Protective Role of an Initial Low-Dose Septic Challenge against Lethal Sepsis in Neonatal Mice: A Pilot Study.

Ruka Nakasone,Masakazu Shinohara,Kazumichi Fujioka,Takumi Kido,Kandai Nozu,Mariko Ashina,Shigeaki Inoue,Harunori Miyauchi,Masafumi Saito

doi:10.3390/jcm10245823

Abstract

Neonatal sepsis is characterized by systemic bacterial invasion followed by a massive inflammatory response. At present, no therapeutic strategy has been found that significantly reduces the mortality of neonatal sepsis. We aimed to investigate the protective role of an initial low-dose septic challenge for the prevention of subsequent lethal sepsis in a mouse model. A stock cecal slurry (CS) solution was prepared from adult ceca. The LD83 (1.5 mg CS/g) was used for all animals. An initial challenge of normal saline (NS) or 0.5 mg CS/g (non-lethal dose) was administered at four days of age, then 1.5 mg CS/g was administered intraperitoneally at seven days of age (72 h post-initial challenge), and survival was monitored. Initial exposure to NS (n = 10) resulted in 90% mortality following exposure to the LD83 CS dose in contrast to an initial exposure to CS (n = 16), which significantly decreased mortality to 6% (p < 0.0001), reduced blood bacterial counts, attenuated inflammatory responses, and suppressed lipid mediators. Initial exposure to a non-lethal CS dose prior to exposure to a lethal CS dose significantly reduces sepsis mortality, a protective effect that might be mediated by modulating abnormal systemic inflammatory responses.

Highlights

Neonatal sepsis is a systemic infection caused by bacterial, viral, or fungal pathogens, and is accompanied by hemodynamic collapse and a variety of other clinical manifestations [1]
Using RT-Polymerase Chain Reaction (PCR) arrays, we found that of the 84 genes screened by the kit, five gene transcripts significantly increased in livers of Veh-cecal slurry (CS) treated (Veh) pups compared to non-septic Veh-Veh treated (Cont) pups
We found that the initial low-dose septic challenge attenuated sepsis severity in a non-surgical neonatal sepsis mouse model

Summary

Introduction

Neonatal sepsis is a systemic infection caused by bacterial, viral, or fungal pathogens, and is accompanied by hemodynamic collapse and a variety of other clinical manifestations [1]. Despite recent advances in neonatal intensive care, sepsis is still one of the most common causes of neonatal mortality [2]. The mortality rate of neonatal sepsis is reported as 11–19%, and it is estimated that approximately three million infants are affected worldwide [3]. The morbidity and mortality of neonatal sepsis increases with decreasing birth weight and gestational age, especially for very preterm infants [4,5]. The significant morbidity and mortality of sepsis in newborns are related to immune characteristics which are peculiar to neonates. Newborns rely primarily on innate immunity, as the adaptive immune properties of newborns prioritize fetomaternal tolerance and contribute little to the protective immunity of the host [7], their innate immune response to infection is underdeveloped, and they have decreased cytokine production and immature neutrophil and dendritic cell function compared to adults [8]

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