Biomedical subjects

Timothy J M Moss

Publications and source records attributed to Timothy J M Moss.

29 records · Page 2Linked to original sources

PubMed2003

Differential effects of maternal and fetal betamethasone injections in late-gestation fetal sheep.

OBJECTIVE: To determine the effects of single or repeated intramuscular injections of betamethasone, given maternally or directly to the fetus, on chronically catheterized, late-gestation fetal sheep. METHODS: Fetal or maternal sheep received either repeated intramuscular injections of betamethasone (0.5 mg/kg body weight at 104, 111, and 118 days' gestation), single betamethasone injection (at 104 days' gestation, followed by saline at 111 and 118 days' gestation), or repeated saline injections; n = 6 or 7 per group. At approximately 130 days' gestation fetuses were catheterized for serial measurements of heart rate, arterial pressure, blood gases, metabolites, and electrolytes. RESULTS: Repeated maternal betamethasone injections reduced birth weight (P =.03) without fetal hypoxemia or hypoglycemia. Circulating fetal calcium and lactate concentrations were reduced (P =.002 and P =.014, respectively) by repeated maternal betamethasone only. Fetal hematocrit tended to be lower after fetal (P =.3) and maternal (P =.07) betamethasone. CONCLUSION: Growth restriction caused by repeated maternal betamethasone treatments is not due to overt chronic placental insufficiency but may be caused by alterations in hormonal mediators of fetal growth or impairment of placental transport of specific nutrients.

Animals↗

PubMed2003

Betamethasone effects on chorioamnionitis induced by intra-amniotic endotoxin in sheep.

OBJECTIVE: Intra-amniotic administration of endotoxin in sheep is a model of subclinical chorioamnionitis. Intrauterine inflammation alters lung development to improve postnatal lung function and may predispose the infant to lung and brain injury. We describe the effects of intra-amniotic endotoxin on cytokines and white cell responses in the membranes and amniotic fluid and investigate the hypothesis that betamethasone treatment suppresses these responses. STUDY DESIGN: Pregnant ewes were allocated at random to receive either intra-amniotic saline solution (control animals), maternal intramuscular betamethasone, intra-amniotic endotoxin by ultrasound guidance (10 mg Escherichia coli 055:B5), or a combination of the betamethasone and endotoxin treatments. Lambs were delivered abdominally at 110 to 125 days of gestation at time points that ranged from 2 hours to 15 days after treatment. RESULTS: When compared with saline solution-injected control animals, the intra-amniotic injection of endotoxin increased white cell counts in amniotic fluid. Levels of interleukin-8, but not interleukin-6, were significantly increased in amniotic fluid from 5 hours to 15 days after intra-amniotic endotoxin injection, and interleukin-8 levels were not decreased by concurrent treatment with betamethasone. After endotoxin treatment, interleukin-1beta and interleukin-8 messenger RNA were expressed in chorion, and interleukin-6 messenger RNA expression was localized to chorionic blood vessel epithelium. The half-life of endotoxin in the amniotic fluid was 1.7 days, and levels remained measurable 15 days after injection. CONCLUSION: These findings confirm that the fetus can survive within amniotic fluid that contains endotoxin, white cells, and cytokines for periods of weeks or more. Betamethasone treatment can suppress the initial inflammation in the amnion-chorion, but interleukin-8 levels and inflammatory cells in amniotic fluid were not suppressed 5 and 15 days after betamethasone treatment, presumably because of the slow clearance of bioactive endotoxin from the amniotic fluid.

Amnion↗

PubMed2002

Maternal glucocorticoids increase endotoxin-induced lung inflammation in preterm lambs.

Antenatal betamethasone (Beta) is widely used in women with asymptomatic chorioamnionitis at risk for preterm delivery, but its effects on fetal inflammation are unstudied. Groups of ewes at 109 +/- 1 days of gestation received the following treatments: intra-amniotic (IA) saline (control), 0.5 mg/kg intramuscular Beta, 10 mg IA endotoxin (Endo), and Beta + 2 h later Endo (Beta + Endo). Beta suppressed Endo-induced lung inflammation at 1 day. However, compared with Endo 5 days after treatment, Beta + Endo lambs had increased alveolar neutrophils, proinflammatory cytokine mRNA expression, and serum amyloid A3 (SAA3) mRNA expression. IL-1beta mRNA expression was localized to the inflammatory cells, whereas SAA3 mRNA expression was induced in the bronchial epithelium and the inflammatory cells. Compared with Endo, Beta + Endo lambs had increased lung inflammation but equivalent lung volumes 15 days after treatment. The late increase in inflammation in the Beta + Endo animals suggests that glucocorticoids impair the ability of the preterm lung to downregulate Endo-induced inflammation after fetal clearance of the glucocorticoids. These results have implications for lung inflammation and bronchopulmonary dysplasia in preterm infants exposed to chorioamnionitis and maternal glucocorticoids.

Acute-Phase Reaction↗

PubMed2002

Early gestational intra-amniotic endotoxin: lung function, surfactant, and morphometry.

We determined the effects in preterm lambs of endotoxin-induced inflammation at early gestational ages on lung function and structure and on the surfactant system. Pregnant ewes were randomized to one of five intra-amniotic endotoxin (Escherichia coli 055:B5) groups: 1 mg injected at 60 days of gestation, 1 mg at 80 days, 1 mg at 100 days, 1 mg at 60 days plus 100 days, or 0.6 mg/ day infused from Day 80 to Day 108. Control lambs received saline treatments. At 125 days, lung function was improved in all endotoxin groups. Marked increases in saturated phosphatidylcholine in lung tissue but not alveolar lavage samples were seen in all endotoxin groups except the 60- plus 100-day group. Surfactant protein mRNA and protein pool sizes were affected differently according to the timing of endotoxin treatment, but a large increase in the amount of mature surfactant protein B in alveolar lavage samples was observed in all endotoxin groups. Lung-to-body weight ratio, alveolar number, total surface area, and alveolar wall thickness were reduced by 80- to 108-day endotoxin. Intra-amniotic inflammatory stimuli in early gestation can alter pulmonary development, with the net effect of improving preterm lung function, despite changes in surfactant and lung growth that are similar to changes in the lungs of ventilated animals developing bronchopulmonary dysplasia.

Analysis of Variance↗

PubMed2002

Lung function, arterial pressure and growth in sheep during early postnatal life following single and repeated prenatal corticosteroid treatments.

BACKGROUND: Antenatal corticosteroid therapy is of great benefit to preterm infants, owing largely to effects on lung maturation. In sheep, repeated betamethasone injections given to the ewe improve lung function following preterm birth but also cause intrauterine growth restriction (IUGR). In humans and in animal models, IUGR is associated with impaired postnatal lung function. The effects on lung function of repeated prenatal betamethasone treatments and associated IUGR following term delivery are unknown. AIM AND STUDY DESIGN: To determine the effects of antenatal betamethasone treatments on postnatal arterial pressure, blood gases, ventilation, pulmonary gas volumes and compliance in serial studies of four groups of lambs until 4 weeks of age. SUBJECTS: Treatment groups were (1) maternal injections of saline at 104, 111 and 118 days of gestation, (2) a single maternal injection of betamethasone (0.5 mg/kg) at 104 days followed by saline at 111 and 118 days, (3) repeated betamethasone injections at 104, 111 and 118 days, or (4) no intervention (term is approximately 150 days). RESULTS: Repeated maternal betamethasone injections reduced birthweight and resulted in reduced postnatal body weights and arterial pressure throughout the first postnatal month. Lung function was not deleteriously affected by single or repeated maternal betamethasone treatments: blood gases, minute ventilation, lung volumes and compliance were not different between groups of lambs. CONCLUSIONS: The absence of alterations in postnatal blood gases contrasts with other models of IUGR in sheep and suggests that changes in lung structure caused by betamethasone may benefit IUGR neonates born at term.

Adrenal Cortex Hormones↗

PubMed2002

Nutrition and the early origins of adult disease.

There is now overwhelming evidence that much of our predisposition to adult illness is determined by the time of birth. These diseases appear to result from interactions between our genes, our intrauterine environment and our postnatal lifestyle. Those at greatest risk are individuals in communities making a rapid transition from lives of 'thrift' to a lives of 'plenty'. From a global perspective, such origins of diabetes, coronary heart disease and stroke, should render research in these fields as one of the highest priorities in human health care. Prevention will be enhanced by elucidation of the mechanisms by which the fetus is programmed by the mother for the life she expects it to live. At the present time, there is evidence that fetal nutrition and premature exposure to cortisol are effective intrauterine triggers, but a multitude of alternative pathways require investigation. It is also likely that programming extends across generations, and may involve the embryo and perhaps the oocyte. An oocyte that becomes an adult human develops in the uterus of its grandmother, so further research is required to describe the role of environments of grandmothers and mothers in predisposing offspring to health or illness in adult life.

Adult↗

PubMed2002

The fetal maturational and inflammatory responses to different routes of endotoxin infusion in sheep.

OBJECTIVES: In clinical practice, chorioamnionitis has been observed to enhance fetal lung maturation in the short term but may predispose to chronic lung disease thereafter. Using the sheep model, we have previously shown that injection of endotoxin into the amniotic cavity results in inflammatory responses and profoundly enhances newborn lung function after preterm birth. The fetus tolerates intra-amniotic doses of endotoxin considerably greater than those that are lethal if given intramuscularly. This study aimed to explore the mechanisms by which endotoxin matures the lungs by determining whether the route of administration influenced the maturational responses of the fetus. STUDY DESIGN: Date-mated ewes at 118 days of pregnancy were allocated at random to receive endotoxin (Escherichia coli lipopolysaccharide 055;B5) directly into the trachea (n = 7), stomach (n = 6), amniotic cavity (n = 7), or peritoneal cavity (n = 4) of the fetal lamb by surgical implantation of an osmotic pump delivering 1 mg of endotoxin over a 24-hour period. Results were compared with those obtained in saline solution-infused controls (n = 9). The lambs were delivered by cesarean section at 125 days' gestation (term is 150 days). RESULTS: Endotoxin infusion into the trachea, stomach, and amniotic cavity each resulted in inflammatory responses in lung fluid and improved postnatal lung function, and effects were similar for each route of administration. These effects occurred with minimal features of systemic inflammation. Intraperitoneal infusion resulted in severe fetal acidosis or death. CONCLUSION: These findings provide further evidence that the lung-maturing effects of intra-amniotic endotoxin are mediated by local factors in the respiratory system rather than by systemic inflammatory responses. Chorioamnionitis may alter lung function and possibly lead to chronic injury without clinical features of systemic inflammation or compromise.

Acidosis↗

PubMed2002

Intra-amniotic endotoxin induces lung maturation by direct effects on the developing respiratory tract in preterm sheep.

OBJECTIVE: Our purpose was to determine whether improved preterm lung function caused by intraamniotic endotoxin treatment requires endotoxin entry into the respiratory tract. STUDY DESIGN: We assessed lung inflammation 2 days after intra-amniotic endotoxin (10 mg, Escherichia coli 055:B5) or saline solution in preterm lambs (123 days' gestation) that had undergone surgery to isolate the gastrointestinal or respiratory systems from the amniotic sac. In other sheep longer-term effects were assessed 7 days after we isolated the fetal respiratory tract and gave endotoxin or saline solution directly to the lungs or into the amniotic sac. We measured pulmonary inflammation, lung function, and surfactant 1 week after treatment (approximately 125 days). RESULTS: Pulmonary inflammation was present after intra-amniotic endotoxin only if there was communication between the respiratory tract and the amniotic sac. Lung function was improved and surfactant was increased only in preterm lambs that received direct pulmonary endotoxin. CONCLUSION: Endotoxin causes functional improvement of the preterm lung by direct effects on the developing respiratory system.

Amnion↗

PubMed2002

Antenatal corticosteroids: the good, the bad and the unknown.

PURPOSE OF REVIEW: The purpose of this review was to summarize recently published clinical and animal-based studies of antenatal corticosteroids, describe current recommendations for practice, and suggest priority areas for future research. RECENT FINDINGS: A single course of antenatal corticosteroids is known to improve newborn lung function after preterm birth and to reduce the risk of newborn death. Current evidence from animal and clinical studies suggests that additional numbers of courses do not further improve lung function and are associated with risks of adverse consequences. These risks principally include restricted intrauterine growth, altered brain development, postnatal insulin resistance and changes to the hypothalamic-pituitary-adrenal axis. SUMMARY: The research challenges in this field are now centred on uncovering the mechanisms by which cortisol is involved in programming the fetus for its future metabolic life, and discovering ways in which the effectiveness and safety of antenatal glucocorticoids can be enhanced.

Cerebral Hemorrhage↗

PubMedDate not supplied

Fetal responses to intra-amniotic endotoxin in sheep.

OBJECTIVE: Our aim was to determine the acute physiologic effects of intra-amniotic endotoxin administration in fetal sheep, and in particular, to determine whether intra-amniotic endotoxin causes an increase in fetal cortisol that could underlie the functional maturation of the fetal lungs previously reported in this model. METHODS: As in our previous experiments, ewes were randomly assigned to receive a single intra-amniotic injection of either endotoxin (20 mg, Escherichia coli [055:B5], n = 5) or saline (n = 5). Between 0.5 hours before endotoxin and 168 hours after its administration, we measured maternal and fetal arterial pressures and heart rates; fetal and maternal blood samples were collected for measurement of blood gases, electrolytes, glucose and lactate concentrations, white cell counts (total and differential), and plasma cortisol. RESULTS: Fetal arterial carbon dioxide tension and lactate concentration were significantly elevated 6 and 12 hours after endotoxin but returned to pre-endotoxin levels by 24 hours. Fetal plasma cortisol concentrations were significantly elevated at 4 hours and peaked 24 hours after endotoxin, returning to control levels by 2 days. Fetal white cell counts initially decreased (4 hours) and then increased (after 24 hours), becoming significantly elevated 6 days after treatment. Other fetal variables, and all measured maternal variables, were unaffected. CONCLUSIONS: Our data suggest that fetal sheep respond to intra-amniotic endotoxin with transient, mild physiologic alterations that follow a time course similar to inflammatory responses reported previously. The elevation in fetal cortisol is insufficient to be the cause of preterm lung maturation shown previously with this treatment.

Amnion↗

PubMedDate not supplied

Effects of intra-amniotic endotoxin on lung structure and function two months after term birth in sheep.

OBJECTIVE: Intra-amniotic endotoxin causes chorioamnionitis and results in improved lung function after preterm delivery in sheep. Our aim was to determine the effects on lung structure and function after term birth in lambs exposed to intra-amniotic or intra-allantoic endotoxin. METHODS: At 119 days' gestation, pregnant ewes bearing singleton fetuses received intra-amniotic or intra-allantoic injections of either saline (allantoic, n = 1; amniotic, n = 10) or Escherichia coli (055:B5) endotoxin (allantoic, n = 5; amniotic, n = 7). Amniotic or allantoic fluid was aspirated for white blood cell counts 24 hours after the injections. Ewes (n = 20) were allowed to deliver spontaneously. At 8 weeks' postnatal age we measured ventilation, lung volumes, and compliance in the offspring and collected their lungs for morphologic analysis. RESULTS: Higher amniotic or allantoic cell counts were confined to the fluid space into which endotoxin was injected. Saline injections did not increase amniotic or allantoic white blood cell counts. Gestation length, birth weight, and postnatal growth were unaffected by endotoxin treatments. Lung volumes and compliances at 8 weeks of age were not different between saline-treated and endotoxin-treated groups. Lung morphometry was not significantly altered by endotoxin, with one minor exception: interlobular septal volume was increased by intra-amniotic endotoxin, but this effect had no functional consequences. CONCLUSIONS: Intra-amniotic or intra-allantoic endotoxin caused a localized inflammatory response but did not cause preterm delivery or intrauterine growth restriction. The functional improvements and corresponding structural alterations in the lungs of preterm lambs, reported previously in this model, were not associated with improved or impaired lung function or marked alterations in lung structure 2 months after birth at term.

Aging↗