Shinichi Asano,1,2 Ravikumar Arvapalli,1 Nandini DPK Manne,1,2 Mani Maheshwari,1,3 Bing Ma,1,2 Kevin M Rice,1 Vellaisamy Selvaraj,1,2 Eric R Blough1–3 1Center for Diagnostic Nanosystems, 2Department of Pharmacology, Pharmaceutical Sciences and Research, School of Pharmacy, 3Department of Pharmacology, Physiology and Toxicology, Joan C Edwards School of Medicine, Marshall University, Huntington, WV, USA Abstract: The severe inflammation observed during sepsis is thought to cause diaphragm dysfunction, which is associated with poor patient prognosis. Cerium oxide (CeO2) nanoparticles have been posited to exhibit anti-inflammatory and antioxidative activities suggesting that these particles may be of potential use for the treatment of inflammatory disorders. To investigate this possibility, Sprague Dawley rats were randomly assigned to the following groups: sham control, CeO2 nanoparticle treatment only (0.5 mg/kg iv), sepsis, and sepsis+CeO2 nanoparticles. Sepsis was induced by the introduction of cecal material (600 mg/kg) directly into the peritoneal cavity. Nanoparticle treatment decreased sepsis-associated impairments in diaphragmatic contractile (Po) function (sham: 25.6±1.6 N/cm2 vs CeO2: 23.4±0.8 N/cm2, vs Sep: 15.9±1.0 N/cm2 vs Sep+CeO2: 20.0±1.0 N/cm2, P<0.05). These improvements in diaphragm contractile function were accompanied by a normalization of protein translation signaling (Akt, FOXO-1, and 4EBP1), diminished proteolysis (caspase 8 and ubiquitin levels), and decreased inflammatory signaling (Stat3 and iNOS). Histological analysis suggested that nanoparticle treatment was associated with diminished sarcolemma damage and diminished inflammatory cell infiltration. These data indicate CeO2 nanoparticles may improve diaphragmatic function in the septic laboratory rat. Keywords: cerium oxide nanoparticles, anti-inflammatory, nitric oxide, diaphragm