Prenatal Endotoxin Exposure Induces Fetal and Neonatal Renal Inflammation via Innate and Th1 Immune Activation in Preterm Pigs

Muk, Tik; Jiang, Pingping; Stensballe, Allan; Skovgaard, Kerstin; Sangild, Per Torp; Nguyen, Duc Ninh

doi:10.3389/fimmu.2020.565484

Cited by 12 publications

(17 citation statements)

References 81 publications

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“…Annotated proteins were further sorted into the effect and exposure protein groups. Compared with the data obtained in our previous study (Muk et al, 2020), the CSF proteome had partial overlap with the corresponding plasma proteome (44.3% overlap of total annotated proteins), indicating that (i) at least some of the identi ed CSF proteins were produced locally in the brain and (ii) CSF protein composition underwent time-dependent dynamic changes.…”

Section: Prenatal Lps Exposure Marginally Alters the Csf Protein Pro Le At Birthcontrasting

confidence: 68%

“…Brie y, 54 fetuses from three pregnant sows (Large White × Danish Landrace × Duroc) were randomly allocated to receive an intra-amniotic injection of either 1 mg LPS/fetus (Escherichia coli, serotype 055:B5; Sigma-Aldrich, Copenhagen, Denmark) or control (saline or no injection; CON) at 103 days of gestation (E103). After 3 days, at E106, which corresponds to 90% gestation (full-term birth is 117 ± 2 days), the fetuses were delivered by cesarean section and randomly allocated either to be sacri ced shortly after delivery at Day 1 (P1; CON n = 14, LPS n = 16) or reared for 5 days (P5; n = 12 for each group) as previously described (Muk et al, 2020). The changes in systemic in ammatory marker levels and blood cell counts were previously published (Nguyen et al, 2018).…”

Section: Animal Experimentation and Tissue Collectionmentioning

confidence: 99%

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Differential Brain and Cerebrospinal Fluid Proteomic Responses to Acute Prenatal Endotoxin Exposure

et al. 2022

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BackgroundChorioamnionitis (CA) is a risk factor for preterm birth and is associated with neurodevelopmental delay and cognitive disorders. Prenatal in ammation-induced brain injury may resolve during the immediate postnatal period, which is a time of rapid metabolic and brain remodeling. Cerebrospinal uid (CSF) collected at birth may be a critical source of predictive biomarkers. Using pigs as a model of preterm infants exposed to CA, we hypothesized that prenatal lipopolysaccharide (LPS) exposure induces proteome changes in the CSF and brain both at birth and later. MethodsFetal piglets (103 days gestation of the full-term 117 days) were administered intra-amniotic (IA) lipopolysaccharide (LPS) 3 days before preterm delivery by caesarian section. CSF and brain tissue were collected on postnatal Days 1 and 5 (P1 and P5). CSF and hippocampal proteins were pro led by LC-MS-based quantitative proteomics. Neuroin ammatory responses in the cerebral cortex, periventricular white matter and hippocampus were evaluated by immunohistochemistry, and gene expression was evaluated by qPCR. ResultsPigs exposed to LPS in utero showed changes in CSF protein levels at birth but not at P5. Complement protein C3, hemopexin, vasointestinal peptide, carboxypeptidase N subunit 2, ITIH1 and plasminogen expression was upregulated in the CSF, while the expression of proteins associated with axon growth and synaptic functions (FGFR1, BASP1, HSPD1, UBER2N, and RCN2), adhesion (Talin1), and neuronal survival (Atox1) was downregulated. Microglia, but not astrocytes, were activated by LPS at P5 in the hippocampus but not in other brain regions. At this time, marginal increases in complement protein C3, LBP, Hif1a, Basp1, Minpp1 and FGFR1 transcription indicated hippocampal proin ammatory responses. ConclusionA brief period of prenatal endotoxin exposure induces proteome changes in the CSF and brain at birth, but most changes resolve a few days later. The developing hippocampus has high neuronal plasticity in response to perinatal in ammation. Changes in CSF protein expression at birth may help to predict later structural brain damage in preterm infants exposed to variable types and durations of CA-related in ammation in utero.

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Section: Prenatal Lps Exposure Marginally Alters the Csf Protein Pro Le At Birthcontrasting

confidence: 68%

Section: Animal Experimentation and Tissue Collectionmentioning

confidence: 99%

Differential Brain and Cerebrospinal Fluid Proteomic Responses to Acute Prenatal Endotoxin Exposure

et al. 2022

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“…At 19 days, male pigs had slightly lower hemoglobin and haematocrit values than females, potentially related to diminished erythropoiesis by the smaller kidneys ( 74 ), but more studies are required to verify sex effects on renal structure and function. This organ could be particularly susceptible to perinatal stressors, as indicated by our recent studies on fetal inflammation on gut, lung, liver, immunity and kidney development in preterm pigs ( 33 , 57 , 75 – 77 ). In the literature on production pigs, males do not consistently show reduced neonatal survival and growth ( 18 – 20 , 30 ), hence sex-specific survival, growth and adaptation may be most pronounced for immature newborns.…”

Section: Discussionmentioning

confidence: 99%

Sex-Specific Survival, Growth, Immunity and Organ Development in Preterm Pigs as Models for Immature Newborns

et al. 2021

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Background: After very preterm birth, male infants show higher mortality than females, with higher incidence of lung immaturity, neurological deficits, infections, and growth failure. In modern pig production, piglets dying in the perinatal period (up to 20%) often show signs of immature organs, but sex-specific effects are not clear. Using preterm pigs as model for immature infants and piglets, we hypothesized that neonatal survival and initial growth and immune development depend on sex.Methods: Using data from a series of previous intervention trials with similar delivery and rearing procedures, we established three cohorts of preterm pigs (90% gestation), reared for 5, 9, or 19 days before sample collection (total n = 1,938 piglets from 109 litters). Partly overlapping endpoints among experiments allowed for multiple comparisons between males and females for data on mortality, body and organ growth, gut, immunity, and brain function.Results: Within the first 2 days, males showed higher mortality than females (18 vs. 8%, P < 0.001), but less severe immune response to gram-positive infection. No effect of sex was observed for thermoregulation or plasma cortisol. Later, infection resistance did not differ between sexes, but growth rate was reduced for body (up to −40%) and kidneys (−6%) in males, with higher leucocyte counts (+15%) and lower CD4 T cell fraction (−5%) on day 9 and lower monocyte counts (−18%, day 19, all P < 0.05). Gut structure, function and necrotizing enterocolitis (NEC) incidence were similar between groups, but intestinal weight (−3%) and brush-border enzyme activities were reduced at day 5 (lactase, DPP IV, −8%) in males. Remaining values for blood biochemistry, hematology, bone density, regional brain weights, and visual memory (tested in a T maze) were similar.Conclusion: Following preterm birth, male pigs show higher mortality and slower growth than females, despite limited differences in organ growth, gut, immune, and brain functions. Neonatal intensive care procedures may be particularly important for compromised newborns of the male sex. Preterm pigs can serve as good models to study the interactions of sex- and maturation-specific survival and physiological adaptation in mammals.

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“…Previous studies have demonstrated global alterations in both innate and adaptive immune cell populations in preterm rats 79,80 and pigs [81][82][83] . Recently a preterm pig model exposed to endotoxin demonstrated immune activation in the kidney 84 . In that study, Lyz1 expression in the kidney was higher in the preterm group as compared to the term group.…”

Section: Discussionmentioning

confidence: 99%

Premature differentiation of nephron progenitor cell and dysregulation of gene pathways critical to kidney development in a model of preterm birth

Cwiek

Suzuki

deRonde

et al. 2021

Sci Rep

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Preterm birth is a leading cause of neonatal morbidity. Survivors have a greater risk for kidney dysfunction and hypertension. Little is known about the molecular changes that occur in the kidney of individuals born preterm. Here, we demonstrate that mice delivered two days prior to full term gestation undergo premature cessation of nephrogenesis, resulting in a lower glomerular density. Kidneys from preterm and term groups exhibited differences in gene expression profiles at 20- and 27-days post-conception, including significant differences in the expression of fat-soluble vitamin-related genes. Kidneys of the preterm mice exhibited decreased proportions of endothelial cells and a lower expression of genes promoting angiogenesis compared to the term group. Kidneys from the preterm mice also had altered nephron progenitor subpopulations, early Six2 depletion, and altered Jag1 expression in the nephrogenic zone, consistent with premature differentiation of nephron progenitor cells. In conclusion, preterm birth alone was sufficient to shorten the duration of nephrogenesis and cause premature differentiation of nephron progenitor cells. These candidate genes and pathways may provide targets to improve kidney health in preterm infants.

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Prenatal Endotoxin Exposure Induces Fetal and Neonatal Renal Inflammation via Innate and Th1 Immune Activation in Preterm Pigs

Cited by 12 publications

References 81 publications

Differential Brain and Cerebrospinal Fluid Proteomic Responses to Acute Prenatal Endotoxin Exposure

Differential Brain and Cerebrospinal Fluid Proteomic Responses to Acute Prenatal Endotoxin Exposure

Sex-Specific Survival, Growth, Immunity and Organ Development in Preterm Pigs as Models for Immature Newborns

Premature differentiation of nephron progenitor cell and dysregulation of gene pathways critical to kidney development in a model of preterm birth

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