Date of Award

2014

Degree Name

Biomedical Sciences

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Eric R. Blough

Second Advisor

Todd L. Green

Third Advisor

Monica Valentovic

Fourth Advisor

Elsa Mangiarua

Fifth Advisor

Robert O. Harris

Abstract

Sepsis is a generalized term that signifies the presence of a pathogen in the blood stream to which the body responds by eliciting a systemic inflammatory response. Although sepsis is the leading cause of death in non-coronary intensive care units in United States, there are currently no FDA approved therapeutic drugs to treat this disorder. Cerium oxide nanoparticles (CeO2) have been shown to exhibit anti-oxidant, anti-inflammatory, and anti-bacterial properties both in vitro and in vivo. Whether CeO2 nanoparticles can be used for the treatment of sepsis is currently unclear.

To investigate whether CeO2 nanoparticles can be used to treat moderate sepsis, twelve week old male Sprague Dawley rats were randomly divided into one of four different groups: control, CeO2 only, sepsis, and sepsis + CeO2. Moderate sepsis was induced by the intraperitoneal injection of cecal material (400mg/kg). The CeO2 nanoparticle treated animals received an intravenous injection of CeO2 nanoparticles (3.5mg/kg) at the time of sepsis induction. Treatment significantly decreased sepsis induced mortality. Treatment associated increases in animal survivability were associated with a significant decrease in serum IL-6, growth regulated alpha protein (KC/GRO), macrophage inflammatory protein-1 beta (MIP-1 β) macrophage derived chemokine (MDC), monocyte chemotactic protein-3 (MCP-3), myoglobin, macrophage inflammatory protein-3 beta (MIP-3β), eotaxin, leptin, macrophage inflammatory protein-2 (MIP-2), interferon gamma induced protein-10 (IP-10), tissue inhibitor of metalloproteinases-1 (TIMP-1), plasminogen activator inhibitor-1 (PAI-1) and blood urea nitrogen (BUN).

In an effort to further investigate whether there is a similar degree of response with smaller size and dose of CeO2 nanoparticles on the attenuation of severe sepsis, twelve week old male Sprague Dawley rats were randomly divided into one of four groups: control, CeO2 only, sepsis and sepsis + CeO2. Severe sepsis was induced by the intraperitoneal injection of cecal material (600mg/kg). The CeO2 nanoparticle treated animals received an intravenous injection of CeO2 nanoparticles (0.5mg/kg) at the time of sepsis induction. Treatment with CeO2 nanoparticles significantly decreased animal mortality and sepsis-induced hypothermia. Treatment associated increases in animal survivability were associated with evidence of diminished Erk 1/2 phosphorylation, Jak/Stat-3 activation, P-selectin levels and expression of vascular cell adhesion molecule-1 (VCAM-1) in the heart. Changes in cardiac signaling appeared to coincide with decreased serum IL-6, leukemia inhibitory factor, myoglobin and creatine kinase. In the liver, CeO2 nanoparticle treatment reduced sepsis-induced increases in hepatic superoxide levels, inducible nitric oxide synthase, and protein nitrosylation. Treatment associated increases in liver function were accompanied by diminished levels of serum reactive oxygen species (ROS) and several inflammatory markers.

CeO2 nanoparticles were also found to attenuate sepsis-induced renal damage by preserving the renal brush border and attenuating the incidence of tubular dilatation. These changes in kidney morphology were accompanied by decreases in levels of serum β-2 microglobulin, kidney injury molecule-1, cystatin-C, osteopontin, BUN, glucose, sodium, and potassium. At the cellular level, CeO2 nanoparticles attenuated the sepsis-induced activation of Stat-3 and the cleavage of caspase-3. Taken together the data from this current study indicate that CeO2 nanoparticles can be used for the prevention of sepsis induced multi-organ dysfunction syndrome and death. Additional studies using other sepsis models or interventional time points may be warranted to determine the potential efficacy of using CeO2 nanoparticles to treat sepsis.

Subject(s)

Septicemia - Treatment - Research

Nanotechnology.

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