Induction of Heme Oxygenase-1 Attenuates the Severity of Sepsis in a Non-Surgical Preterm Mouse Model

Fujioka, Kazumichi; Kalish, Flora; Zhao, Hui; Lu, Sabrina; Wong, Stephanie; Wong, Ronald J.; Stevenson, David K.

doi:10.1097/shk.0000000000000689

Cited by 26 publications

(32 citation statements)

References 35 publications

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“…Although the pathogenesis of cholestasis associated with severe hemolysis was not our focus, our findings support the notion that there are several existing physiologic systems (HO, heme/hemoglobin-binding proteins, hemopexin [19], albumin, and haptoglobin [5]) available to attend to the potential toxicity of FH. Deficiencies among any of those systems should be evaluated when considering the role of HO deficiency in the pathogenesis of various oxidative injuries in the neonate [17,20,21]. Our data affirm differences between newborn and adult mice with respect to HO activity at baseline and after exposure to FH or MHA.…”

Section: Discussionsupporting

confidence: 61%

“…Although our study suggests that HO-1 deficiency may play a predominant role in the pathogenesis of stress-related conditions [20,21], it is not usually sufficient by itself to cause injury, except perhaps in extreme circumstances. In the case of hemolysis, other proteins (e.g., albumin, haptoglobin [5], and hemopexin [19]) also play protective roles.…”

Section: Discussionmentioning

confidence: 99%

“…Nonetheless, one of the simplest clues on the importance of HO and the various binding-proteins for heme may be the occurrence of cholestatic liver disease in association with hemolysis, reflecting not only an insufficient HO capacity but also an exhausted binding capacity in the processing of FH. A similar mechanism may be involved in the pathogenesis of severe or lethal sepsis [20]. Besides the upregulation of HO, the administration of hemopexin may be protective in this circumstance.…”

Section: Discussionmentioning

confidence: 99%

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Heme Oxygenase Activity and Heme Binding in a Neonatal Mouse Model

Kourula

Ang²,

Zhao³

et al. 2017

Neonatology

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Background: Severe hemolytic disease of the newborn leads to the release of pro-oxidative free heme (FH). Heme oxygenase (HO) is primarily responsible for detoxifying FH. Objective: To investigate the protective effects of HO in a model of heme overload. Methods: For in vitro studies, NIH3T3 HO-1-luc cells were incubated with 10, 30, or 60 µM FH or methemalbumin (MHA). HO-1 promoter activity was assessed 3, 6, and 24 h after treatment. Cell survival was indexed by viability assays. For in vivo studies, 1- and 5-week-old wild-type (Wt) or HO-1-heterozygous (Het, HO-1^+/-) mice were given 60 µmol FH or MHA/kg intraperitoneally. After 24 h, plasma aspartate aminotransferease (AST)/alanine transaminase (ALT) and hemopexin, liver HO activity, and lipid peroxidation (LP) were determined. Results: In HO-1-luc cells, HO-1 promoter activity peaked 6 h after incubation with 30 µM FH (1.6-fold) or 60 µM MHA (2.1-fold) over baseline. Twenty-four hours after exposure to 60 µM FH, a decrease in viability of 80% was found, compared with no decrease after exposure to 60 µM MHA. In 1-week-old Wt and HO-1 Het pups given 60 µmol FH/kg, HO activity significantly increased 3.5- and 3.1-fold, respectively. No changes in LP or AST/ALT levels were observed. In adult Wt and HO-1 Het mice, HO activity increased (3.0- and 2.6-fold, respectively). LP and AST levels significantly increased 28.4- and 2.7-fold, respectively, in adult HO-1 Het mice.Hemopexin levels at baseline were higher in adults compared with newborns for both Wt and Het mice. In addition, FH induced hemopexin levels in both adults and newborns, but to a lesser degree in newborns. Conclusions: FH is highly toxic in vitro, but its toxicity is abolished when bound to albumin. Newborns appear to be protected from the pro-oxidative effects of FH, which may be mediated by heme binding and a higher absolute HO activity at baseline and after FH-mediated induction.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Heme Oxygenase Activity and Heme Binding in a Neonatal Mouse Model

Kourula

Ang²,

Zhao³

et al. 2017

Neonatology

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“…The cecal slurry model for neonatal polymicrobial sepsis was developed to address this need, whereby the cecal contents of animals are harvested, suspended in sterile dextrose 5% in water (D5W), and intraperitoneally injected into newborn mice 2 . This has, since, become an increasingly popular model to study sepsis in both newborn and adult animals and has substantially advanced mechanistic insights in the disease's process 4,5,6,7,8,9,10,11,12,13,14,15 .…”

Section: Introductionmentioning

confidence: 99%

A Controlled Mouse Model for Neonatal Polymicrobial Sepsis

Brook

Amenyogbe

Ben‐Othman

et al. 2019

JoVE

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Neonatal sepsis remains a global burden. A preclinical model to screen effective prophylactic or therapeutic interventions is needed. Neonatal mouse polymicrobial sepsis can be induced by injecting cecal slurry intraperitoneally into day of life 7 mice and monitoring them for the following week. Presented here are the detailed steps necessary for the implementation of this neonatal sepsis model. This includes making a homogeneous cecal slurry stock, diluting it to a weight-and litter-adjusted dose, an outline of the monitoring schedule, and a definition of observed health categories used to define humane endpoints. The generation of a homogeneous cecal slurry stock from pooled donors allows for the administration into many litters over time, reducing the variation between donors, and preventing the use of potentially toxic glycerol. The monitoring strategy used allows for the anticipation of survival outcome and the identification of mice that would later progress to death, allowing for an earlier identification of the humane endpoint. Two main behavioral features are used to define the health scores, namely, the ability of the neonatal mice to right themselves when placed on their back and their level of mobility. These criteria could potentially be applied to address humane endpoints in other studies of neonatal disease in mice, as long as a pilot study is performed to confirm accuracy. In conclusion, this approach provides a standardized method to model newborn sepsis in mice, while providing resources to assess animal welfare used to define early humane endpoints for challenged animals.

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“…(15) use a cecal slurry model in 4 day-old mice to mimic the septic condition of human neonates and study the role of heme oxygenase-1 (HO-1). The latter is thought to exert a protective role via its anti-inflammatory, antioxidative and anti-apoptotic functions.…”

mentioning

confidence: 99%