Insights into the Black Box of Intra-Amniotic Infection and Its Impact on the Premature Lung: From Clinical and Preclinical Perspectives

Abstract

Intra-amniotic infection (IAI) is one major driver for preterm birth and has been demonstrated by clinical studies to exert both beneficial and injurious effects on the premature lung, possibly due to heterogeneity in the microbial type, timing, and severity of IAI. Due to the inaccessibility of the intra-amniotic cavity during pregnancies, preclinical animal models investigating pulmonary consequences of IAI are indispensable to elucidate the pathogenesis of bronchopulmonary dysplasia (BPD). It is postulated that on one hand imbalanced inflammation, orchestrated by lung immune cells such as macrophages, may impact on airway epithelium, vascular endothelium, and interstitial mesenchyme, resulting in abnormal lung development. On the other hand, excessive suppression of inflammation may as well cause pulmonary injury and a certain degree of inflammation is beneficial. So far, effective strategies to prevent and treat BPD are scarce. Therapeutic options targeting single mediators in signaling cascades and mesenchymal stromal cells (MSCs)-based therapies with global regulatory capacities have demonstrated efficacy in preclinical animal models and warrant further validation in patient populations. Ante-, peri- and postnatal exposome analysis and therapeutic investigations using multiple omics will fundamentally dissect the black box of IAI and its effect on the premature lung, contributing to precisely tailored and individualized therapies.

Bronchopulmonary dysplasia in adults: Exploring pathogenesis and phenotype

“…Whether or not the amniotic cavity is a sterile environment is a hotly debated topic in the current literature; however, several studies have demonstrated a variety of organisms live within the amniotic fluid, ranging from Gram-positive and negative bacteria, viruses, and fungi to genital mycoplasma species, such as Ureaplasma. 36,[38][39][40][41][42] Several inflammatory mediators have been implicated in the prenatal pathogenesis of BPD, including interleukin (IL)-1α, IL-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α. 37,43 These proinflammatory cytokines have been shown to alter both structure and function of lung tissue in several animal trials.…”

“…The term “chorioamnionitis” is commonly used to describe a variety of inflammatory disorders and antenatal infections with a spectrum of severity 35 . Associated clinical findings include some combination of maternal fever, maternal or fetal tachycardia, maternal leukocytosis, uterine tenderness, or purulent vaginal discharge; however, these findings correlate poorly with diagnosis of true intraamniotic infection 35,36 . As a result, the National Institute of Child Health and Development proposed the term “intrauterine inflammation, infection, or both” (abbreviated as “Triple I”) as a replacement for “chorioamnionitis” in 2016 35 …”

“…35 Associated clinical findings include some combination of maternal fever, maternal or fetal tachycardia, maternal leukocytosis, uterine tenderness, or purulent vaginal discharge; however, these findings correlate poorly with diagnosis of true intraamniotic infection. 35,36 As a result, the National Institute of Child Health and Development proposed the term "intrauterine inflammation, infection, or both" (abbreviated as "Triple I") as a replacement for "chorioamnionitis" in 2016. 35 True chorioamnionitis can be acute or chronic and is diagnosed by neutrophilic or lymphocytic infiltration of the fetal membranes.…”

“…“Triple I,” more accurately captures the full spectrum of pathologies that can predispose the fetal lung to developing BPD. Whether or not the amniotic cavity is a sterile environment is a hotly debated topic in the current literature; however, several studies have demonstrated a variety of organisms live within the amniotic fluid, ranging from Gram‐positive and negative bacteria, viruses, and fungi to genital mycoplasma species, such as Ureaplasma 36,38–42 …”

Microbial signatures in amniotic fluid at preterm birth and association with bronchopulmonary dysplasia

“…In another study, bacterial colonization of the upper airways with Enterococcu s Enterobacter Staphylococcus and Escherichia species was identified to be associated with BPD [ 8 ]. But the impact of microbiota on the immature lung and the risk for BPD remains controversial [ 9 ]. The two largest meta-analyses on this topic found an association between chorioamnionitis or the pulmonary colonization with bacteria of the genus Ureaplasma and BPD, but both reports point to the uncertainty due to potential biases in the published data despite the statistically significant impact on BPD [ 10 , 11 ].…”