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Dose-response Effect of Glutathione added in Parenteral Nutrition on Lung Oxidative Stress and Alveolarization in Newborn Guinea Pig
oxidation of redox and loss of alveoli. Our team is funded to
191
start a clinical study soon.
Dose-response Effect of Glutathione added in Parenteral Nutrition on Lung Oxidative
DOI: 10.1016/j.freeradbiomed.2017.10.204
Stress and Alveolarization in Newborn Guinea Pig Jean-Claude Lavoie1, Ibrahim Mohamed1, and Thérèse Rouleau1 1
Oxygen Induced Tissue Hypoxia Ken-ichiro Matsumoto1, James B. Mitchell2, and Murali C.
Université de Montréal, Canada
Krishna2
Peroxides contaminating parenteral nutrition (PN) are associated with oxidized redox potential of glutathione in blood of preterm newborns (<30 wks) and in lungs of animal. An oxidized redox and the peroxides are associated to bronchopulmonary dysplasia in preterm newborns and induce loss of alveoli in animals. Glutathione detoxifies peroxides
and
normalises
redox
potential.
The
low
glutathione in preterm newborns limits capacity to detoxify peroxides.
Glutathione
is
derived
from
liver
where
methionine is transformed in cysteine of which availability limits the glutathione synthesis. Peroxides inhibit this transformation. Hypothesis: Addition of glutathione into PN compensates for the low hepatic capacity to supply glutathione, and consequently preserves the lung integrity. Methods: At day 3 of life, through a jugular catheter, guinea pigs (N=55) received PN (dextrose, amino acids, lipids, vitamins, electrolytes) enriched in glutathione (0, 50, 120, 165, 270, 370, 650 μg GSSG/kg/d). A control group (no manipulation, fed by mouth) served as reference. After 4 days, lungs were taken for determination of GSH, GSSG, redox
potential
(capillary
electrophoresis)
and
alveolarization index (AI) (number of intercepts between a 1 mm line and histological structures). Data (mean ± sem) from animals on PN were compared by ANOVA, p<0.05. Results: The low AI observed with low doses (μg/kg/d) of GSSG (0-120: 26±1) was corrected with higher level (165650: 30±1, p<0.01; control: 29±1). The oxidized redox (mV)
obtained
with
low
GSSG
(0-165:-209±1)
was
corrected with higher GSSG (270-650: -217±2, p<0.01; control: -216±2). GSH (nmol/mg prot) was not modified by GSSG in PN (30±1); control: 36±1. The high GSSG in lungs (nmol/mg prot) with low doses of GSSG (0-270: 0.82±0.08) was corrected with higher GSSG (370-650: 0.38±0.04, p<0.01; control: 0.49±0.07). Conclusion: detoxification
134
192
Addition of
of
glutathione
peroxides
(lower
into GSSG),
PN
allows
preventing
1
National
Institute
of
Radiological
Sciences,
National
Institutes for Quantum and Radiological Science and Technology, Japan 2
National Cancer Institute, National Institutes of Health,
USA The effect of oxygenation challenges to the in vivo pharmacokinetics of nitroxyl contrast agents in squamous cell carcinoma (SCC) tumor tissue and normal muscle was investigated. In addition, difference of T1 relaxivity (ΔR1) in
the normal muscle and the SCC tumor tissues were compared under several gas-challenging conditions. SCC tumor cells were injected into the right thighs of C3H/Hen MTV- female mice and allowed to grow for 9 days, which resulted in a tumor of approximate size of 0.7 cm3.
Pharmacokinetic profiles of three nitroxyl contrast agents, 3carboxy-2,2,5,5-tetramethyl-pyrrolidine-N-oxyl carbamoyl-2,2,5,5-tetramethyl-pyrrolidine-N-oxyl
(CxP),
3-
(CmP),
and 4-hydroxy-tetramethylpiper-idine-N-oxyl (TPL), having different lipophilicities were compared using MR redox imaging. To perform T1 mapping, spin echo images were
obtained using a multi-slice multi-echo (MSME) sequence with 5 TRs (repetition time: 4800, 3200, 1600, 800 and 400 ms). Exposure to 100% oxygen resulted in a rapid decay rate of TPL in tumor tissue, while no effect or slightly slower decay rate was observed in normal muscle. The 100% oxygen breathing also made distribution of nitroxyl probes into tissue lower. As a result, 100% oxygen breathing can make relatively large difference of TPL concentration between normal and tumor tissue. Carbogen and 1.5 atm hyperbaric oxygen (HBO) challenges could increase ΔR1 in the tissue, while 100% oxygen breathing decreased the ΔR1
in both the normal and the tumor tissue. The pO2 in the
healthy muscle tissue during 100% oxygen breathing measured by the EPR method also showed lower or similar
SfRBM 2017
191
start a clinical study soon.
Dose-response Effect of Glutathione added in Parenteral Nutrition on Lung Oxidative
DOI: 10.1016/j.freeradbiomed.2017.10.204
Stress and Alveolarization in Newborn Guinea Pig Jean-Claude Lavoie1, Ibrahim Mohamed1, and Thérèse Rouleau1 1
Oxygen Induced Tissue Hypoxia Ken-ichiro Matsumoto1, James B. Mitchell2, and Murali C.
Université de Montréal, Canada
Krishna2
Peroxides contaminating parenteral nutrition (PN) are associated with oxidized redox potential of glutathione in blood of preterm newborns (<30 wks) and in lungs of animal. An oxidized redox and the peroxides are associated to bronchopulmonary dysplasia in preterm newborns and induce loss of alveoli in animals. Glutathione detoxifies peroxides
and
normalises
redox
potential.
The
low
glutathione in preterm newborns limits capacity to detoxify peroxides.
Glutathione
is
derived
from
liver
where
methionine is transformed in cysteine of which availability limits the glutathione synthesis. Peroxides inhibit this transformation. Hypothesis: Addition of glutathione into PN compensates for the low hepatic capacity to supply glutathione, and consequently preserves the lung integrity. Methods: At day 3 of life, through a jugular catheter, guinea pigs (N=55) received PN (dextrose, amino acids, lipids, vitamins, electrolytes) enriched in glutathione (0, 50, 120, 165, 270, 370, 650 μg GSSG/kg/d). A control group (no manipulation, fed by mouth) served as reference. After 4 days, lungs were taken for determination of GSH, GSSG, redox
potential
(capillary
electrophoresis)
and
alveolarization index (AI) (number of intercepts between a 1 mm line and histological structures). Data (mean ± sem) from animals on PN were compared by ANOVA, p<0.05. Results: The low AI observed with low doses (μg/kg/d) of GSSG (0-120: 26±1) was corrected with higher level (165650: 30±1, p<0.01; control: 29±1). The oxidized redox (mV)
obtained
with
low
GSSG
(0-165:-209±1)
was
corrected with higher GSSG (270-650: -217±2, p<0.01; control: -216±2). GSH (nmol/mg prot) was not modified by GSSG in PN (30±1); control: 36±1. The high GSSG in lungs (nmol/mg prot) with low doses of GSSG (0-270: 0.82±0.08) was corrected with higher GSSG (370-650: 0.38±0.04, p<0.01; control: 0.49±0.07). Conclusion: detoxification
134
192
Addition of
of
glutathione
peroxides
(lower
into GSSG),
PN
allows
preventing
1
National
Institute
of
Radiological
Sciences,
National
Institutes for Quantum and Radiological Science and Technology, Japan 2
National Cancer Institute, National Institutes of Health,
USA The effect of oxygenation challenges to the in vivo pharmacokinetics of nitroxyl contrast agents in squamous cell carcinoma (SCC) tumor tissue and normal muscle was investigated. In addition, difference of T1 relaxivity (ΔR1) in
the normal muscle and the SCC tumor tissues were compared under several gas-challenging conditions. SCC tumor cells were injected into the right thighs of C3H/Hen MTV- female mice and allowed to grow for 9 days, which resulted in a tumor of approximate size of 0.7 cm3.
Pharmacokinetic profiles of three nitroxyl contrast agents, 3carboxy-2,2,5,5-tetramethyl-pyrrolidine-N-oxyl carbamoyl-2,2,5,5-tetramethyl-pyrrolidine-N-oxyl
(CxP),
3-
(CmP),
and 4-hydroxy-tetramethylpiper-idine-N-oxyl (TPL), having different lipophilicities were compared using MR redox imaging. To perform T1 mapping, spin echo images were
obtained using a multi-slice multi-echo (MSME) sequence with 5 TRs (repetition time: 4800, 3200, 1600, 800 and 400 ms). Exposure to 100% oxygen resulted in a rapid decay rate of TPL in tumor tissue, while no effect or slightly slower decay rate was observed in normal muscle. The 100% oxygen breathing also made distribution of nitroxyl probes into tissue lower. As a result, 100% oxygen breathing can make relatively large difference of TPL concentration between normal and tumor tissue. Carbogen and 1.5 atm hyperbaric oxygen (HBO) challenges could increase ΔR1 in the tissue, while 100% oxygen breathing decreased the ΔR1
in both the normal and the tumor tissue. The pO2 in the
healthy muscle tissue during 100% oxygen breathing measured by the EPR method also showed lower or similar
SfRBM 2017