Therapeutic Potential of Cerium Oxide Nanoparticles for the Treatment of Peritonitis Induced by Polymicrobial Insult in Sprague-Dawley Rats.
OBJECTIVE
Peritonitis is a life-threatening disease that is associated with high mortality. The purpose of this study was to determine if cerium oxide nanoparticles can be used to diminish intra-abdominal infection-induced mortality and systemic inflammatory response syndrome in the laboratory rat.


METHODS
Randomized, controlled animal study and cell culture study.


METHODS
University research laboratory.


METHODS
Male Sprague-Dawley rats aged 12 weeks, RAW 246.7 macrophage cell line.


METHODS
Intra-abdominal infection or peritonitis was induced by intraperitoneal injection of cecal material (600 mg/kg in 5% sterile dextrose water at a dosage of 5 mL/kg) obtained from healthy donors. Rats in control and peritonitis groups received 200 μL of sterile deionized water IV via the tail vein, whereas rats in cerium oxide-only group and peritonitis+cerium oxide group received cerium oxide nanoparticles (0.5 mg/kg) IV at the time of polymicrobial injection. Survival rate was monitored for 14 days, while in other experiments, animals were killed at 3 and 18 hours after induction of peritonitis for biochemical analysis.


RESULTS
Administration of a single dose (0.5 mg/kg) of cerium oxide nanoparticles IV to rats in the peritonitis group significantly improved survival rates and functioned to restore core body temperature toward baseline. Treatment-induced increases in animal survivability were associated with reduced systemic and hepatic oxidative stress, diminished serum cytokines, and chemokine levels. Changes in serum inflammatory markers with treatment were accompanied by decreased monocyte and lymphocyte extravasation into the peritoneal cavity along with decreased infiltration of macrophages into liver. In the heart, treatment diminished extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase-Stat-3 signaling and attenuated endothelial expression of P-selectin and vascular cell adhesion molecule-1.


CONCLUSIONS
Cerium oxide nanoparticles attenuate the systemic inflammatory response associated with peritonitis, suggesting potential use as a novel therapeutic agent for the treatment of severe intra-abdominal infection.
1Department of Pharmacology, Physiology and Toxicology, Marshall University, Joan C. Edwards School of Medicine, Huntington, WV. 2Center for Diagnostic Nanosystems, Marshall University, Huntington, WV. 3Department of Mechanical Engineering and Engineering Mechanics, Michigan Technological University, Houghton, MI. 4School of Materials Science and Engineering, Shandong University, Ji'nan, China. 5Department of Pharmaceutical Sciences and Research, Marshall University, Huntington, WV.
Nandini D P K
ND
Manne
Ravikumar
R
Arvapalli
Niraj
N
Nepal
Srinivasarao
S
Thulluri
Vellaisamy
V
Selvaraj
Tolou
T
Shokuhfar
Kun
K
He
Kevin M
KM
Rice
Shinichi
S
Asano
Mani
M
Maheshwari
Eric R
ER
Blough
D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D002563:Cerium / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015151:Immunoblotting; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008297:Male; D053758:Nanoparticles / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000502:physiology; D010538:Peritonitis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012016:Reference Values; D015996:Survival Rate; D016896:Treatment Outcome
D017382:Reactive Oxygen Species; D002563:Cerium; C030583:ceric oxide