Lung Fibrosis is Ameliorated by Pirfenidone Fed in Diet After the Second Dose In A Three-Dose Bleomycin-Hamster Model

Abstract

Interstitial lung fibrosis (ILF) is a life-threatening disease which has no known drug for prevention and cure. In the present study, we evaluated the antifibrotic potential of pirfenidone (PD) (5-methyl-1-phenyl-2-(1H)-pyridone) in a three-dose bleomycin (BL)-hamster model of lung fibrosis. Hamsters were intratracheally (IT) instilled with three consecutive doses of bleomycin sulfate (2.5 U/kg/5mL, 2.0 U/kg/5mL, 1.5 U/kg/3.75 mL) or an equivalent volume of saline at weekly intervals. Hamsters were fed a diet after the second dose of BL containing 0.5% PD and hamsters in the control groups were fed the same diet without the drug. The four groups were saline-instilled fed control diet (SCD); saline-instilled fed the same diet containing PD (SPD); BL-instilled fed control diet (BCD); and BL-instilled fed the diet containing PD (BPD). Hamsters were sacrificed at 28 days after IT instillation of last dose of saline or BL and their lungs processed for various assays. Lung hydroxyproline, an index of fibrosis, in SCD, SPD, BCD and BPD were 830, 804, 1609, 1235 micrograms/lung, respectively. Lung prolyl hydroxylase activities in the SPD, BCD and BPD groups were 103%, 313%, 157% of the control SCD group (5.99 x 10(4) dpm/lung/30 min) respectively. Malondialdehyde equivalent levels and superoxide dismutase activity in the corresponding groups were 99, 79, 240 and 145 nmoles/lung and 412, 433, 538 and 410 units/lung respectively. Lung myeloperoxidase activities in the corresponding groups were 56%, 179%, and 116% of the control group (0.44 units/lung). It is concluded that PD is a novel antifibrotic drug that has therapeutic potential in arresting the progression of an ongoing fibrotic process in the lung.

Pirfenidone Prevents the Development of a Vulnerable Substrate for Atrial Fibrillation in a Canine Model of Heart Failure

“…7,10,30,[42][43][44] The present results suggest that PFD attenuates CHF-related arrhythmogenic atrial remodeling via a complex set of actions, affecting multiple levels and components of the fibrosis formation and degradation signaling cascade.…”

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

“…P. Li, Li, He, Yi, & Kaplan, 2004), Methylprednisolone (Phan, Thrall, & Williams, 1981), Prednisolone (Chaudhary, Schnapp, & Park, 2006;Entzian et al, 1998) 1986) etc. ), and Pirfenidone (Ammar et al, 2006;Gurujeyalakshmi, Hollinger, & Giri, 1999;Iyer, Gurujeyalakshmi, & Giri, 1999;Iyer, Hyde, & Giri, 2000;Iyer, Margolin, Hyde, & Giri, 1998;Iyer et al, 1995;Kakugawa et al, 2004;Mansoor, Chen, Schelegle, & Giri, 1999;Schelegle, Mansoor, & Giri, 1997). Considering the extensive number of compounds we will discuss only a few representative examples in greater detail.…”

Ex vivomicro-computed tomography analysis of bleomycin-induced lung fibrosis for preclinical drug evaluation

“…bleomycin-induced lung fibrosis in hamsters and mice [6,13], and has received marketing authorisation for the treatment of mild-to-moderate IPF in Europe. In contrast, oral prednisolone given therapeutically to rats following bleomycin administration does not ameliorate fibrosis [9,14].…”