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High mobility group box protein 1 neutralization therapy in ovine bacteremia: Lessons learned from an ovine septic shock model incorporating intensive care support.

Abstract：

:Sepsis is a highly complex and often fatal syndrome which varies widely in its clinical manifestations, and therapies that target the underlying uncontrolled immune status in sepsis are needed. The failure of preclinical approaches to provide significant sepsis survival benefit in the clinic is often attributed to inappropriate animal disease models. It has been demonstrated that high mobility group box protein 1 (HMGB1) blockade can reduce inflammation, mortality and morbidity in experimental sepsis without promoting immunosuppression. Within this study, we explored the use of ovine anti-HMGB1 antibodies in a model of ovine septic shock incorporating intensive care supports (OSSICS). Results: Septic sheep exhibited elevated levels of HMGB1 within 12 h after the induction of sepsis. In this study, sepsis was induced in six anaesthetized adult Border Leicester × Merino ewes via intravenous instillation of E. coli and sheep monitored according to intensive care unit standard protocols for 26 h, with the requirement for noradrenaline as the primary endpoint. Septic sheep exhibited a hyperdynamic circulation, renal dysfunction, deranged coagulation profile and severe metabolic acidosis. Sheep were assigned a severity of illness score, which increased over time. While a therapeutic effect of intravenous anti-HMGB1 antibody could not be observed in this model due to limited animal numbers, a reduced bacterial dose induced a septic syndrome of much lower severity. With modifications including a reduced bacterial dose, a longer timeframe and broad spectrum antibiotics, the OSSICS model may become a robust tool for preclinical assessment of sepsis therapeutics.

journal_name

Exp Ther Med

journal_title

Experimental and therapeutic medicine

authors

Stevens NE,Nash CH,Fraser CK,Kuchel TR,Maiden MJ,Chapman MJ,Diener KR,Hayball JD

doi

10.3892/etm.2019.7961

subject

Has Abstract

pub_date

2019-11-01 00:00:00

pages

3271-3280

issue

eissn

1792-0981

issn

1792-1015

pii

ETM-0-0-7961

journal_volume

pub_type

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High mobility group box protein 1 neutralization therapy in ovine bacteremia: Lessons learned from an ovine septic shock model incorporating intensive care support.