract

Radiation-induced complications of the respiratory system are a common side effect of thoracic radiotherapy with no viable treatment option. Here, we investigated the potential therapeutic effect of the orphan drug pirfenidone for treating radiation-induced pulmonary fibrosis. C57BL/6 mice received a single fraction of 16 Gy to the thorax and were subsequently treated with 300 mg/kg/day pirfenidone for four weeks. Survival and body weight of the mice were quantified. Micro-CT in vivo lung imaging was performed to dynamically observe the developmental process of pulmonary fibrosis. The lungs were excised at the end of the experiment and evaluated for histological changes. Compared to the irradiated mice that received no pirfenidone, mice treated with pirfenidone after irradiation had an extended median survival time (>140 days vs. 73 days, P < 0.01). The accumulation of collagen and fibrosis in lung tissues after irradiation was decreased with pirfenidone treatment. Pirfenidone also reduced the expression of TGF-β1 and phosphorylation of Smad3 in lung tissues. The dose level of Pirfenidone used in this study attenuated pulmonary fibrosis and prolonged the life span of irradiated mice. It may offer a promising approach to treat or minimize radiation-induced pulmonary fibrosis.

Pirfenidone facilitates immune infiltration and enhances the antitumor efficacy of PD-L1 blockade in mice

“…Western blot analysis was performed as previously described 8 using the following antibodies: anti-Smad2/3 (1:1000; CAT#8828S, Cell Signaling Technology), anti-p-Smad2/3 (1:1000; CAT#8685S, Cell Signaling Technology), anti-PD-L1 (1:1000, CAT#66248-1-lg, Proteintech), GAPDH (1:5000; CAT#AS1039, Aspen Biological). Briefly, tissues were homogenized, mixed with 5 X loading buffer and boiled to denaturation.…”

“…Lung histological analysis was conducted as previously described. 8 Briefly, lung tissue was fixed in 4% formalin and embedded in paraffin, and subsequently cut into 5-µm thick sections and stained with hematoxylin and eosin (H&E) and Masson's trichrome (Aspen Biological, Wuhan, China). The sections stained with Masson's trichrome were subjected to Ashcroft score by two senior pathologists blinded to the experimental information.…”

“…Pirfenidone (PFD) is a small pyridine compound synthesized by Morgolin in 1974 and approved for the treatment of mild to moderate IPF in 2011 and 2014 in Europe and the United States, respectively. 7 Although the exact mechanism of action is not fully understood, studies conducted by us 8 as well as others 9 suggest that PFD exerts dramatic antifibrotic properties through downregulating TGFβ signaling, reducing fibroblast proliferation, and inhibiting collagen synthesis. Recently, a study using transcriptomic approach revealed that in IPF patients, genes altered by PFD are enriched not only in "extracellular matrix," but also in "immune response."…”

Chemokine receptor 2-targeted molecular imaging in pulmonary fibrosis

“…While anti-IL-1b antibodies are not a standard IPF treatment, pirfenidone is one of two drugs approved for patients (3). Pirfenidone treatment is reported to reduce fibrosis in bleomycin-, radiation-, and graft-versus-host-induced lung fibrosis models (22,23,41,42). Thus, we examined pirfenidone modulation of lung 64 Cu-DOTA-ECL1i PET uptake.…”

Treatment of progressive fibrosing interstitial lung diseases: a milestone in the management of interstitial lung diseases

“…Nintedanib, an intracellular inhibitor of tyrosine kinases [27,28], has shown antifibrotic, anti-inflammatory and vascular remodelling effects in several non-clinical models of fibrosis [29,30]. Pirfenidone, a small molecule with antifibrotic, anti-inflammatory and anti-oxidative effects, suppresses the production of transforming growth factor-β, the proliferation and differentiation of myofibroblasts, and the deposition of collagen, and has favourable effects in non-clinical models of lung fibrosis [31][32][33][34]. Both drugs have demonstrated efficacy in IPF and could be effective to slow down progressive fibrosis in PF-ILDs irrespective of the trigger for the injury.…”