Abstract
Chorioamnionitis (CA) predisposes to preterm birth and affects the fetal mucosal surfaces (i.e., gut, lungs, and skin) via intra-amniotic (IA) inflammation, thereby accentuating the proinflammatory status in newborn preterm infants. It is not known if CA may affect more distant organs, such as the kidneys, before and after preterm birth. Using preterm pigs as a model for preterm infants, we investigated the impact of CA on fetal and neonatal renal status and underlying mechanisms. Fetal pigs received an IA dose of lipopolysaccharide (LPS), were delivered preterm by cesarean section 3 days later (90% gestation), and compared with controls (CON) at birth and at postnatal day 5. Plasma proteome and inflammatory targets in kidney tissues were evaluated. IA LPS-exposed pigs showed inflammation of fetal membranes, higher fetal plasma creatinine, and neonatal urinary microalbumin levels, indicating renal dysfunction. At birth, plasma proteomics revealed LPS effects on proteins associated with renal inflammation (up-regulated LRG1, down-regulated ICA, and ACE). Kidney tissues of LPS pigs at birth also showed increased levels of kidney injury markers (LRG1, KIM1, NGLA, HIF1A, and CASP3), elevated molecular traits related to innate immune activation (infiltrated MPO+ cells, complement molecules, oxidative stress, TLR2, TLR4, S100A9, LTF, and LYZ), and Th1 responses (CD3+ cells, ratios of IFNG/IL4, and TBET/GATA3). Unlike in plasma, innate and adaptive immune responses in kidney tissues of LPS pigs persisted to postnatal day 5. We conclude that prenatal endotoxin exposure induces fetal and postnatal renal inflammation in preterm pigs with both innate and adaptive immune activation, partly explaining the potential increased risks of kidney injury in preterm infants born with CA.
Highlights
IntroductionPreterm birth (before 37 weeks of gestation, 15 million cases per year, and ∼10% of all pregnancies) is a global health problem and a leading cause of infant mortality and morbidity [1, 2]
Preterm birth is a global health problem and a leading cause of infant mortality and morbidity [1, 2]
Acute-phase response to IA LPS at birth, but not on postnatal day 5, was confirmed by the increased expressions of liver genes. 64 genes in total were validated in transcription level in liver tissues (Supplementary Table 6), and eight genes were significantly changed in at birth, including Complement C3 (C3), Serum Amyloid A (SAA), S100A8, TRL4, ITUH4, CXCL10, TTR, and CD14 molecule (CD14) (Figure 1D); only two genes were significantly changed at postnatal day 5 (Supplementary Table 6)
Summary
Preterm birth (before 37 weeks of gestation, 15 million cases per year, and ∼10% of all pregnancies) is a global health problem and a leading cause of infant mortality and morbidity [1, 2]. CA is often associated with multiple neonatal complications after preterm birth, including necrotizing enterocolitis (NEC), bronchopulmonary dysplasia, periventricular leukomalacia, and sepsis, depending on the location, timing, and severity of maternal inflammation [6]. Despite these associations, it remains unclear how CA interacts with reduced gestational age at birth (preterm birth) to affect infant organs, both at birth and later. Exposure to IA LPS or microbes often elevates levels of immune cells and pro-inflammatory cytokines in the amniotic fluid, which are thought first to interact with fetal mucosal surfaces (e.g., gut, lung, and skin) to evoke local tissue inflammation, and later the inflammatory signals may or may not extend to the circulation and other internal organs [11, 12]. The effects on other internal organs, both at birth and in postnatal periods, remain elusive
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