Pentoxifylline Regulates Plasminogen Activator Inhibitor-1 Expression and Protein Kinase A Phosphorylation in Radiation-Induced Lung Fibrosis.

Jong-Geol Lee,Sehwan Shim,Won-Suk Jang,Jae Kyung Myung,Kyeong Min Kim,Min-Jung Kim,Sun-Joo Lee,Young-Woo Jin,Sunhoo Park,Seung-Sook Lee,Chang-Hwan Bae

doi:10.1155/2017/1279280

Abstract

Purpose. Radiation-induced lung fibrosis (RILF) is a serious late complication of radiotherapy. In vitro studies have demonstrated that pentoxifylline (PTX) has suppressing effects in extracellular matrix production in fibroblasts, while the antifibrotic action of PTX alone using clinical dose is yet unexplored. Materials and Methods. We used micro-computed tomography (micro-CT) and histopathological analysis to evaluate the antifibrotic effects of PTX in a rat model of RILF. Results. Micro-CT findings showed that lung density, volume loss, and mediastinal shift are significantly increased at 16 weeks after irradiation. Simultaneously, histological analysis demonstrated thickening of alveolar walls, destruction of alveolar structures, and excessive collagen deposition in the irradiated lung. PTX treatment effectively attenuated the fibrotic changes based on both micro-CT and histopathological analyses. Western analysis also revealed increased levels of plasminogen activator inhibitor- (PAI-) 1 and fibronectin (FN) and PTX treatment reduced expression of PAI-1 and FN by restoring protein kinase A (PKA) phosphorylation but not TGF-β/Smad in both irradiated lung tissues and epithelial cells. Conclusions. Our results demonstrate the antifibrotic effect of PTX on radiation-induced lung fibrosis and its effect on modulation of PKA and PAI-1 expression as possible antifibrotic mechanisms.

Highlights

In the clinic, radiation-induced lung fibrosis (RILF) is the main chronic adverse effect of radiotherapy [1,2,3]
We used micro-CT and histopathological analyses to demonstrate that PTX attenuated RILF and explored possible target molecules involved in its antifibrotic effects
Quantification of fibrosis revealed that irradiation significantly induced lung fibrosis

Summary

Introduction

Radiation-induced lung fibrosis (RILF) is the main chronic adverse effect of radiotherapy [1,2,3]. A recent study demonstrated that increased FN expression was significantly reduced by plasminogen activator- (PAI-) 1 inhibitor in human lung fibroblasts [7]. Knockout of the PAI-1 gene or knockdown of PAI-1 by small interfering RNA attenuates, whereas overexpression of PAI-1 enhances, fibrotic responses [7,8,9,10]. All these lines of evidence suggest that PAI-1 plays an essential role in the development of fibrosis

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Conclusion