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

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-1ß, and CXCR2) were performed. The gene expression of IL1ß 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-1ß 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.

Exposure to systemic and intrauterine inflammation leads to decreased pup survival via different placental mechanisms.

PROBLEM: Exposure to systemic maternal inflammation (i.e., maternal sepsis, influenza, human immunodeficiency virus, or pyelonephritis) and intrauterine (IU) inflammation (i.e., chorioamnionitis or preterm labor) have been associated with adverse perinatal sequelae. Whether systemic and localized inflammation leading to adverse outcomes have similar placental mechanisms remain unclear. METHOD OF STUDY: We conducted a study by murine modeling systemic and localized IU inflammation with injections of either intraperitoneal (IP) or IU interleukin-1ß (IL-1ß) and compared fetoplacental hemodynamic changes, cytokine/chemokine expression, and fetal loss. RESULTS: IU IL-1ß exposure reduced offspring survival by 31.1% and IP IL-1ß exposure by 34.5% when compared with control pups. Despite this similar outcome in offspring survival, Doppler analysis revealed a stark difference: IU group displayed worsened fetoplacental hemodynamic changes while no differences were found between IP and control groups. While both IU and IP groups had increases in pro-inflammatory cytokines and chemokines, specific gene expression trends differed between the two groups, once again highlighting their mechanistic differences. CONCLUSION: While both IP and IU IL-1ß exposure similarly affected pup survival, only IU inflammation resulted in fetoplacental hemodynamic changes. We speculate that exposure to maternal systemic and IU inflammation plays a key role in fetal injury by utilizing different placental inflammatory pathways and mechanisms.

Cultural Adaptation of a Community-Based Hearing Health Intervention for Korean American Older Adults with Hearing Loss.

Although hearing loss is known to be associated with many adverse health outcomes in older adults, current hearing healthcare remains expensive and inaccessible to most ethnic minorities in the US. We aim to adapt an affordable, community-based hearing intervention to older Korean Americans (KAs), describe the cultural adaption process, and report pilot trial outcomes. We undertook the first four stages of Barrera & Castro's cultural adaptation framework: information gathering, preliminary adaptation design, adaptation test, and adaptation refinement in 15 older KAs with hearing loss and 15 of their communication partners. We developed a culturally adapted intervention consisting of provision of an affordable listening device and aural rehabilitative training. Six weeks post-intervention, participants' mean hearing handicap score (range: 0-40) reduced from 15.7 to 6.4. Communication partners demonstrated improved social-emotional function. Post-intervention focus group revealed increased hearing benefit, confidence in hearing health navigation, and awareness in hearing health among study participants. The adapted intervention was well-accepted and feasible among older KAs. This study is the first to report the cultural adaptation process of a hearing care model into older KAs and its methodology may be applied to other minority groups.

Melatonin for prevention of placental malperfusion and fetal compromise associated with intrauterine inflammation-induced oxidative stress in a mouse model.

Melatonin has been shown to reduce oxidative stress and mitigate hypercoagulability. We hypothesized that maternally administered melatonin may reduce placental oxidative stress and hypercoagulability associated with exposure to intrauterine inflammation (IUI) and consequently improve fetoplacental blood flow and fetal sequelae. Mice were randomized to the following groups: control (C), melatonin (M), lipopolysaccharide (LPS; a model of IUI) (L), and LPS with melatonin (ML). The expression of antioxidant mediators in the placenta was significantly decreased, while that of pro-inflammatory mediators was significantly increased in L compared to C and ML. The systolic/diastolic ratio, resistance index, and pulsatility index in uterine artery (UtA) and umbilical artery (UA) were significantly increased in L compared with other groups when analyzed by Doppler ultrasonography. The expression of antioxidant mediators in the placenta was significantly decreased, while that of pro-inflammatory mediators was significantly increased in L compared to C and ML. Vascular endothelial damage and thrombi formation, as evidenced by fibrin deposits, were similarly increased in L compared to other groups. Maternal pretreatment with melatonin appears to modulate maternal placental malperfusion, fetal cardiovascular compromise, and fetal neuroinflammation induced by IUI through its antioxidant properties.

Administration of melatonin for prevention of preterm birth and fetal brain injury associated with premature birth in a mouse model.

PROBLEM: Maternal inflammation leads to preterm birth and perinatal brain injury. Melatonin, through its anti-inflammatory effects, has been shown to be protective against inflammation-induced perinatal adverse effects. However, the immunomodulatory effects of melatonin on preterm birth and prematurity-related morbidity remain unknown. We wanted to investigate the effects of maternally administered melatonin on preterm birth and perinatal brain injury in a mouse model of maternal inflammation. METHOD OF STUDY: A model of maternal inflammation employing lipopolysaccharide (LPS) was used to mimic the most common clinical scenario of preterm birth, that of maternal inflammation. Mice were randomly divided into the following groups: control, LPS, and LPS with melatonin pre-treatment. Doppler ultrasonography was used to obtain fetal and maternal hemodynamic measurements in utero. Placenta and fetal brains were harvested and analyzed for proinflammatory markers and signs of perinatal brain injury, respectively. Surviving offspring were assessed for neuromotor outcomes. RESULTS: Melatonin pre-treatment lowered the level of proinflammatory cytokines in the uterus and the placenta, significantly improved LPS-induced acute fetal neuroinflammation and perinatal brain injury, as well as significantly upregulated the SIRT1/Nrf2 signaling pathway to reduce LPS-induced inflammation. Melatonin also prevented adverse neuromotor outcomes in offspring exposed to maternal inflammation. CONCLUSION: Maternally administered melatonin modulated immune responses to maternal inflammation and decreased preterm birth and perinatal brain injury. These results suggest that melatonin, a safe treatment during pregnancy, may be used as an experimental therapeutic in clinical trials.