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Author(s): Kavin G. Shah [sup.1], Rongqian Wu [sup.1] [sup.2], Asha Jacob [sup.1] [sup.2], Ernesto P. Molmenti [sup.1], Jeffrey Nicastro [sup.1], Gene F. Coppa [sup.1], Ping Wang [sup.1] [sup.2] Author Affiliations: [...], Purpose Animal milk fat globule-EGF factor 8 (MFG-E8) has been shown to be beneficial in attenuating the inflammatory response in sepsis. In this study, we examined the effect of recombinant human MFG-E8 (rhMFG-E8) in an animal model of sepsis in an effort to develop it as a potential therapy against sepsis in humans. Methods Rats were subjected to sepsis by cecal ligation and puncture (CLP), and at 5 h post-CLP, they were given different doses of rhMFG-E8 (20, 40, 80, 160 [mu]g/kg BW) in normal saline. At 20 h post-CLP, samples were collected for further analysis. A 10-day survival study was also performed. Results At 20 h after CLP, organ injury indicators, serum IL-6 and TNF-[alpha], and plasma HMGB-1 levels were significantly increased as compared to sham-operated animals. Treatment with 20 [mu]g/kg rhMFG-E8 significantly reduced these levels. With higher doses, further reductions in AST and ALT (59-62%), creatinine (65-68%), and lactate (46-57%), and serum IL-6 and TNF-[alpha] were obtained. The 160 [mu]g/kg dose produced the greatest reduction in serum TNF-[alpha]. With treatment with 20 [mu]g/kg rhMFG-E8, HMGB-1 levels decreased by 80%, returning back to sham values. In a 10-day survival study, vehicle-treated animals produced a 36% survival rate, while rhMFG-E8 significantly improved the survival rate to 68-72%. Treatment with increasing doses of rhMFG-E8 significantly reduced the number of apoptotic cells detected and markedly attenuated the tissue damages observed in the lungs. Conclusions These data suggest that recombinant human MFG-E8 is beneficial in ameliorating sepsis in an animal model of sepsis.

Author(s): Tatenobu Goto [sup.1], Mohamed Hamed Hussein [sup.3] [sup.5], Shin Kato [sup.1], Ghada Abdel-Hamid Daoud [sup.4], Takenori Kato [sup.1], Hiroki Kakita [sup.1], Haruo Mizuno [sup.1], Masaki Imai [sup.2], Tetsuya Ito [...], Purpose To evaluate effects of endothelin receptor antagonist ETR-P1/fl in a neonatal sepsis model. Method Eighteen anesthetized and mechanically ventilated 3-day-old piglets were divided into three groups. Six piglets received cecal ligation and perforation (CLP group). Six piglets were administrated a continuous infusion of ETR-P1/fl (0.05 mg/kg/h), an antisense homology box-derived peptide with an endothelin A receptor antagonist effect, starting 30 min after CLP (ETR-P1/fl group). Six piglets acted as the sham group. Mean arterial pressure (MAP), heart rate, cardiac output, arterial blood gas, body temp (BT), serum nitrite and nitrate (NOx), tumor necrosis factor (TNF)-[alpha], and high-mobility group box 1 (HMGB-1) were measured before CLP and at 1, 3, 6, and 9 h after CLP. Results Cecal ligation and perforation exposure evoked a state of shock and showed deteriorated cardiac output, pulmonary hypertension, decreased MAP, low oxygen saturation, and base excess (BE) with elevated TNF-[alpha], NOx, and HMGB1. ETR-P1/fl administration resulted in higher MAP at 6 and 9 h after CLP, less negative BE, lower mean pulmonary arterial pressure (mPAP)/MAP ratio at 9 h after CLP, and lower TNF-[alpha], NOx, and HMGB-1 compared to the CLP group. BT showed no differences between the groups. Survival time in the ETR-P1/fl group was longer than in the CLP group (18.9 ± 2.3 h vs. 9.0 ± 0.8 h, p < 0.01). Conclusions ETR-P1/fl treatment significantly attenuated the elevation of NOx, TNF-[alpha], and HMGB-1, which improved the systemic hypotension, pulmonary hypertension, and blood gases, thereby causing improvement of survival time in a progressive neonatal sepsis CLP model.