Adhesion molecules and liver inflammation after radiation: Role of PECAM-1.
Final Report Abstract
The central objective of the project was to improve our understanding of radiation-induced hepatic cellular and molecular changes, by focusing on inflammatory mediators and adhesion molecules. Here, we gave special emphasis to inflammatory mediators and adhesion molecules that cooperatively regulate migration of various leukocyte populations. For this purpose, rat and mouse models of acute liver damage were established, and, additionally, the mechanisms of leukocyte transmigration were studied in vitro. Our data demonstrated that morphological evidence for acute hepatic damage is first visible in the region of the portal fields, with neutrophils being the first leukocyte sub-population recruited, followed by mono-nuclear phagocytes. Thereby, TNF-α-regulated CD31/PECAM-1 expression in endothelial cells seems to be of great importance for the transmigration of the cells into the liver. Loss of PECAM-1 in transgenic mice was shown to be accompanied by immigration of higher numbers of leukocytes along with significantly more severe liver injury. Blocking of TNF-α signaling appears to be a promising strategy to reduce hepatic damage. Another significant finding of the studies was the observation that inflammatory mediators are released a considerable time before inflammatory cells are recruited to the liver, and hepatic damage becomes overt. As the regenerative capacities of the liver are high, accordingly, we observed restitutio ad integrum within 96 hours after thioacetamide (TAA) administration. In complementation to our previous investigations of the acute changes induced by liver irradiation at cellular and molecular levels, we developed a new clinically highly relevant model of fractionated (2Gy/day; total 60Gy) liver-focused irradiation in comparison with single-dose gamma-irradiation (25Gy). Here, our focus was to understand the long-term effects of irradiation. Interestingly, in both groups we observed only minor signs of inflammation with immigration of very small numbers of neutrophils into the irradiated liver 3 months after irradiation. Thereby, our data revealed no significant liver (hepatocyte and cholangiocyte) damage caused by either single-dose or fractionated irradiation. This suggests that both regimens of irradiation can be safely used as therapeutic option for hepatic cancer. Additionally, we could show that a link exists between inflammation and fat accumulation in hepatocytes, and observed an influence of TNF-α signaling on the expression of the fatty acid translocase FAT/CD36. In sum, normal liver seems to be highly resistant to therapeutic irradiation. TNF-α-regulated PECAM-1 is suggested to be an important mechanism in cell transmigration into the portal area of the liver. Blocking of TNF-α could be a beneficial approach to prevent radiation-induced stress in liver cancer patients. Moreover, our data provide evidence that high single-dose irradiation of the liver might be safely administrated to patients, which may facilitate the use of radiation therapy for patients bearing liver cancer.
Publications
- Ferroportin-1 is a nuclear negative acute-phase protein in rat liver: A comparison with other iron-transport proteins. Lab Invest. 2012; 92(6):842-56
Naz N, Malik IA, Sheikh N, Ahmad S, Khan S, Moriconi F, Blaschke M, Ramadori G
(See online at https://doi.org/10.1038/labinvest.2012.52) - The anti-TNF-α antibody infliximab indirectly regulates PECAM-1 gene expression in two models of in vitro blood cell activation. Lab Invest.2012; 92(2):166-77
Moriconi F, Malik IA, Amanzada A, Blaschke M, Khan S, and Ramadori G
(See online at https://doi.org/10.1038/labinvest.2011.160) - Differential Regulation of Ferritin Subunits and Iron Transport Proteins: An Effect of Targeted Hepatic X-Irradiation. Biomed Res Int. 2013: 353106
Naz N, Ahmad S, Cameron S, Moriconi F, Rave-Fränk M, Christiansen H, Hess CF, Amanzada A, Ramadori G, Malik IA
(See online at https://doi.org/10.1155/2013/353106) - Rat model of fractionated (2 Gy/day) 60 Gy irradiation of the liver: long-term effects. Radiat Environ Biophys. 2013; 52(3):321-38
Rave-Fränk M, Malik IA, Christiansen H, Naz N, Sultan S, Amanzada A, Blaschke M, Cameron S, Ahmad S, Hess CF, Ramadori G, Moriconi F
(See online at https://doi.org/10.1007/s00411-013-0468-7) - Induction of chemokines and cytokines before neutrophils and macrophage recruitment in different regions of rat liver after TAA administration. Lab Invest. 2014; 94(2):235-47
Amanzada A, Moriconi F, Mansuroglu T, Cameron S, Ramadori G, A Malik I
(See online at https://doi.org/10.1038/labinvest.2013.134) - Regulation of Iron Uptake in Primary Culture Rat Hepatocytes: The Role of Acute Phase Cytokines. Shock 2014; 41(4):337-45
Ahmad S, Sultan S, Naz N, Ahmad G, Alwahsh SM, Cameron S, Moriconi F, Ramadori G, Malik IA
(See online at https://doi.org/10.1097/SHK.0000000000000107,) - Role of PECAM-1 in radiation-induced liver inflammation. J Cell Mol Med. 2015 Oct;19 (10):2441-52
Malik IA, Stange I, Martius G, Cameron S, Rave-Fränk M, Hess CF, Ellenrieder V, and Wolff HA
(See online at https://doi.org/10.1111/jcmm.12630) - The anti-TNF-α antibody infliximab inhibits the expression of fat-transporter-protein FAT/CD36 in a selective hepatic-radiation mouse model. Int J Mol Sci. 2015;16(3):4682-97
Martius G, Cameron S, Rave-Fränk M, Hess CF, Wolff HA, Malik IA
(See online at https://doi.org/10.3390/ijms16034682) - Induction of Lipocalin 2 in a Rat Model of Lung Irradiation. Int J Mol Sci. 2016 Apr 28;17(5)
Sultan S, Ahmad S, Rave-Fränk M, Malik IA, Hess CF, Christiansen H, Cameron S
(See online at https://doi.org/10.3390/ijms17050637)
