Melatonin for prevention of fetal lung injury associated with intrauterine inflammation and for improvement of lung maturation

Abstract

Inflammation is associated with injury to immature lungs, and melatonin administration to preterm newborns with acute respiratory distress improves pulmonary outcomes. We hypothesized that maternally administered melatonin may reduce inflammation, oxidative stress, and structural injury in fetal lung and help fetal lung maturation in a mouse model of intrauterine inflammation (IUI). Mice were randomized to the following groups: control (C), melatonin (M), lipopolysaccharide (LPS; a model of IUI) (L), and LPS with melatonin (ML). Pro‐inflammatory cytokines, components of the Hippo pathway, and Yap1/Taz were analyzed in the fetal lung at E18 by real‐time RT‐qPCR. Confirmatory histochemistry and immunohistochemical analyses (surfactant protein B, vimentin, HIF‐1β, and CXCR2) were performed. The gene expression of IL1β in the fetal lung was significantly increased in L compared to C, M, and ML. Taz expression was significantly decreased in L compared to C and M. Taz gene expression in L was significantly decreased compared with those in ML. Immunohistochemical analyses showed that the expression of HIF‐1β and CXCR2 was significantly increased in L compared to C, M, and ML. The area of surfactant protein B and vimentin were significantly decreased in L than C, M, or ML in the fetal and neonatal lung. Antenatal maternally administered melatonin appears to prevent fetal lung injury induced by IUI and to help lung maturation. The results from this study results suggest that melatonin could serve as a novel safe preventive and/or therapeutic medicine for preventing fetal lung injury from IUI and for improving lung maturation in prematurity.

Silencing lncRNA TUG1 Alleviates LPS-Induced Mouse Hepatocyte Inflammation by Targeting miR-140/TNF

“…There is a close relationship between inflammation and oxidative stress, and they promote each other ( Lee et al, 2020 ). It has been reported that oxidative stress is an essential liver injury mechanism caused by paracetamol ( Shi et al, 2020 ).…”

Melatonin for the prevention of fetal injury associated with intrauterine inflammation

“…In another study, pregnant mice pretreated with melatonin before LPS-induced IUI showed significantly reduced inflammatory mediators, and it prevented an increase of the oxidative stress marker (4-hydroxy-2-nonenal) in the placenta. 83 It was immunohistologically confirmed that microglial activation was reduced in the brain, demonstrating that melatonin is a powerful antioxidant drug that is efficacious in protecting neurons from injury. When injected with melatonin, fetal neuroinflammation reduced via antioxidant properties.…”

“…A pregnant mouse model, with IUI induced by LPS, when pretreated with melatonin, showed attenuated production of an oxidative marker (hypoxia-inducible factor-1β) and proinflammatory mediators in the fetal lungs compared with those of the untreated group and increased production of surfactant protein B compared with those of the control group. 83 Furthermore, melatonin preserved the structural integrity of the lungs, which was compromised in mice that were not treated with melatonin. Structural deformities such as widening of the interalveolar septum, dysplasia of the epithelium, and decreased saccules per unit area, which are findings observed in BPD, were better preserved in the melatonin treated group.…”

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

“…), or intra-amniotic (i.a.) route [ 40 , 44 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ] ( Table 1 ). Few rodent studies applied viable microorganisms, such as Ureaplasma spp.…”

“…In response to inflammatory cytokines, oxidative stress markers (e.g., superoxide dismutase), proteinases (e.g., matrix metalloprotease 9), growth factors (e.g., transforming growth factor beta 1, fibroblast growth factors), arginine-related metabolites, and vascularization-related mediators (e.g., vascular endothelial growth factor, actin alfa 2) were found to be changed at transcriptional and translational levels [ 57 , 58 , 59 , 61 , 62 , 64 , 65 , 68 , 75 , 76 ]. Studies performing longitudinal investigation showed persistent regulation of some abovementioned mediators up to the young adulthood period (P21) [ 64 ], indicating a sustained impact of prenatal infection on pulmonary molecular signature even after the recession of acute-phase inflammation.…”