Takatsugu Kojima

Endothelin is a potent secretagogue for atrial natriuretic peptide in cultured rat atrial myocytes.

Using cultured neonatal rat atrial cardiocytes, we have studied the effect of synthetic porcine endothelin (pET), a novel potent vasoconstrictor isolated from endothelial cells, on the release of immunoreactive (IR) rat atrial natriuretic peptide (rANP). pET stimulated IR-rANP secretion in a dose-dependent manner (10(-10)-10(-7) M) with an approximate half-maximally stimulatory dose of 2 x 10(-10) M. The pET-induced IR-rANP secretion was attenuated by Ca2+-channel blocker nicardipine, but no further stimulation was induced when combined with a Ca2+-channel agonist BAY-K 8644. pET in combination with tetradecanoyl-phorbol-acetate resulted in a synergistic effect on IR-rANP secretion. These data suggest that ET may play as an endogenous secretagogue for rANP by modulating Ca2+ influx through the voltage-dependent Ca2+-channels in atrial cardiocytes.

Endothelin stimulates accumulations for cellular atrial natriuretic peptide and its messenger RNA in rat cardiocytes

The effect of endothelin-1 (ET-1) on secretion and synthesis of rat atrial natriuretic peptide (rANP) as well as its mRNA levels was studied in primary cultures of neonatal rat atrial cardiocytes. ET-1 dose-dependently (10(-10)-10(-7) M) increased media and cellular rANP-like immunoreactivity as well as its cytoplasmic mRNA levels in rat cardiocytes during 24 hrs incubation. These results suggest that ET-1 directly stimulates expression of the rANP gene in cardiocytes, thereby leading to enhanced synthesis and secretion of rANP.

Serum eosinophil derived neurotoxin may reflect more strongly disease severity in childhood atopic dermatitis than eosinophil cationic protein

Serum levels of eosinophil cationic protein (ECP) have been shown to be a good parameter of the disease severity of patients with atopic dermatitis (AD). However, the relationship between the disease severity and the eosinophil derived neurotoxin (EDN) has not been established in AD patients. The purpose of this study is to examine serum ECP and EDN levels in relation to the disease severity in AD children. Serum ECP and EDN levels were assessed in relation to the skin scores in 34 AD children (18 boys and 16 girls; age 0.6 to 7years: mean+/-S.D. 2.2+/-1.9) and six non-atopic control children (three boys and three girls; age 1 to 3years: mean+/-S.D. 1.7+/-0.9). Serum ECP and EDN levels of the patients with AD were significantly increased compared with the non-atopic controls. Serum EDN levels of the patients were also related to the disease severity. The skin scores were more significantly correlated with serum EDN levels than ECP levels. We concluded that serum EDN may reflect more strongly disease severity as eosinophilic activation in AD children than serum ECP.

Increased soluble ICAM-1 in tracheal aspirates of infants with bronchopulmonary dysplasia

Raised concentrations of soluble intracellular adhesion molecule 1 (sICAM-1) in tracheal aspirates from premature infants may predict development of bronchopulmonary dysplasia (BPD). We measured sICAM-1 in tracheal aspirates and serum samples from 15 newborn babies (9 with BPD, 6 without BPD) at 2-4, 6-7, and 12-14 days of age. sICAM-1 concentrations in tracheal aspirates were significantly raised at 6-7 and 12-14 days of age in infants who later developed BPD compared with infants who did not develop BPD. Serum samples from the two groups did not differ significantly in sICAM-1. Raised sICAM-1 in tracheal aspirate was a good predictor of lung injury in infants who later developed BPD.

Eosinophilia in premature infants: correlation with chronic lung disease

We attempted to clarify the possible pathophysiological significance of eosinophilia in bronchopulmonary dysplasia (BPD). The subjects studied were 17 premature infants, i.e. seven with respiratory distress syndrome (RDS) followed by bronchopulmonary dysplasia (the BPD group: four with stage IV and three with stage III BPD) and 10 infants without BPD (the non‐BPD group), who comprised seven with RDS, two with meconium aspiration syndrome and one with transient tachypnea of the newborn. Peripheral eosinophil counts, the number of nuclei of eosinophils and serum eosinophilic cationic protein (ECP) levels, and ECP and polymorphonuclear leukocyte (PMN) elastase levels of intratracheal aspirates (TA) were determined once a week during the first 4 weeks of life. Peripheral eosinophil counts were higher in infants with BPD than those in the non‐BPD group. Hypersegmented nuclei of peripheral eosinophils with more than four nuclei were more frequently present in the infants with BPD. A good correlation was observed between peripheral eosinophil counts and serum ECP levels. ECP levels of the TA in the infants with BPD were significantly elevated. There was a good correlation between ECP and PMN elastase levels of the TA. Lung tissue specimens of two infants of the BPD group, both of whom had patent ductus arteriosus (PDA), were obtained from the lower portion of the left lung when they underwent an operative procedure for PDA at 24 and 25 days of life, respectively. Immunohistochemical staining of eosinophil‐derived granular major basic protein (MBP) was performed on the lung tissue specimens. Infiltration of a few MBP‐staining eosinophils was observed on the specimens from both infants. Our results suggest that peripheral eosinophils in sick premature infants may be activated and appear to be correlated with the severity of BPD. Further studies will be needed to more clarify the physiological role of eosinophils in premature infants.

Endothelin-1 has a priming effect on production of superoxide anion by alveolar macrophages : its possible correlation with bronchopulmonary dysplasia

The purpose of this study was to clarify the role of endothelin (ET)-1 in the development of bronchopulmonary dysplasia (BPD). Tracheal aspirates were obtained from 27 newborn babies with respiratory distress (13 with BPD and 14 without BPD) who were mechanically ventilated. Production of superoxide anion(O-2) by rabbit alveolar macrophages was determined by preincubation with the tracheal aspirate supernatant (TAS) and stimulation with phorbol myristate acetate (PMA). O-2 production was demonstrated only when PMA was added to the experimental system and was enhanced with TAS of infants who later developed BPD compared with TAS from infants without BPD. The effects of ET-1 and ET-3 on O-2 production and the blockade by anti-ET-1 antibody and BQ123 (ET A receptor antagonist) were also examined. The enhancing effect was blocked by either anti-ET-1 antibody or BQ123. PMA-stimulated production of O-2 increased when cells were preincubated with several doses of ET-1 (5 × 10-13 to 2 × 10-12 M), whereas ET-3 was without effect. TAS contained significant amounts of immunoreactive ET-1, and there was a close positive correlation (r = 0.764) between the activity of O-2 production and immunoreactive ET-1 levels in TAS samples. These results may be interpreted to indicate that ET-1 synthesized by and secreted from tracheal epithelial cells and/or alveolar macrophages has a priming effect on alveolar macrophages to produce O-2, thus possibly contributing to the development of BPD.

Changes in vasopressin, atrial natriuretic factor, and water homeostasis in the early stage of bronchopulmonary dysplasia.

ABSTRACT: Arginine vasopressin (AVP), atrial natriuretic factor, and water balance were examined in the infants with or without hronchopulmonary dysplasia (BPD) during the first 4 wk of life. Fourteen premature infants, nine in the early stage of BPD secondary to respiratory distress syndrome (BPD infants) and five healthy low birthwt infants (LBW infants), were the subjects of this study. The water and sodium balance, renal function, and plasma AVP and atrial natriuretic factor concentrations were determined during the first 4 wk of life. Plasma AVP and atrial natriuretic factor levels of BPD infants at the 4th wk of life were higher than those of LBW infants at the corresponding age. Urine osmolality was higher and free water clearance was lower in BPD infants at the 4th wk of life when compared with each parameter in LBW infants, respectively. PaCo2 of BPD infants at the 4th wk of life was more elevated than that of LBW infants. These results suggest that elevated plasma AVP level may be related with pulmonary abnormalities and that atrial natriuretic factor may hence compensate the water retention resulted from the functionally activated AVP in the early stage of BPD.

Plasma endothelin-1 like immunoreactivity levels in neonates.

We attempted to determine the plasma endothelin-1-like immunoreactivity (ET-1) levels and to evaluate its physiological significance in 29 neonates: 5 with respiratory distress syndrome (RDS), 3 with transient tachypnoea of the newborn (TTN), 4 with neonatal asphyxia, 5 with bronchopulmonary dysplasia (BPD) following RDS, 7 healthy preterm infants and 5 healthy full-term infants. Plasma ET-1 levels in infants with RDS were significantly higher than those in healthy full-term infants through the 1st week of life. Plasma ET-1 levels in infants with neonatal asphyxia were high on the first 2 days of life and then gradually decreased to those of healthy full-term infants. Plasma levels in infants with TTN were the same as those in healthy full-term infants. Plasma ET-1 levels in infants with BPD were high when compared with those in healthy preterm infants during the first 2 months of life. This study showed that plasma levels were markedly elevated for a long time in the infants with respiratory distress. We speculate that plasma ET-1 may be a specific marker for pulmonary endothelium injury in infants with respiratory distress.

Plasma immunoreactive endothelin-1 concentration in human fetal blood: its relation to asphyxia.

ABSTRACT: To elucidate the effects of birth stress on immunoreactive endothelin-1 (irET-1) concentrations in fetal blood, we determined irET-1 levels in cord plasma in different modes of delivery associated with or without complications such as asphyxia. The irET-1 concentrations in both the umbilical artery and vein were significantly higher than those found in maternal venous blood at delivery, although there was no significant difference between preterm and full-term infants. When plasma irET-1 concentrations of healthy infants born by vaginal delivery and by cesarean section without labor were compared, the former had significantly (p < 0.05) higher levels than the latter (15.4 ± 4.9 pg/mL versus 11.1 ± 3.1 pg/mL). Furthermore, umbilical venous plasma obtained from vaginally delivered infants complicated by asphyxia showed significantly (p < 0.001) higher irET-1 levels (28.2 ± 9.4 pg/ mL) than those of nonasphyxiated infants (14.2 ± 4.5 pg/ mL). These data suggest that birth stress, especially asphyxia, may contribute to the increase in fetal circulating irET-1 levels.

Reliability of Urinary N-Acetyl-β-D-Glucosaminidase as an Indicator of Renal Tubular Damage in Neonates

Urinary N-acetyl-beta-D-glucosaminidase (NAG) was determined in infants during the first year of life to clarify its evolutional change and the reliability of this enzyme as a marker of renal tubular damage in the newborn period. During the first 2 weeks of life, there was no difference in the urinary levels between preterm (gestational age of 33-36 weeks) and full-term infants. The urinary NAG index (NAG is expressed as the ratio of the enzyme activity to milligrams of creatinine) during the first month of life was significantly elevated when compared with that of any other succeeding period and gradually decreased during the first year of life. The index in newborn infants on tobramycin was significantly elevated and maintained a higher value during the 5 days after withdrawal of the medication. Infants with asphyxia had a higher urinary NAG index during the first week of life. These data suggest that the urinary NAG index is a useful indicator of renal tubular damage during the newborn period.