title: Single-dose gamma-irradiation induces up-regulation of chemokine gene expression and recruitment of granulocytes into the portal area but not into other regions of rat hepatic tissue.
abstract: Liver damage is a serious clinical complication of gamma-irradiation. We therefore exposed rats to single-dose gamma-irradiation (25 Gy) that was focused on the liver. Three to six hours after irradiation, an increased number of neutrophils (but not mononuclear phagocytes) was observed by immunohistochemistry to be attached to portal vessels between and around the portal (myo)fibroblasts (smooth muscle actin and Thy-1(+) cells). MCP-1/CCL2 staining was also detected in the portal vessel walls, including some cells of the portal area. CC-chemokine (MCP-1/CCL2 and MCP-3/CCL7) and CXC-chemokine (KC/CXCL1, MIP-2/CXCL2, and LIX/CXCL5) gene expression was significantly induced in total RNA from irradiated livers. In laser capture microdissected samples, an early (1 to 3 hours) up-regulation of CCL2, CXCL1, CXCL8, and CXCR2 gene expression was detected in the portal area but not in the parenchyma; with the exception of CXCL1 gene expression. In addition, treatment with an antibody against MCP-1/CCL2 before irradiation led to an increase in gene expression of interferon-gamma and IP-10/CXCL10 in liver tissue without influencing the recruitment of granulocytes. Indeed, the CCL2, CXCL1, CXCL2, and CXCL5 genes were strongly expressed and further up-regulated in liver (myo)fibroblasts after irradiation (8 Gy). Taken together, these results suggest that gamma-irradiation of the liver induces a transient accumulation of granulocytes within the portal area and that (myo)fibroblasts of the portal vessels may be one of the major sources of the chemokines involved in neutrophil recruitment. Moreover, inhibition of more than one chemokine (eg, CXCL1 and CXCL8) may be necessary to reduce leukocytes recruitment.
authors.affiliation: Department of Internal Medicine, University Hospital Göttingen, 37075 Göttingen, Germany.
authors.forename: Ihtzaz Ahmed
authors.initials: IA
authors.lastname: Malik
authors.forename: Federico
authors.initials: F
authors.lastname: Moriconi
authors.forename: Nadeem
authors.initials: N
authors.lastname: Sheikh
authors.forename: Naila
authors.initials: N
authors.lastname: Naz
authors.forename: Sajjad
authors.initials: S
authors.lastname: Khan
authors.forename: Jozsef
authors.initials: J
authors.lastname: Dudas
authors.forename: Tümen
authors.initials: T
authors.lastname: Mansuroglu
authors.forename: Clemens Friedrich
authors.initials: CF
authors.lastname: Hess
authors.forename: Margret
authors.initials: M
authors.lastname: Rave-Fränk
authors.forename: Hans
authors.initials: H
authors.lastname: Christiansen
authors.forename: Giuliano
authors.initials: G
authors.lastname: Ramadori
mesh_terms: D000818:Animals; D054426:Chemokine CXCL2 / Q000097:blood; D018925:Chemokines / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005720:Gamma Rays; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000378:metabolism* / Q000528:radiation effects; D007962:Leukocytes / Q000166:cytology; D008099:Liver / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D008297:Male; D016133:Polymerase Chain Reaction / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D015854:Up-Regulation
chemical_list: D054426:Chemokine CXCL2; D018925:Chemokines; D017382:Reactive Oxygen Species