Z Gastroenterol 2016; 54(12): 1343-1404
DOI: 10.1055/s-0036-1597359
1. Fibrogenesis
Georg Thieme Verlag KG Stuttgart · New York

Effects of radiation and/or tumor necrosis factor alpha on cell damage in a healthy liver: a role for PECAM-1

IA Malik
1   University Medical Center, Goettingen, Institute for Anatomy and Cell Biology, Goettingen, Germany
,
AR Asif
3   University Medical Center, Goettingen, Institute for Clinical Chemistry, Goettingen, Germany
,
G Ramadori
2   University Medical Center, Goettingen, Clinic for Gastroenterology and Endocrinology, Goettingen, Germany
,
J Wilting
1   University Medical Center, Goettingen, Institute for Anatomy and Cell Biology, Goettingen, Germany
› Author Affiliations
Further Information
Malik, Ihtzaz Ahmed

Publication History

Publication Date:
19 December 2016 (online)

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    The liver is considered to be radiosensitive; however, the mechanisms of radiation-induced liver damage are poorly understood. Platelet endothelial cell adhesion molecule 1 (PECAM-1/CD31) is an adhesion molecule and expressed mainly in blood cells and endothelial cells. Its expression is decreased during inflammatory processes. Tumor necrosis factor (TNF)-alpha, which is induced by radiation, is known to downregulate PECAM-1.

    The aim of the current study was to investigate if combined treatment with TNF-alpha and irradiation would enhance liver damage through regulation of the PECAM-1 signaling pathway. This was studied in-vivo in mouse models of single-dose selective liver irradiation w/wo TNF-alpha administered intraperitoneally shortly before irradiation. The mice were sacrificed at different time points, serum and tissues were collected for further analyses. RNA- and protein analyses were performed by RT-PCR and Western blotting, respectively.

    Both irradiation and TNF-alpha administration alone induced elevated aspartate aminotransferase (AST)-levels (hepatic damage) in serum, compared to sham-irradiated mice (control). This hepatic damage was further enhanced in mice that received combined treatment with irradiation and TNF-alpha. In parallel to hepatic damage, a time-dependent decrease in the expression level of hepatic PECAM-1 was found in mice that received each single irradiation or TNF-alpha treatment. The administration of irradiation together with TNF-alpha showed additional decline in the expression of PECAM-1. In contrast, increased expression of hepatic lipocalin-2 (LCN-2), an acute phase protein, was detected at mRNA and protein levels after irradiation or TNF-alpha treatment. The level of LCN-2 was further increased in mice that received combined treatment with TNF-alpha and irradiation, compared to irradiation or TNF-alpha alone. This induction seems to be mediated by the activation of the signal transducer and activator of transcription (STAT)-3 signaling pathway.

    In order to study the role of PECAM-1 in hepatic damage, the liver of both wild-type (WT) and PECAM-1 knock-out (KO)-mice were selectively irradiated (25 Gy). PECAM-1 KO mice showed higher liver damage in parallel to increased LCN-2 expression compared to WT-mice at RNA and protein levels. By means of Western blotting, an increased level of cell death-related proteins (SOD-1, BAX) was observed after irradiation in both WT- and PECAM-1 KO mice. However, the level of Cyt-C was reduced only in PECAM-1 KO mice after irradiation. Our study shows a synergistic effect of radiation and TNF-alpha on hepatic cell-damage, probably through regulation of PECAM-1. Our results may help to develop protective strategies to reduce radiation-induced defects in normal liver tissue, as well as strategies, which may increase the effects of radiation on tumor tissue.


     

    No conflict of interest has been declared by the author(s).

    Malik, Ihtzaz Ahmed