Role of C/EBP Delta in IR-Induced Sepsis
Abstract
Sepsis poses a significant threat to Warfighters who suffer combat injuries that predispose them to infection. An increased risk of sepsis induced mortality is indicated for war Veterans, elderly, and critically ill patients. According to the Centers for Disease Control and Prevention, sepsis is the second-leading cause of death in non-coronary ICU (intensive care unit) patients, the tenth-most-common cause of death overall in the United States, and poses a major economic burden. Exposure of Warfighters to high doses of ionizing radiation (IR) may be a likely scenario during a nuclear accident or in the clinic, patients may be exposed to high doses of radiation to the abdominal or pelvic region (e.g., to treat ovarian or bladder cancers). Acute exposure to high doses of IR results in toxicity to rapidly proliferating cells in the gastrointestinal tract and bone marrow. Acute radiation exposure leads to gastrointestinal syndrome primarily due to a loss of intestinal crypt cells and disruption of the intestinal barrier, which results in translocation of the intestinal microflora and the onset of a systemic inflammatory cascade leading to septicemia and death. Early detection and intervention are critical to prevent induced sepsis-associated death. Thus, it is essential to understand the molecular underpinnings of ionizing radiation (IR)-induced gut-associated sepsis in order to develop therapeutic interventions, as there are no effective agents available to treat or prevent sepsis. In this context, the goal of this proposed project is to investigate the role of the transcription factor CCAAT/enhancer-binding protein delta (Cebpd, C/EBPdelta) in IR-induced gut-associated sepsis. Our recently published study demonstrates that loss of C/EBPdelta in mice results in increased thrombocytopenia, neutropenia, myelosuppression, and increased intestinal injury. Further, our preliminary results demonstrate an increased expression of the TLR genes, TLR2 and TLR4, and the proinflammatory cytokines, IL-6 and TNF-alpha in Cebpd-KO mice post-irradiation. Similarly, these very same processes are implicated as key hallmarks of sepsis. Although studies by us and other groups have implicated C/EBPdelta as having regulatory functions in inflammatory, anti-inflammatory signaling, and immune response, very little research has been conducted to examine the role of C/EBPdelta in IR-induced sepsis. Because gut-associated sepsis is the major cause of lethality after exposure to total body irradiation, we hypothesize that attenuation of the inflammatory responses by C/EBPdelta, mediated at least in part through inhibition of TLR4 expression, may play an important role in suppressing radiation-induced sepsis. We will test this hypothesis through the following specific aims. In Aim 1, we will determine whether IR-induced intestinal injury in Cebpd-KO mice is due to increased TLR4-mediated inflammatory response. Our studies will unravel the role of unrestrained TLR4-mediated proinflammatory signaling, which leads to the increased intestinal injury via breakdown of intestinal barrier and translocation of gut microflora to distant sites such as the liver to simulate sepsis like complications in the Cebpd-deficient mice after exposure to radiation. In Aim 2, we will determine whether Cebpd-KO mice show perturbed macrophage response post-IR. Specifically, we will analyze the recruitment of immune cells to the intestine and characterize the M1/M2 phenotype of macrophages from Cebpd-WT and KO mice and verify the role of Cebpd-deficient macrophages in contributing to the intestinal injury by transplantation in a mouse model of macrophage deletion. Overall Impact: The proposed experiments hold broad significance by addressing the critical gaps in our understanding of C/EBPdelta and its role in IR-induced sepsis at a cellular and mechanistic level and may lead to new avenues for therapeutic intervention.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510489
Entities
People
- Snehalata A Pawar
Organizations
- United States Army
- University of Arkansas for Medical Sciences