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NPC1 Deficiency in Mice is Associated with Fetal Growth Restriction, Neonatal Lethality and Abnormal Lung Pathology.

ABSTRACT: The rare lysosomal storage disorder Niemann-Pick disease type C1 (NPC1) arises from mutation of NPC1, which encodes a lysosomal transmembrane protein essential for normal transport and trafficking of cholesterol and sphingolipids. NPC1 is highly heterogeneous in both clinical phenotypes and age of onset. Previous studies have reported sub-Mendelian survival rates for mice homozygous for various Npc1 mutant alleles but have not studied the potential mechanisms underlying this phenotype. We performed the first developmental analysis of a Npc1 mouse model, Npc1em1Pav, and discovered significant fetal growth restriction in homozygous mutants beginning at E16.5. Npc1em1Pav/em1Pav mice also exhibited cyanosis, increased respiratory effort, and over 50% lethality at birth. Analysis of neonatal lung tissues revealed lipid accumulation, notable abnormalities in surfactant, and enlarged alveolar macrophages, suggesting that lung abnormalities may be associated with neonatal lethality in Npc1em1Pav/em1Pav mice. The phenotypic severity of the Npc1em1Pav model facilitated this first analysis of perinatal lethality and lung pathology in an NPC1 model organism, and this model may serve as a useful resource for developing treatments for respiratory complications seen in NPC1 patients.

SUBMITTER: Rodriguez-Gil JL

PROVIDER: S-EPMC7019814 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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NPC1 Deficiency in Mice is Associated with Fetal Growth Restriction, Neonatal Lethality and Abnormal Lung Pathology.

Rodriguez-Gil Jorge L JL Watkins-Chow Dawn E DE Baxter Laura L LL Yokoyama Tadafumi T Zerfas Patricia M PM Starost Matthew F MF Gahl William A WA Malicdan May Christine V MCV Porter Forbes D FD Platt Frances M FM Pavan William J WJ

Journal of clinical medicine 20191219 1

The rare lysosomal storage disorder Niemann-Pick disease type C1 (NPC1) arises from mutation of <i>NPC1</i>, which encodes a lysosomal transmembrane protein essential for normal transport and trafficking of cholesterol and sphingolipids. NPC1 is highly heterogeneous in both clinical phenotypes and age of onset. Previous studies have reported sub-Mendelian survival rates for mice homozygous for various <i>Npc1</i> mutant alleles but have not studied the potential mechanisms underlying this phenot ...[more]

PMID: 31861571

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Project description:Background: Infants born preterm or small for gestational age (SGA, due to fetal growth restriction) both show an increased risk of neonatal infection. However, it remains unclear how the co-occurrence of preterm birth and SGA may affect neonatal immunity and infection risk. We hypothesized that fetal growth restricted (FGR) preterm newborns possess impaired immune competence and increased susceptibility to systemic infection and sepsis, relative to corresponding normal birth weight (NBW) newborns. Methods: Using preterm pigs as a model for preterm infants, gene expression in lipopolysaccharide (LPS) stimulated cord blood was compared between NBW and FGR (lowest 25% birth weight percentile) preterm pigs. Next, clinical responses to a systemic Staphylococcus epidermidis (SE) challenge were investigated in newborn FGR and NBW preterm pigs. Finally, occurrence of spontaneous infections were investigated in 9 d-old FGR and NBW preterm pigs, with or without neonatal antibiotics treatment. Results: At birth, preterm FGR piglets showed diminished ex vivo cord blood responses to LPS for genes related to both innate and adaptive immunity, and also more severe septic responses following SE infection (e.g., higher blood lactate, decreased blood pH, neutrophil and platelet counts, relative to NBW pigs). After 9 d, FGR pigs had higher incidence and severity of spontaneous infections (e.g., higher bacterial densities in the bone marrow), increased regulatory T cell numbers, reduced neutrophil phagocytosis capacity, and impaired ex vivo blood gene responses to LPS, especially when receiving neonatal antibiotics. Conclusion: FGR at preterm birth is associated with poor immune competence, impaired infection resistance, and greater sepsis susceptibility in the immediate postnatal period. Our results may explain the increased morbidity and mortality of SGA preterm infants and highlight the need for clinical vigilance for this highly sensitive subgroup of preterm neonates.

Project description:IntroductionEarly-onset fetal growth restriction is a pregnancy complication often coinciding with abnormal Doppler flow in the umbilical artery. Absent or reversed end-diastolic flow in the umbilical artery is associated with adverse perinatal outcome. As the optimal management of this condition is unclear, the objective of this study was to analyze the time interval from admission to delivery of pregnancies with early-onset fetal growth restriction, while pursuing a policy of postponing delivery unless active management of labor would be required because of fetal distress or maternal condition. We also assessed short- and long-term perinatal outcome.Material and methodsIn this historical cohort study, all pregnant women with singleton pregnancies, admitted during 2004-2015 with early-onset fetal growth restriction were included. Pregnancies with absent or reversed end-diastolic flow (AREDF) were compared with pregnancies with a positive end-diastolic Doppler flow (PEDF). Time until delivery was determined and perinatal outcome was assessed for both groups.ResultsIn our study, 111 women were allocated to the PEDF group and 109 to the AREDF group. In the AREDF group, fetal distress was more often an indication for delivery, in comparison with the PEDF group (p = .004). Median time until delivery in patients admitted between 26 and 28 weeks' gestation was 6+5 weeks in the PEDF group and 1+4 weeks in the AREDF group (p = .001). No statistically significant difference was found between the Doppler groups in the composite adverse neonatal outcome, which includes at least one of the following outcomes: infant respiratory distress syndrome, sepsis, bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage >grade 2, periventricular leukomalacia and perinatal death (p = .63).ConclusionsIn this study, comprising pregnancies with early-onset fetal growth restriction, fetal distress was observed more frequently in the AREDF group with the consequence of delivery at an earlier stage of gestation, compared with the PEDF group. AREDF was not associated with increased perinatal morbidity and mortality compared with PEDF.

Project description:Immune cells are critically involved in placental development and functioning, and inadequate regulation of the maternal immune system is associated with placental pathology and pregnancy complications. This study aimed to explore numbers of decidual immune cells in pregnancies complicated with fetal growth restriction (FGR) and stillbirth (SB), and in placentas with histopathological lesions: maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), delayed villous maturation (DVM), chorioamnionitis (CA), and villitis of unknown etiology (VUE). Placental tissue from FGR (n = 250), SB (n = 64), and healthy pregnancies (n = 42) was included. Histopathological lesions were classified according to criteria developed by the Amsterdam Placental Workshop Group. Tissue slides were stained for CD68 (macrophages), CD206 (M2-like macrophages), CD3 (T cells), FOXP3 [regulatory T (Treg) cells], and CD56 [natural killer (NK) cells]. Cell numbers were analyzed in the decidua basalis using computerized morphometry. The Mann-Whitney U-test and Kruskal Wallis test with the Dunn's as post-hoc test were used for statistical analysis. Numbers of CD68+ macrophages were higher in FGR compared to healthy pregnancies (p < 0.001), accompanied by lower CD206+/CD68+ ratios (p < 0.01). In addition, in FGR higher numbers of FOXP3+ Treg cells were seen (p < 0.01) with elevated FOXP3+/CD3+ ratios (p < 0.01). Similarly, in SB elevated FOXP3+ Treg cells were found (p < 0.05) with a higher FOXP3+/CD3+ ratio (p < 0.01). Furthermore, a trend toward higher numbers of CD68+ macrophages was found (p < 0.1) in SB. Numbers of CD3+ and FOXP3+ cells were higher in placentas with VUE compared to placentas without lesions (p < 0.01 and p < 0.001), accompanied by higher FOXP3+/CD3+ ratios (p < 0.01). Elevated numbers of macrophages with a lower M2/total macrophage ratio in FGR suggest a role for a macrophage surplus in its pathogenesis and could specifically indicate involvement of inflammatory macrophages. Higher numbers of FOXP3+ Treg cells with higher Treg/total T cell ratios in VUE may be associated with impaired maternal-fetal tolerance and a compensatory response of Treg cells. The abundant presence of placental lesions in the FGR and SB cohorts might explain the increase of Treg/total T cell ratios in these groups. More functionality studies of the observed altered immune cell subsets are needed.

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NPC1 Deficiency in Mice is Associated with Fetal Growth Restriction, Neonatal Lethality and Abnormal Lung Pathology.

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NPC1 Deficiency in Mice is Associated with Fetal Growth Restriction, Neonatal Lethality and Abnormal Lung Pathology.

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