Fetal ethanol exposure and zinc homeostasis in the newborn alveolar macrophage 公开

Konomi, Juna Viktoria (2014)

Permanent URL: https://etd.library.emory.edu/concern/etds/bg257f52v?locale=zh
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Abstract

Alcohol exposure increases risk of extreme premature birth (<32 weeks gestational age) by over 34 fold. One of the major complications of pre-term birth is lung immaturity which contributes up to 75% of early mortality and morbidity in the pre-term infant. Alcohol further exacerbates an already dysfunctional lung through alteration of lung development and induction of oxidative stress which results in arrested alveolarization and vascular development, increasing risk of pulmonary infections in animal models of fetal ethanol exposure. Zinc is essential for the immune system and its deficiency increases susceptibility to infection and exacerbates existing infections. Alcohol may also affect maternal-placental-fetal transfer of zinc by altering zinc transporter expression in the placental surface or by inducing an inflammatory state in the placenta that impairs zinc transport to the fetus.

Using a mouse model of chronic ethanol exposure in utero, we investigated whether zinc homeostasis was disturbed in the ethanol-exposed alveolar macrophage (AM) and whether these effects could be reversed with zinc treatments. In exploring mechanisms by which ethanol altered zinc homeostasis in the newborn AM, we focused in characterization of cytokine profiles in placental tissues from a pre-term population that was exposed to alcohol in utero.

In utero ethanol exposure was associated with decreased expression of zinc transporters, intracellular zinc levels, and bacterial clearance in the AM when compared to no ethanol exposure. In vitro zinc treatments increased expression of zinc transporters and this was concomitant with restored intracellular zinc levels and AM bacterial clearance in the ethanol-exposed pups. Additionally, fetal alcohol exposure was associated with an increase in pro-inflammatory cytokines in the placenta.

These studies suggest that zinc insufficiency is a critical component in the impaired AM immune functions associated with fetal alcohol exposure. Furthermore, it supports zinc supplements as a novel therapeutic approach for attenuating the derangements in AM bacterial clearance and risk for respiratory infections in the newborn with fetal alcohol exposure.

Table of Contents

TABLE OF CONTENTS
CHAPTER 1: INTRODUCTION ........................................................1
CHAPTER 2: LITERATURE REVIEW .................................................5
ALCOHOL

Alcohol and zinc deficiency .........................................................5
Alcohol metabolism ....................................................................6
Alcohol biomarkers .....................................................................7
Alcohol and disease ..................................................................11
ZINC

Zinc sources and bioavailability ...................................................17
Zinc metabolism .......................................................................19
Zinc functions ..........................................................................20
Zinc deficiency ........................................................................21
Zinc excess ............................................................................22
Zinc biomarkers .......................................................................23
Zinc transporters .....................................................................25
Zinc transporters in the lung ......................................................33
MATERNAL OUTCOMES
Zinc requirements during pregnancy ............................................34
Zinc deficiency and supplementation in pregnancy outcomes ...........34
Zinc biomarkers in pregnancy .....................................................35
Zinc transporters in pregnancy ...................................................36
Alcohol and pregnancy ..............................................................37
Alcohol biomarkers during pregnancy ............................................38
FETAL OUTCOMES
Alcohol exposure in utero ...........................................................40
Lung development ....................................................................41
Fetal alcohol exposure and lung immune response ...........................42
Zinc deficiency and neonatal outcomes ........................................43
Zinc deficiency and neonatal immunity .........................................45
Zinc supplementation and neonatal outcomes ................................46
Alcohol, zinc and FASD ..............................................................47
Animal models of alcohol exposure ...............................................48
Our model of fetal alcohol exposure .............................................49
Newborn biomarkers of fetal alcohol exposure ................................49
INFLAMMATION AND PREGNANCY
Placental development and the effect of alcohol ............................51
Cytokines and pregnancy ..........................................................53
Alcohol and cytokines during pregnancy .......................................54
CHAPTER 3: ZINC INSUFFICIENCY MEDIATES ETHANOL-INDUCED ALVEOLAR

MACROPHAGE DYSFUNCTION IN THE PREGNANT FEMALE MOUSE
Abstract ................................................................................56
Introduction ...........................................................................57
Materials and Methods .............................................................59
Results .................................................................................62
Discussion .............................................................................65
CHAPTER 4: ZINC INSUFFICIENCY MEDIATES THE FETAL ALVEOLAR MACROPHAGE

DYSFUNCTION ASSOCIATED WITH FETAL ETHANOL EXPOSURE
Abstract ................................................................................79
Introduction ...........................................................................80
Materials and Methods .............................................................82
Results .................................................................................85
Discussion .............................................................................87
CHAPTER 5: FETAL ALCOHOL EXPOSURE IS ASSOCIATED WITH INCREASED

CYTOKINE PRODUCTION IN THE PLACENTA OF THE PREMATURE NEWBORN
Abstract ..............................................................................102
Introduction .........................................................................103
Materials and Methods ............................................................105
Results ................................................................................108
Discussion ............................................................................109
CHAPTER 6: CONCLUSIONS, LIMITATIONS, FUTURE DIRECTIONS, PUBLIC

HEALTH IMPLICATIONS
CONCLUSIONS

Experimental studies ...............................................................116
Clinical study .........................................................................118
LIMITATIONS

Experimental studies ...............................................................119
Clinical study .........................................................................120
FUTURE DIRECTIONS ...............................................................121
IMPLICATIONS FOR PUBLIC HEALTH ............................................124
REFERENCES ..........................................................................126

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