Fumihiko Namba

Placental Features of Chorioamnionitis Colonized With Ureaplasma Species in Preterm Delivery

Ureaplasma spp. is detected in the urogenital tract, including the vagina, cervix, chorioamnion, and placenta. Their colonization is associated with histologic chorioamnionitis (CAM), often observed in placentas from preterm delivery. We isolated Ureaplasma spp. from 63 preterm placentas among 151 specimens, which were delivered at <32 wk of gestation. Of the 63 placentas, 52 (83%) revealed CAM in cultures positive for Ureaplasma spp., however, CAM was observed only in 30% (26/88) of cultures negative for Ureaplasma spp. (p < 0.01). Colonization by Ureaplasma spp. was an independent risk factor for CAM (OR, 11.27; 95% CI, 5.09–24.98). Characteristic neutrophil infiltration was observed in the amnion and subchorion (bistratified pattern) in cultures positive for Ureaplasma spp. FISH analysis of CAM placenta with male infant pregnancy indicated that bistratified infiltrated neutrophils showed the XX karyotype and umbilical vein infiltrated neutrophils showed XY karyotype. The distribution of sulfoglycolipid, the receptor of Ureaplasma spp., was mainly detected in the amnion. Ureaplasmal urease D protein and ureB gene were both detected in the amnion, indicating direct colonization by Ureaplasma spp.

Heme oxygenase-1 regulates postnatal lung repair after hyperoxia: role of β-catenin/hnRNPK signaling.

In the newborn, alveolarization continues postnatally and can be disrupted by hyperoxia, leading to long-lasting consequences on lung function. We wanted to better understand the role of heme oxygenase (HO)-1, the inducible form of the rate-limiting enzyme in heme degradation, in neonatal hyperoxic lung injury and repair. Although it was not observed after 3 days of hyperoxia alone, when exposed to hyperoxia and allowed to recover in air (O2/air recovered), neonatal HO-1 knockout (KO) mice had enlarged alveolar spaces and increased lung apoptosis as well as decreased lung protein translation and dysregulated gene expression in the recovery phase of the injury. Associated with these changes, KO had sustained low levels of active β-catenin and lesser lung nuclear heterogeneous nuclear ribonucleoprotein K (hnRNPK) protein levels, whereas lung nuclear hnRNPK was increased in transgenic mice over-expressing nuclear HO-1. Disruption of HO-1 may enhance hnRNPK-mediated inhibition of protein translation and subsequently impair the β-catenin/hnRNPK regulated gene expression required for coordinated lung repair and regeneration.

Expression level and subcellular localization of heme oxygenase-1 modulates its cytoprotective properties in response to lung injury: a mouse model.

Premature infants exposed to hyperoxia suffer acute and long-term pulmonary consequences. Nevertheless, neonates survive hyperoxia better than adults. The factors contributing to neonatal hyperoxic tolerance are not fully elucidated. In contrast to adults, heme oxygenase (HO)-1, an endoplasmic reticulum (ER)-anchored protein, is abundant in the neonatal lung but is not inducible in response to hyperoxia. The latter may be important, because very high levels of HO-1 overexpression are associated with significant oxygen cytotoxicity in vitro. Also, in contrast to adults, HO-1 localizes to the nucleus in neonatal mice exposed to hyperoxia. To understand the mechanisms by which HO-1 expression levels and subcellular localization contribute to hyperoxic tolerance in neonates, lung-specific transgenic mice expressing high or low levels of full-length HO-1 (cytoplasmic, HO-1-FL(H) or HO-1-FL(L)) or C-terminally truncated HO-1 (nuclear, Nuc-HO-1-TR) were generated. In HO-1-FL(L), the lungs had a normal alveolar appearance and lesser oxidative damage after hyperoxic exposure. In contrast, in HO-1-FL(H), alveolar wall thickness with type II cell hyperproliferation was observed as well worsened pulmonary function and evidence of abnormal lung cell hyperproliferation in recovery from hyperoxia. In Nuc-HO-1-TR, the lungs had increased DNA oxidative damage, increased poly (ADP-ribose) polymerase (PARP) protein expression, and reduced poly (ADP-ribose) (PAR) hydrolysis as well as reduced pulmonary function in recovery from hyperoxia. These data indicate that low cytoplasmic HO-1 levels protect against hyperoxia-induced lung injury by attenuating oxidative stress, whereas high cytoplasmic HO-1 levels worsen lung injury by increasing proliferation and decreasing apoptosis of alveolar type II cells. Enhanced lung nuclear HO-1 levels impaired recovery from hyperoxic lung injury by disabling PAR-dependent regulation of DNA repair. Lastly both high cytoplasmic and nuclear expression of HO-1 predisposed to long-term abnormal lung cellular proliferation. To maximize HO-1 cytoprotective effects, therapeutic strategies must account for the specific effects of its subcellular localization and expression levels.

Utility of a new transcutaneous jaundice device with two optical paths in premature infants

Background: Hyperbilirubinemia may cause dysfunction of the central nervous system of newborn infants. Recently, a new transcutaneous bilirubin device has been developed, which is not limited by maturity or melanin concentration of the skin. However, there have been few reports limiting the subjects to preterm and very low‐birthweight (VLBW) infants.

Drug treatment for bronchopulmonary dysplasia in Japan: questionnaire survey.

Bronchopulmonary dysplasia (BPD) is one of the most common complications in premature infants. Although several different drugs have been developed for BPD, there is a wide variation in the choice of drug used among facilities. The aim of this study was to carry out a survey of the current drugs used to treat BPD in Japan. Questionnaires regarding the current use of drugs for BPD were sent to tertiary neonatal units. The response rate was 80% (77/96). Most units used antenatal steroids and oral diuretics for the prevention and treatment of BPD, respectively. Only 4% used caffeine for prevention, whereas 88% used systemic corticosteroids for treatment. Few units used inhaled anticholinergics and i.v. vitamins for the prevention and treatment of BPD, respectively. It was found that the drugs used to treat BPD vary greatly among institutions. Further research is required to develop evidence‐based clinical guidelines for BPD in premature infants.

Use of high-flow nasal cannula in neonates: Nationwide survey in Japan

High‐flow nasal cannula is a new modality of respiratory support and is increasing in popularity despite the lack of supporting evidence. We investigated the prevalence of its use in tertiary neonatal units in Japan. A paper‐based survey was conducted. The response rate was 83%. High‐flow nasal cannula was used in 46/80 units (58%), of which 96% used the high‐flow nasal cannula without guidelines. It was used for several indications, including weaning off nasal continuous positive airway pressure and post‐extubation respiratory support. The main perceived benefits of the cannula included better access to the neonate and reduced risk of nasal trauma. This survey found that high‐flow nasal cannula is used without clear criteria and that clinical practice varies across neonatal units in Japan. Its use in neonates needs to be urgently evaluated.

Role of sex in morbidity and mortality of very premature neonates

The aim of this study was to investigate the effect of sex on survival and short‐term outcomes of very low‐birthweight infants (VLBWI) born in Japan.

Sex-related differences in long-term pulmonary outcomes of neonatal hyperoxia in mice.

ABSTRACT Aim: Premature infants are often exposed to hyperoxia to maintain adequate oxygenation, which may lead to the development of bronchopulmonary dysplasia (BPD). Sex-specific differences exist in the development and severity of BPD. Only a few studies have examined the mechanisms underlying these sex-related differences. The aim of the present study is to examine the sex-related long-term effects of neonatal hyperoxia on the lungs of adult mice. Materials and Methods: Newborn mice were exposed to 95% oxygen (hyperoxia) for 96 hours and were allowed to recover in room air to adulthood (8 weeks of age). Lung tissues were excised at 4 days, 14 days, or 8 weeks of age. Short-term effects of neonatal hyperoxia on the mouse lung and sex-related differences in pulmonary function, airway hyper-responsiveness, and lung structure in adult mice were assessed. Results: Neonatal hyperoxia was found to have no differential effect on body weight, muscarinic acetylcholine receptor gene expression, or bronchiolar epithelial thickness in adult mice. Respiratory resistance was increased and sensitivity to methacholine was decreased in male adult mice following exposure to neonatal hyperoxia, whereas delayed alveolarization was observed in female adult mice following exposure to neonatal hyperoxia. Conclusions: The findings of the present study demonstrate that neonatal hyperoxia differentially affects pulmonary outcome in female and male adult mice.

Anti-Annexin A2 IgM Antibody in Preterm Infants: Its Association with Chorioamnionitis

Intrauterine infection is associated with chorioamnionitis (CAM), which can lead to preterm delivery. We previously reported that the levels of IgM and the incidence of CAM were elevated in preterm infants with neonatal pulmonary emphysema. The pathogen and target of this IgM remain unclear. By using Western blot and amino acid sequences, we have determined one of the target proteins: annexin A2. Immunohistochemical analysis showed that annexin A2 was expressed at fetal chorion and amnion membranes. Among very low birth weight (VLBW) infants with hyper-IgM (≥30 mg/dL), 58.8% showed a high titer against annexin A2 (more than ×16), which accounted for about 20%–40% of the total IgM. Anti-annexin A2 IgM antibody inhibited plasmin generation. Furthermore, the median of anti-annexin A2 IgM titer from preterm infants who were delivered with high-grade (grade III) CAM was significantly higher than those from preterm infants without CAM (p = 0.011) and with low-grade CAM (grade I and II) (p = 0.010). Here, we indicate the fetal autoimmunoreactivity against the fetomaternal interface in preterm infants.

Genetic ablation of Bach1 gene enhances recovery from hyperoxic lung injury in newborn mice via transient upregulation of inflammatory genes

Background:BTB and CNC homology 1 (Bach1) is a transcriptional repressor of heme oxygenase (HO)-1. The effects of Bach1 disruption on hyperoxic lung injury in newborn mice have not been determined. We aimed to investigate the role of Bach1 in the newborns exposed to hyperoxia.Methods:Bach1−/− and WT newborn mice were exposed to 21% or 95% oxygen for 4 d and were then allowed to recover in room air. Lung histology was assessed and lung Bach1, HO-1, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1 mRNA levels were evaluated using RT-PCR. Lung inflammatory cytokine levels were determined using cytometric bead arrays.Results:After 10 d recovery from neonatal hyperoxia, Bach1−/− mice showed improved lung alveolarization compared with WT. HO-1, IL-6, and MCP-1 mRNA levels and IL-6 and MCP-1 protein levels were significantly increased in the Bach1−/− lungs exposed to neonatal hyperoxia. Although an increase in apoptosis was observed in the Bach1−/− and WT lungs after neonatal hyperoxia, there were no differences in apoptosis between these groups.Conclusion:Bach1−/− newborn mice were well-recovered from hyperoxia-induced lung injury. This effect is likely achieved by the antioxidant/anti-inflammatory activity of HO-1 or by the transient overexpression of proinflammatory cytokines.