Abstract
Background
Sepsis in preterm infants is associated with systemic inflammatory responses. The stress-response protein heme oxygenase-1 (HO-1) has protective anti-inflammatory properties. Recently, we reported a protective role of HO-1 using our non-surgical cecal slurry (CS) model in wild-type (WT) mouse pups. Here, we extend these findings to investigate the association of HO-1 deficiency with sepsis severity.
Methods
Adapting the Wynn model, we induced sepsis in 4-day-old HO-1-deficient (HO-1+/−, Het) pups to determine if HO-1 deficiency affected survival rates at the LD40 (2.0 mg/g) of WT pups. To see if HO-1 induction affected sepsis severity, we gave 30-μmol heme/kg subcutaneously to 3-day-old mice 24 h prior to sepsis induction.
Results
Post-sepsis induction, Het pups had a mortality of 85.0% (n = 20) and increased expression of the pro-inflammatory gene in the livers and affected hematologic profiles. Heme treatment 24 h prior to sepsis induction significantly increased liver HO activity, reduced mortality to 24.5% (n = 17), attenuated inflammatory responses, reduced spleen bacterial counts, and significantly increased peripheral neutrophils.
Conclusions
A partial deficiency in HO-1 increased the progression and mortality in sepsis. Furthermore, induction of HO-1 significantly reduced the mortality even in Het pups. Thus, we conclude that HO-1 plays an important role in the protection against preterm sepsis.
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Acknowledgements
We thank Dr. Hendrik J. Vreman for an invaluable advice on our experimental design. This work was supported by the Christopher Hess Research Fund, the H.M. Lui Research Fund (Hong Kong), the Mary L. Johnson Research Fund, and the Child Health Research Institute at Stanford, and the Kobe Sinryokukai Association (Japan), JSPS KAKENHI Grant Number 16H06971 (Japan), and the Mother and Child Health Foundation (Japan).
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Fujioka, K., Kalish, F., Zhao, H. et al. Heme oxygenase-1 deficiency promotes severity of sepsis in a non-surgical preterm mouse model. Pediatr Res 84, 139–145 (2018). https://doi.org/10.1038/s41390-018-0028-6
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DOI: https://doi.org/10.1038/s41390-018-0028-6
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