Pentoxifylline Regulates Plasminogen Activator Inhibitor-1 Expression and Protein Kinase A Phosphorylation in Radiation-Induced Lung Fibrosis.
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.
Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, KIRAMS, Seoul, Republic of Korea.
Jong-Geol
0000-0002-4312-6282
JG
Lee
Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, KIRAMS, Seoul, Republic of Korea.
Sehwan
0000-0002-6226-9270
S
Shim
Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, KIRAMS, Seoul, Republic of Korea.
Min-Jung
0000-0003-1954-1096
MJ
Kim
Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, KIRAMS, Seoul, Republic of Korea; Department of Pathology, Korea Cancer Center Hospital, KIRAMS, Seoul, Republic of Korea.
Jae Kyung
0000-0001-9612-5323
JK
Myung
Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, KIRAMS, Seoul, Republic of Korea.
Won-Suk
0000-0003-2713-5506
WS
Jang
Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, KIRAMS, Seoul, Republic of Korea.
Chang-Hwan
CH
Bae
Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, KIRAMS, Seoul, Republic of Korea.
Sun-Joo
0000-0002-3756-7364
SJ
Lee
Molecular Imaging Research Center, KIRAMS, Seoul, Republic of Korea.
Kyeong Min
0000-0001-6284-0644
KM
Kim
Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, KIRAMS, Seoul, Republic of Korea.
Young-Woo
YW
Jin
Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, KIRAMS, Seoul, Republic of Korea; Department of Pathology, Korea Cancer Center Hospital, KIRAMS, Seoul, Republic of Korea.
Seung-Sook
SS
Lee
Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, KIRAMS, Seoul, Republic of Korea; Department of Pathology, Korea Cancer Center Hospital, KIRAMS, Seoul, Republic of Korea.
Sunhoo
0000-0001-6293-9257
S
Park
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D005353:Fibronectins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D010431:Pentoxifylline / Q000008:administration & dosage*; D010766:Phosphorylation / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D011650:Pulmonary Alveoli / Q000473:pathology / Q000528:radiation effects; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000473:pathology; D011878:Radiotherapy / Q000009:adverse effects; D051381:Rats; D055114:X-Ray Microtomography
D005353:Fibronectins; D017395:Plasminogen Activator Inhibitor 1; D017868:Cyclic AMP-Dependent Protein Kinases; D010431:Pentoxifylline