Abstract
Ionizing radiation (IR)-induced intestinal damage is characterized by a loss of intestinal crypt cells, intestinal barrier disruption and translocation of intestinal microflora resulting in sepsis-mediated lethality. We have shown that mice lacking C/EBPδ display IR-induced intestinal and hematopoietic injury and lethality. The purpose of this study was to investigate whether increased IR-induced inflammatory, oxidative and nitrosative stress promote intestinal injury and sepsis-mediated lethality in Cebpd−/− mice. We found that irradiated Cebpd−/− mice show decreased villous height, crypt depth, crypt to villi ratio and expression of the proliferation marker, proliferating cell nuclear antigen, indicative of intestinal injury. Cebpd−/− mice show increased expression of the pro-inflammatory cytokines (Il-6, Tnf-α) and chemokines (Cxcl1, Mcp-1, Mif-1α) and Nos2 in the intestinal tissues compared to Cebpd+/+ mice after exposure to TBI. Cebpd−/− mice show decreased GSH/GSSG ratio, increased S-nitrosoglutathione and 3-nitrotyrosine in the intestine indicative of basal oxidative and nitrosative stress, which was exacerbated by IR. Irradiated Cebpd-deficient mice showed upregulation of Claudin-2 that correlated with increased intestinal permeability, presence of plasma endotoxin and bacterial translocation to the liver. Overall these results uncover a novel role for C/EBPδ in protection against IR-induced intestinal injury by suppressing inflammation and nitrosative stress and underlying sepsis-induced lethality.
Highlights
The likelihood of civilians as well as military forces encountering radiological hazard has increased many folds with proliferation of radioactive material, nuclear weapons and nuclear power facilities[1,2,3]
The production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), induced by Ionizing radiation (IR) promotes the induction of apoptosis and clonogenic cell death, which leads to mucosal breakdown[10,11,12,13,14,15]
We have previously shown that compared to 40% mortality in Cebpd+/+ mice, 100% of Cebpd−/− mice die by day 9–13 after exposure to a TBI dose of 8.5 Gy, which occurs due to the increased cell death of the intestinal stem cells of the crypts as well as injury to the bone marrow[32]
Summary
The likelihood of civilians as well as military forces encountering radiological hazard has increased many folds with proliferation of radioactive material, nuclear weapons and nuclear power facilities[1,2,3]. The process of inflammation is amplified by recruitment of neutrophils and transmigration of monocytes and activation of resident mast cells producing pro-inflammatory mediators like IL-1β, IL-6, CXCL1 and TNF-α11–14 This leads to the upregulation of pro-inflammatory cytokines, chemokines, and growth factors in the microvascular and mucosal compartments, presumably by recruited immune cells and by enterocytes, depending on the severity of tissue trauma[14,15]. We have previously shown that C/EBPδ-deficiency in mice leads to IR-induced lethality due to the underlying injury to the intestine and hematopoietic tissues[32]. We further investigated whether the increased IR-induced intestinal injury in Cebpd−/− mice occurs due to an impaired ability to regulate inflammation and oxidative as well as nitrosative stress responses
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