In:
Neonatology, S. Karger AG, Vol. 112, No. 4 ( 2017), p. 376-383
Abstract:
〈 b 〉 〈 i 〉 Background: 〈 /i 〉 〈 /b 〉 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. 〈 b 〉 〈 i 〉 Objective: 〈 /i 〉 〈 /b 〉 To investigate the protective effects of HO in a model of heme overload. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 For in vitro studies, NIH3T3 HO-1- 〈 i 〉 luc 〈 /i 〉 cells were incubated with 10, 30, or 60 µ 〈 smlcap 〉 M 〈 /smlcap 〉 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 〈 sup 〉 +/- 〈 /sup 〉 ) 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. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 In HO-1- 〈 i 〉 luc 〈 /i 〉 cells, HO-1 promoter activity peaked 6 h after incubation with 30 µ 〈 smlcap 〉 M 〈 /smlcap 〉 FH (1.6-fold) or 60 µ 〈 smlcap 〉 M 〈 /smlcap 〉 MHA (2.1-fold) over baseline. Twenty-four hours after exposure to 60 µ 〈 smlcap 〉 M 〈 /smlcap 〉 FH, a decrease in viability of 80% was found, compared with no decrease after exposure to 60 µ 〈 smlcap 〉 M 〈 /smlcap 〉 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. 〈 b 〉 〈 /b 〉 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. 〈 b 〉 〈 i 〉 Conclusions: 〈 /i 〉 〈 /b 〉 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.
Type of Medium:
Online Resource
ISSN:
1661-7800
,
1661-7819
Language:
English
Publisher:
S. Karger AG
Publication Date:
2017
detail.hit.zdb_id:
2403535-X
SSG:
12
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