Antenatal and early postnatal dexamethasone treatment decreases cortisol secretion in preterm infants

Glucocorticoids are used antenatally to accelerate the maturation of fetal respiratory and cardiovascular systems when a threat of preterm delivery exists. Postnatally, they are used to prevent and treat respiratory distress syndrome. This study investigates the effects of antenatal (ACT) and early postnatal corticosteroid treatment (PCT) on serum cortisol and plasma catecholamine and adenosine 3',5'-cyclic monophosphate (cAMP) concentrations in preterm neonates. The infants in the ACT group had a significantly lower cortisol concentration than the infants in the non-ACT group on the first day of life. After birth, the infants were further divided into non-PCT and PCT groups. PCT suppressed cortisol levels significantly after 2 days, and the cortisol levels were still lower 2 days after discontinuation of PCT. No effect of PCT on plasma cAMP or catecholamine concentrations was observed. The results indicate that both ACT and a short PCT can significantly suppress basal cortisol levels in preterm infants.     

Effects of antenatal glucocorticoid therapy on hippocampal histology of preterm infants

Objective

To investigate if antenatal glucocorticoid treatment has an effect on hippocampal histology of the human preterm newborn.

Patients and Methods

Included were consecutive neonates with a gestational age between 24 and 32 weeks, who were born between 1991 to 2009, who had died within 4 days after delivery and underwent brain autopsy. Excluded were neonates with congenital malformations and neonates treated postnatally with glucocorticoids.The brains were routinely fixed, samples of the hippocampus were stained with haematoxylin and eosin and sections were examined for presence or absence of large and small neurons in regions of the hippocampus. Additional staining with GFAP, neurofilament and vimentin was performed to evaluate gliosis and myelination. The proliferation marker Ki67 was used to evaluate neuronal proliferation. Staining with acid fuchsin-thionin was performed to evaluate ischemic damage.

Results

The hippocampi of ten neonates who had been treated with antenatal glucocorticoids showed a lower density of large neurons (p = 0.01) and neurons irrespective of size (p = 0.02) as compared to eleven neonates who had not been treated with glucocorticoids. No difference was found in density of small neurons, in myelination, gliosis, proliferation or ischemic damage.

Conclusion

We found a significantly lower density of neurons in the hippocampus of neonates after antenatal glucocorticoid treatment. Although the pathophysiological and clinical interpretations of these findings are not clear, they are consistent with those from experiments in mice and rhesus monkeys.     

Effects of fibrogenic mediators on the development of pancreatic fibrosis in a TGF-beta1 transgenic mouse model

The pancreas morphology of transgenic mice that overexpress transforming growth factor-beta1 (TGF-beta1) in the pancreas resembles partially morphological features of chronic pancreatitis, such as progressive accumulation of extracellular matrix (ECM). Using this transgenic mouse model, we characterized the composition of pancreatic fibrosis and involved fibrogenic mediators. On day 14 after birth, fibrotic tissue was mainly composed of collagen type I and III. At this time, mRNA levels of TGF-beta1 were increased. On day 70, the ECM composition was expanded by increased deposition of fibronectin, whereas connective tissue growth factor, fibroblast growth factor (FGF)-1, and FGF-2 mRNA expression levels were elevated in addition to TGF-beta1. In parallel, the number of pancreatic stellate cells (PSC) increased over time. In vitro, TGF-beta1 stimulated collagen type I expression but not fibronectin expression in PSC, in contrast to FGF-2, which stimulated both. This confirms that TGF-beta1 mediates pancreatic fibrosis through activation of PSC and deposition of collagen type I and III at early time points. Furthermore, this points to an indirect mechanism in which TGF-beta regulates pancreatic ECM assembly by induction of additional growth factors.     

Postnatal thyroxine administration for idiopathic respiratory distress syndrome in preterm infants

Thirty-six preterm infants of less than 34 weeks of gestation with idiopathic respiratory distress syndrome (IRDS) were studied. Eighteen of them were treated with intravenous thyroxine (T4) and compared with 18 control prematures to evaluate the effect of postnatal T4 administration on the course of IRDS. After treatment, serum T4 levels were similar to those of healthy term infants. No statistically significant effect on mortality rate, duration of mechanical ventilation (p greater than 0.3), need of high oxygen environment (p greater than 0.05) and development of bronchopulmonary dysplasia (p greater than 0.2) was observed between the two groups. These observations show that postnatal use of T4 does not carry any benefit for preterm infants with IRDS.     

Effects of undernutrition on respiratory mechanics and lung parenchyma remodeling.

Undernutrition thwarts lung structure and function, but there are disagreements about the behavior of lung mechanics in malnourished animals. To clarify this issue, lung and chest wall mechanical properties were subdivided into their resistive, elastic, and viscoelastic properties in nutritionally deprived (ND) rats and correlated with the data gathered from histology (light and electron microscopy and elastic fiber content), and bronchoalveolar lavage fluid analysis (lipid and protein content). Twenty-four Wistar rats were assigned into two groups. In the control (Ctrl) group the animals received food ad libitum. In the ND group, rats received one-third of their usual daily food consumption until they lost 40% of their initial body weight. Lung static elastance, viscoelastic and resistive pressures (normalized by functional residual capacity), and chest wall pressures were higher in the ND group than in the Ctrl group. The ND group exhibited patchy atelectasis, areas of emphysema, interstitial edema, and reduced elastic fiber content. The amount of lipid and protein in bronchoalveolar lavage fluid was significantly reduced in the ND group. Electron microscopy showed 1) type II pneumocytes with a reduction in lamellar body content, multilamellated structures, membrane vesicles, granular debris, and structurally aberrant mitochondria; and 2) diaphragm and intercostals with atrophy, disarrangement of the myofibrils, and deposition of collagen type I fibers. In conclusion, undernutrition led to lung and chest wall mechanical changes that were the result from a balance among the following modifications: 1) distorted structure of diaphragm and intercostals, 2) surfactant content reduction, and 3) decrease in elastic fiber content.     

Effects of posture on the respiratory mechanics of the chick embryo

In the chicken embryo, pulmonary ventilation and pulmonary gas exchange begin approximately one day before the completion of hatching. We asked to what extent the posture inside the egg, and the presence of the eggshell and membranes, may alter the mechanical behaviour of the respiratory system. The passive mechanical properties of the respiratory system were studied in chicken embryos during the internal pipping phase (rupture of the air cell) or the external pipping phase (hole in the eggshell). Tracheal pressure and changes in lung volume were recorded during mechanical ventilation, first, with the embryo curled up inside the egg, then again after exteriorization from the eggshell. In the internal pippers, respiratory system compliance increased and expiratory resistance decreased after exteriorization, whereas the mean inspiratory impedance did not change. In the external pippers, exteriorization had no significant effects on respiratory compliance, resistance, or impedance, and the values were similar to those of newly hatched chicks. We conclude that, in the chicken embryo, at a time when pulmonary ventilation becomes an important mechanism for gas exchange, the curled up posture inside the egg does not provide any significant mechanical constraint to breathing.     

Effects of ultrasonic nebulization on pulmonary mechanics and blood gases in obstructive disease

Administration of ultrasonically nebulized mist to 17 patients with obstructive lung disease resulted in a temporary deterioration of mechanical lung function with decreases in vital capacity (VC), forced expired volume in one second expressed as a percentage of VC (FEV₁%), and compliance and with increased inspiratory and expiratory airway resistance. Despite hyperventilation there was an associated decrease in arterial oxygen tension. Although concomitant administration of a bronchodilator afforded protection against the bronchospastic reaction, blood gas derangements were still provoked.     

Expression of SP-C and Ki67 in lungs of preterm infants dying from respiratory distress syndrome

This study aimed at exploring the expression of Surfactant protein-C (SP-C) and Ki67 in autopsy lung tissues of premature infants dying from respiratory distress syndrome (RDS) who were exposed to mechanical ventilation and elevated oxygen concentrations. The possible influence of pulmonary surfactant (PS) on the expression of SP-C and Ki67 was also investigated. Thirty preterm infants were selected who were histologically and clinically diagnosed as RDS. Preterm infants with RDS were divided into 4 groups, according to the time of death: infants ventilated for 1–3 days, 4–8 days, 9–16 days and >6 days. Five premature infants died within 1 day after delivery for non- pulmonary reasons served as controls. The expression of SP-C and Ki67 in lungs was detected by immunohistochemistry. Compared with the control group, the expression of SP-C and Ki67 in RDS infants decreased significantly after 1–3 days of ventilation, but increased after 4 days and reached peak value after 9–16 days. No significant difference in the expression of SP-C and Ki67 was found between infants treated with PS and those without. Thus our results suggest SP-C and Ki67 may have participated in the pulmonary pathological process in ventilated/oxygen treated preterm infants with RDS, and exogenous surfactant had no effect on the expression of SP-C and Ki67 in the lungs of ventilated/oxygen treated preterm infants with RDS.Key words: respiratory distress syndrome, surfactant protein-C, Ki67, preterm.     

Insulin-like growth factors and binding proteins in early milk from mothers of preterm and term infants

Breast-fed preterm infants often show a better outcome, partly ascribed to the benefit of insulin-like growth factors (IGFs) and their binding proteins (IGFBP). We compared IGF-I, IGF-II, IGFBP-2 and IGFBP-3 levels, measured by radioimmunoassays in milk samples from 30 mothers of preterm (<31 weeks) and from 19 mothers of term (>37 weeks) infants at days 7 and 21 postpartum. Proteolysis of IGFBP-2 within mother's milk and digestion of (125)I-IGF-II and (125)I-IGFBP-2 by gastric juice from neonates were assessed by electrophoretic techniques. Mean concentrations did not differ between preterm and term milk: IGF-I (2.8 +/- 0.2 vs. 2.3 +/- 0.1 ng/ml), IGF-II (12.0 +/- 0.4 vs. 12.2 +/- 0.5 ng/ml), IGFBP-3 (100.0 +/- 5.1 vs. 80.0 +/- 5.8 ng/ml), but did so for IGFBP-2 (3,144 +/- 172 vs. 2,428 +/- 188 ng/ml, p < 0.02). Immunoblots revealed 42% (p < 0.05) more IGFBP-2 fragments of 14 and 25 kDa in preterm milk. Incubation with gastric juice caused cleavage of (125)I-IGFBP-2 and partial cleavage of (125)I-IGF-II. Mutual complexation protected IGF-II and IGFBP-2 from cleavage, suggesting that both are likely to arrive in the bowel in an intact form to exert promotive effects. The results provide further evidence that IGFBP-2 and IGF-II in breast milk are relevant factors for the early development of preterm infants.     

Cardiovascular mechanics in the early stages of pulmonary hypertension: a computational study

We formulate and study a new mathematical model of pulmonary hypertension. Based on principles of fluid and elastic dynamics, we introduce a model that quantifies the stiffening of pulmonary vasculature (arteries and arterioles) to reproduce the hemodynamics of the pulmonary system, including physiologically consistent dependence between compliance and resistance. This pulmonary model is embedded in a closed-loop network of the major vessels in the body, approximated as one-dimensional elastic tubes, and zero-dimensional models for the heart and other organs. Increasingly severe pulmonary hypertension is modeled in the context of two extreme scenarios: (1) no cardiac compensation and (2) compensation to achieve constant cardiac output. Simulations from the computational model are used to estimate cardiac workload, as well as pressure and flow traces at several locations. We also quantify the sensitivity of several diagnostic indicators to the progression of pulmonary arterial stiffening. Simulation results indicate that pulmonary pulse pressure, pulmonary vascular compliance, pulmonary RC time, luminal distensibility of the pulmonary artery, and pulmonary vascular impedance are much better suited to detect the early stages of pulmonary hypertension than mean pulmonary arterial pressure and pulmonary vascular resistance, which are conventionally employed as diagnostic indicators for this disease.     

Nutritive and non-nutritive sucking in preterm infants

Nutritive and non-nutritive sucking was studied in 9 preterm infants with postmenstrual ages ranging from 28 to 33 weeks and postnatal ages ranging from 0 to 8 weeks. During nutritive sucking, sucking bursts were longer than sucking pauses. During non-nutritive sucking the opposite was seen. The sucking rate was lower during nutritive sucking. During nutritive sucking the respiratory rate was higher during the pauses than during the bursts. During non-nutritive sucking the respiratory rate was higher during sucking. It is concluded that non-nutritive sucking cannot serve as a model for studying feeding mechanisms in the preterm infant.     

Effects of O2 on the ventilatory response to CO2 in preterm infants.

To measure the effects of O2 on the ventilatory response to CO2 in preterm infants, we studied eight babies (birth wt 1-2 kg; gestational age 32-36 wk) 10 times during the first 11 days of life. After breathing 21% O2 for 3 min, they were given 15%, 21%, 40%, or 100% O2 for 4 min and then 2% CO2 plus the various concentrations of O2 for 4 min each. The mean slopes of the CO2 response curves were 0.013, 0.027, 0.034, and 0.056 1/(min-kg-mmHg PACO2) with 15%, 21%, 40%, and 100% inspired O2, respectively. Thus, the more hypoxic the infant, the flatter was the response to CO2. These findings suggest that in preterm infants 1) the response to inhaled CO2 is the reverse of that seen in adult man where the higher the inspired O2 concentration, the flatter the response, and 2) the respiratory center is depressed during hypoxia.     

Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice

Single-walled carbon nanotubes (SWCNT) are new materials of emerging technological importance. As SWCNT are introduced into the life cycle of commercial products, their effects on human health and environment should be addressed. We demonstrated that pharyngeal aspiration of SWCNT elicited unusual pulmonary effects in C57BL/6 mice that combined a robust but acute inflammation with early onset yet progressive fibrosis and granulomas. A dose-dependent increase in the protein, LDH, and gamma-glutamyl transferase activities in bronchoalveolar lavage were found along with accumulation of 4-hydroxynonenal (oxidative biomarker) and depletion of glutathione in lungs. An early neutrophils accumulation (day 1), followed by lymphocyte (day 3) and macrophage (day 7) influx, was accompanied by early elevation of proinflammatory cytokines (TNF-alpha, IL-1beta; day 1) followed by fibrogenic transforming growth factor (TGF)-beta1 (peaked on day 7). A rapid progressive fibrosis found in mice exhibited two distinct morphologies: 1) SWCNT-induced granulomas mainly associated with hypertrophied epithelial cells surrounding SWCNT aggregates and 2) diffuse interstitial fibrosis and alveolar wall thickening likely associated with dispersed SWCNT. In vitro exposure of murine RAW 264.7 macrophages to SWCNT triggered TGF-beta1 production similarly to zymosan but generated less TNF-alpha and IL-1beta. SWCNT did not cause superoxide or NO.production, active SWCNT engulfment, or apoptosis in RAW 264.7 macrophages. Functional respiratory deficiencies and decreased bacterial clearance (Listeria monocytogenes) were found in mice treated with SWCNT. Equal doses of ultrafine carbon black particles or fine crystalline silica (SiO2) did not induce granulomas or alveolar wall thickening and caused a significantly weaker pulmonary inflammation and damage.