Fetal ethanol exposure and zinc homeostasis in the newborn alveolar macrophage Público
Konomi, Juna Viktoria (2014)
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
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
Discussion65
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
About this Dissertation
| School | |
|---|---|
| Department | |
| Degree | |
| Submission | |
| Language |
|
| Research Field | |
| Palabra Clave | |
| Committee Chair / Thesis Advisor | |
| Committee Members |
Primary PDF
| Thumbnail | Title | Date Uploaded | Actions |
|---|---|---|---|
|
|
Fetal ethanol exposure and zinc homeostasis in the newborn alveolar macrophage () | 2018-08-28 13:06:38 -0400 |
|
Supplemental Files
| Thumbnail | Title | Date Uploaded | Actions |
|---|