PubMed Health⌕ Search

Biomedical subjects

Alan H Jobe

Publications and source records attributed to Alan H Jobe.

At least 19 recordsLinked to original sources
PubMed2006

Antenatal inflammation induced TGF-beta1 but suppressed CTGF in preterm lungs.

Chorioamnionitis is frequently associated with preterm birth and increases the risk of adverse outcomes such as bronchopulmonary dysplasia (BPD). Transforming growth factor (TGF)-beta1 is a key regulator of lung development, airway remodeling, lung fibrosis, and regulation of inflammation, and all these processes contribute to the development of BPD. Connective tissue growth factor (CTGF) is a downstream mediator of some of the profibrotic effects of TGF-beta1, vascular remodeling, and angiogenesis. TGF-beta1-induced CTGF expression can be blocked by TNF-alpha. We asked whether chorioamnionitis-associated antenatal inflammation would regulate TGF-beta1, the TGF-beta1 signaling pathway, and CTGF in preterm lamb lungs. Fetal sheep were exposed to 4 mg of intra-amniotic endotoxin or saline for 5 h, 24 h, 72 h, or 7 days before preterm delivery at 125 days gestation (full term = 150 days). Intra-amniotic endotoxin increased lung TGF-beta1 mRNA and protein expression. Elevated TGF-beta1 levels were associated with TGF-beta1-induced phosphorylation of Smad2. CTGF was selectively expressed in lung endothelial cells in control lungs, and intra-amniotic endotoxin caused CTGF expression to decrease to 30% of control values and TNF-alpha protein to increase. The antenatal inflammation-induced TGF-beta1 expression and Smad signaling in the fetal lamb lung may contribute to impaired lung alveolarization and reduced lung inflammation. Decreased CTGF expression may inhibit vascular development or remodeling and limit lung fibrosis during remodeling. These effects may contribute to the impaired alveolar and pulmonary vascular development that is the hallmark of the new form of BPD.

Animals↗
PubMed2006

IL-1 alpha causes lung inflammation and maturation by direct effects on preterm fetal lamb lungs.

Intra-amniotic endotoxin induces IL-1, causes chorioamnionitis, lung inflammation, lung injury and lung maturation in preterm lambs. Intra-amniotic IL-1alpha also causes chorioamnionitis, lung inflammation and lung maturation. We asked if IL-1alpha effects on the preterm lung are mediated by direct signaling to the lung rather than by indirect effects from the chorioamnionitis. To study IL-1 effects independently of chorioamnionitis, the lungs and the amniotic fluid were surgically separated in fetal sheep by diverting fetal lung fluid via a tracheostomy tube to a sialastic bag. A mini-osmotic pump delivered an intratracheal infusion of recombinant sheep IL-1alpha (10 microg) or saline (control) over 24 h. Preterm lambs were delivered 1d or 7d after the start of the infusion at 124d gestational age (Term = 150d). IL-1alpha recruited inflammatory cells and increased pro-inflammatory cytokine mRNA expression in the fetal lungs. Compared with controls, IL-1alpha did not alter lung antioxidant enzyme activity or alveolar numbers. IL-1alpha had minimal effects on the mRNA or protein expression of proteins essential for vascular development. IL-1alpha induced large increases in alveolar surfactant saturated phosphatidylcholine and increased lung gas volumes. Lung inflammation and maturation result from direct exposure of the fetal lung to a single cytokine - IL-1alpha.

Animals↗
PubMed2006

Mechanisms to explain surfactant responses.

Surfactant is now standard of care for infants with respiratory distress syndrome. Surfactant treatments are effective because of complex metabolic interactions between surfactant and the preterm lung. The large treatment dose functions as substrate; it is taken up by the preterm lung and is reprocessed and secreted with improved function. The components of the treatment surfactant remain in the preterm lung for days. If lung injury is avoided, then surfactant inhibition is minimized. Prenatal corticosteroids complement surfactant to further enhance lung function. The magic of surfactant therapy results from the multiple interactions between surfactant and the preterm lung.

Adrenal Cortex Hormones↗
PubMed2006

Laparotomy versus peritoneal drainage for necrotizing enterocolitis or isolated intestinal perforation in extremely low birth weight infants: outcomes through 18 months adjusted age.

OBJECTIVE: Extremely low birth weight (ELBW; < or =1000 g) infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP) are treated surgically with either initial laparotomy or peritoneal drain placement. The only published data comparing these therapies are from small, retrospective, single-center studies that do not address outcomes beyond nursery discharge. The objective of this study was to conduct a prospective, multicenter, observational study to (1) develop a hypothesis about the relative effect of these 2 therapies on risk-adjusted outcomes through 18 to 22 months in ELBW infants and (2) to obtain data that would be useful in designing and conducting a successful trial of this hypothesis. METHODS: A prospective, cohort study was conducted at 16 clinical centers within the National Institute of Child Health and Human Development Neonatal Research Network. To assist in risk adjustment, the attending pediatric surgeon recorded the preoperative diagnosis and intraoperative diagnosis and identified infants who were considered to be too ill for laparotomy. Predefined measures of short- and longer-term outcome included (1) either predischarge death or prolonged parenteral nutrition (>85 days) after enrollment and (2) either death or neurodevelopmental impairment on a standardized examination at 18 to 22 months' adjusted age. RESULTS: Severe NEC or IP occurred in 156 (5.2%) of 2987 ELBW infants; 80 were treated with initial drainage, and 76 were treated with initial laparotomy. By 18 to 22 months, 78 (50%) had died; 112 (72%) had died or were shown to be impaired. Outcome was worse in the subgroup with NEC. Laparotomy was never performed in 76% (28 of 36) of drain-treated survivors. CONCLUSIONS: Drainage was commonly used, and outcome was poor. Our findings, particularly the risk-adjusted odds ratio favoring laparotomy for death or impairment, indicate the need for a large, multicenter clinical trial to assess the effect of the initial surgical therapy on outcome at > or =18 months.

Child Development↗
PubMed2005

Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy.

BACKGROUND: Hypothermia is protective against brain injury after asphyxiation in animal models. However, the safety and effectiveness of hypothermia in term infants with encephalopathy is uncertain. METHODS: We conducted a randomized trial of hypothermia in infants with a gestational age of at least 36 weeks who were admitted to the hospital at or before six hours of age with either severe acidosis or perinatal complications and resuscitation at birth and who had moderate or severe encephalopathy. Infants were randomly assigned to usual care (control group) or whole-body cooling to an esophageal temperature of 33.5 degrees C for 72 hours, followed by slow rewarming (hypothermia group). Neurodevelopmental outcome was assessed at 18 to 22 months of age. The primary outcome was a combined end point of death or moderate or severe disability. RESULTS: Of 239 eligible infants, 102 were assigned to the hypothermia group and 106 to the control group. Adverse events were similar in the two groups during the 72 hours of cooling. Primary outcome data were available for 205 infants. Death or moderate or severe disability occurred in 45 of 102 infants (44 percent) in the hypothermia group and 64 of 103 infants (62 percent) in the control group (risk ratio, 0.72; 95 percent confidence interval, 0.54 to 0.95; P=0.01). Twenty-four infants (24 percent) in the hypothermia group and 38 (37 percent) in the control group died (risk ratio, 0.68; 95 percent confidence interval, 0.44 to 1.05; P=0.08). There was no increase in major disability among survivors; the rate of cerebral palsy was 15 of 77 (19 percent) in the hypothermia group as compared with 19 of 64 (30 percent) in the control group (risk ratio, 0.68; 95 percent confidence interval, 0.38 to 1.22; P=0.20). CONCLUSIONS: Whole-body hypothermia reduces the risk of death or disability in infants with moderate or severe hypoxic-ischemic encephalopathy.

Acidosis↗
PubMed2005

Recruited inflammatory cells mediate endotoxin-induced lung maturation in preterm fetal lambs.

RATIONALE: Chorioamnionitis is paradoxically associated with a decreased incidence of respiratory distress syndrome in preterm infants. In preterm lambs, intraamniotic endotoxin and interleukin 1 (IL-1) induce lung inflammation followed by lung maturation. OBJECTIVE: To test if inflammatory cells are required to mediate induced lung maturation. METHODS: Lung inflammation was induced by intraamniotic injection of endotoxin or IL-1. Inflammatory cell recruitment to the lung was inhibited by an anti-CD18 blocking antibody given intramuscularly to the fetus. Preterm lambs were delivered at 124-d gestation (term = 150 d) 2 or 7 d after exposure to endotoxin/IL-1 or endotoxin/IL-1 + anti-CD18 antibody. MEASUREMENTS: Lung inflammation was measured by bronchoalveolar lavage fluid cell count, inflammatory scoring of lung parenchyma, and expression of proinflammatory cytokines and inducible nitric oxide synthase. Lung maturation was quantitated by surfactant protein mRNA expression, saturated phosphatidylcholine pool size, and pressure-volume curves. MAIN RESULTS: Inhibition of CD18 significantly reduced endotoxin-induced but not IL-1-induced fetal lung inflammatory cell recruitment and activation as well as expression of proinflammatory cytokines. Compared with control lungs, both endotoxin and IL-1 induced lung maturation. Anti-CD18 antibody administration inhibited only endotoxin-induced but not IL-1-induced increases in surfactant protein mRNA and surfactant saturated phosphatidylcholine. Exposure to anti-CD18 antibody moderated endotoxin-induced increases in lung volumes but had no effect on IL-1-induced increases in lung volumes. CONCLUSIONS: (1) Endotoxin- but not IL-1-induced inflammatory cell recruitment in the preterm fetal lamb lung is CD18 dependent; (2) recruited inflammatory cells mediate some aspects of fetal lung maturation.

Animals↗
PubMed2005

Chronic endotoxin exposure does not cause sustained structural abnormalities in the fetal sheep lungs.

Chronic early gestational chorioamnionitis is associated with development of bronchopulmonary dysplasia in preterm infants. A single intra-amniotic exposure to endotoxin decreased alveolarization and reduced expression of endothelial proteins in 125-day gestational age preterm lambs. We hypothesized that prolonged exposure to intra-amniotic endotoxin would cause progressive lung inflammation and inhibit alveolar and pulmonary vascular development. Endotoxin (1 mg/day) or saline was administered via an intra-amniotic osmotic pump from 80 to 108 days of gestational age (continuous pump) or by four weekly 10-mg intra-amniotic endotoxin injections starting at 100 days of gestational age (multiple dose). Lung morphometry, lung inflammation, vascular effects, and lung maturation were measured at delivery. The continuous pump lambs delivered at 100 days (approximately 70% of total endotoxin exposure) had lung inflammation, fewer saccules, and decreased endothelial proteins endothelial nitric oxide synthase and VEGF receptor 2 expression compared with controls. The continuous pump (delivered at 138 days) and multiple dose lambs (delivered at 130 and 145 days) had mild persistent lung inflammation and no significant differences in lung morphometry or expression of endothelial proteins compared with controls. Surfactant saturated phosphatidylcholine pool sizes were increased in all endotoxin-exposed groups, but lung function was not changed relative to controls. Contrary to our hypothesis, a prolonged fetal exposure to intra-amniotic endotoxin caused mild persistent inflammation but did not lead to progressive structural abnormalities in lungs of near-term gestation lambs.

Amniotic Fluid↗
PubMed2005

Experimental intrauterine Ureaplasma infection in sheep.

OBJECTIVE: Prenatal Ureaplasma spp exposure is associated with preterm birth and modulates the neonates' susceptibility to respiratory distress syndrome and bronchopulmonary dysplasia. We hypothesized that intra-amniotic ureaplasmas would cause lung inflammation and alter fetal lung development. STUDY DESIGN: Pregnant ewes bearing singleton fetuses were given an intra-amniotic injection of 20 x 10 6 CFUs of U parvum (serovar 3) or vehicle, either 1, 3, 6, or 10 weeks before the delivery of preterm lambs at 124 days of gestation (n = 4-10 per group) for evaluation of inflammation and fetal lung maturation. RESULTS: Ureaplasmas were recovered from amniotic and fetal lung fluids after intra-amniotic injection. Body weight and umbilical arterial pH were reduced by Ureaplasma exposure for 10 weeks ( P < .05). Ureaplasmas caused progressive lung inflammation and improvements in lung function that were associated with increased surfactant lipids (control, 0.13 +/- 0.02 micromol/kg; 10 weeks of Ureaplasma exposure, 7.43 +/- 3.0 micromol/kg; P < .001) and surfactant protein messenger RNA expression. CONCLUSION: Long-term exposure to ureaplasmas in amniotic fluid alters ovine fetal development.

Analysis of Variance↗
PubMed2005

The effects of intra-amniotic injection of periodontopathic lipopolysaccharides in sheep.

OBJECTIVE: Periodontal disease may cause several complications of pregnancy, including fetal death. The purpose of this study was to investigate in sheep the effects of the intra-amniotic injection of lipopolysaccharide from 3 periodontopathic organisms and to compare these effects with those resulting from similar injection of Escherichia coli lipopolysaccharide. The outcomes that were studied included the rates of fetal death and the features of inflammation and lung maturation in survivors. STUDY DESIGN: At 118 days of pregnancy, ewes that were bearing single fetuses were allocated at random to receive intra-amniotic injections of saline solution (n = 13 fetuses), or lipopolysaccharide from Porphyromonas gingivalis (in doses from 0.1 to 10 mg [n = 22 fetuses]), Actinobacillus actinomycetemcomitans (10 mg [n = 6 fetuses]; 1 mg [n = 6 fetuses]), Fusobacterium nucleatum (10 mg [n = 6 fetuses]) or Escherichia coli (10 mg [n = 14 fetuses]; 1 mg [n = 7 fetuses]). Surviving fetuses were delivered abdominally at 125 days of gestation (term, 150 days). RESULTS: When compared with Escherichia coli lipopolysaccharide at similar dosages, periodontopathic lipopolysaccharides had high rates of fetal lethality. Only 6 of 22 fetuses that were exposed to intra-amniotic Porphyromonas gingivalis lipopolysaccharide survived doses of 0.1 to 10 mg, and only 3 of 6 fetuses survived 10-mg Actinobacillus actinomycetemcomitans lipopolysaccharide. Escherichia coli lipopolysaccharide did not cause fetal loss when given at doses of 10 mg (n = 14 fetuses) or 1 mg (n = 7 fetuses). Fetuses that survived exposure to these lipopolysaccharides showed features of inflammation in amniotic fluid and cord blood at birth and enhanced lung maturation. CONCLUSION: Lipopolysaccharides from these 3 periodontopathic organisms have much higher rates of fetal lethality than Escherichia coli lipopolysaccharide but can cause similar intrauterine inflammatory responses and improvements in lung volumes in survivors. Sources of inflammation that are distant from the uterus may underlie a proportion of unexplained stillbirth and other complications of pregnancy.

Acid-Base Equilibrium↗
PubMed2005

Antenatal associations with lung maturation and infection.

Chronic clinically unapparent chorioamnionitis is a common antenatal exposure for very preterm infants, and these infants have variable degrees of lung maturation and a high risk of developing bronchopulmonary dysplasia. Exposure of fetal sheep to intra-amniotic endotoxin or IL-1alpha induces chorioamnionitis and lung injury (decreased alveolarization and microvascular injury), which resolves to a phenotype of striking lung maturation (increased surfactant, improved gas exchange and lung mechanics). The immune responses of the fetus also are suppressed or induced (matured) in time and dose-dependent ways by either chorioamnionitis or antenatal corticosteroids. These experimental observations contribute to explanations of why preterm infants have variable degrees of lung maturation at birth and unpredictably develop bronchopulmonary dysplasia BPD.

Animals↗
PubMed2005

The clever fetus: responding to inflammation to minimize lung injury.

Clinical and experimental information indicate that fetal exposure to inflammation can induce lung maturation. This inflammation may be chronic and indolent. We present clinical and experimental information that challenge assumptions about chorioamnionitis associated infection/inflammatory exposures to the fetus. We question the assumption that the fetal compartment is sterile, and that delivery is inevitable if chronic infection/inflammation is present. We demonstrate that the preterm fetus can develop a brisk and adequate inflammatory response, and the fetus also can quickly modulate and downregulate inflammation to prevent injury. The fetus at risk of early preterm delivery may be exposed to both chorioamnionitis and glucocorticoids. Both exposures can either increase or decrease fetal inflammatory responses depending on the timing of the exposures. The immunomodulatory ability of the fetus to fetal exposures remains an unexplored research field.

Animals↗
PubMed2005

Pulmonary and systemic induction of SAA3 after ventilation and endotoxin in preterm lambs.

Serum amyloid A (SAA), an acute phase reactant (APR) protein, is induced in liver during systemic inflammation. Serum amyloid A3 (SAA3), an isoform of SAA, is induced in both liver and extra hepatic sites in response to proinflammatory stimuli such as cytokines. Previously, we showed a modest increase in plasma cytokine levels in a preterm lamb model of lung injury. The study objective was to determine the relative contributions of lung and liver to the acute phase response during postnatal lung injury. Preterm (130d) and near term (141d) newborn lambs (term=150d) were randomized to either no ventilation (controls), ventilation+intratracheal (IT) endotoxin (endo) or ventilation+IT saline. A group of near term lambs were exposed to ventilation+IV endotoxin. In the lungs, ventilation alone increased SAA3 mRNA 3- and 13-fold while ventilation+IT endotoxin increased SAA3 mRNA 64 and 366-fold above controls in preterm and near term lambs, respectively. In the liver, SAA3 mRNA was induced by ventilation alone (three-fold) and ventilation+IT endotoxin (45-fold) above controls in both preterm and near term animals. Ventilation + IV endotoxin caused the highest increase in SAA3 mRNA (212-fold) in the liver of near term animals. A different isoform, identified as SAA-Liver inducible was maximally induced in liver by ventilation alone with minimal further response to endotoxin. Lung SAA3 mRNA expression was detected primarily in airway epithelium, bronchial glands, perichondrium of bronchial cartilage and vascular smooth muscle cells. Our experiments show rapid induction of an APR gene in lung in response to proinflammatory stimuli.

Acute Disease↗
PubMed2005

Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia.

OBJECTIVE: A number of definitions of bronchopulmonary dysplasia (BPD), or chronic lung disease, have been used. A June 2000 National Institute of Child Health and Human Development/National Heart, Lung, and Blood Institute Workshop proposed a severity-based definition of BPD for infants <32 weeks' gestational age (GA). Mild BPD was defined as a need for supplemental oxygen (O2) for > or =28 days but not at 36 weeks' postmenstrual age (PMA) or discharge, moderate BPD as O2 for > or =28 days plus treatment with <30% O2 at 36 weeks' PMA, and severe BPD as O2 for > or =28 days plus > or =30% O2 and/or positive pressure at 36 weeks' PMA. The objective of this study was to determine the predictive validity of the severity-based, consensus definition of BPD. METHODS: Data from 4866 infants (birth weight < or =1000 g, GA <32 weeks, alive at 36 weeks' PMA) who were entered into the National Institute of Child Health and Human Development Neonatal Research Network Very Low Birth weight (VLBW) Infant Registry between January 1, 1995 and December 31, 1999, were linked to data from the Network Extremely Low Birth Weight (ELBW) Follow-up Program, in which surviving ELBW infants have a neurodevelopmental and health assessment at 18 to 22 months' corrected age. Linked VLBW Registry and Follow-up data were available for 3848 (79%) infants. Selected follow-up outcomes (use of pulmonary medications, rehospitalization for pulmonary causes, receipt of respiratory syncytial virus prophylaxis, and neurodevelopmental abnormalities) were compared among infants who were identified with BPD defined as O2 for 28 days (28 days definition), as O2 at 36 weeks' PMA (36 weeks' definition), and with the consensus definition of BPD. RESULTS: A total of 77% of the neonates met the 28-days definition, and 44% met the 36-weeks definition. Using the consensus BPD definition, 77% of the infants had BPD, similar to the cohort identified by the 28-days definition. A total of 46% of the infants met the moderate (30%) or severe (16%) consensus definition criteria, identifying a similar cohort of infants as the 36-weeks definition. Of infants who met the 28-days definition and 36-weeks definition and were seen at follow-up at 18 to 22 months' corrected age, 40% had been treated with pulmonary medications and 35% had been rehospitalized for pulmonary causes. In contrast, as the severity of BPD identified by the consensus definition worsened, the incidence of those outcomes and of selected adverse neurodevelopmental outcomes increased in the infants who were seen at follow-up. CONCLUSION: The consensus BPD definition identifies a spectrum of risk for adverse pulmonary and neurodevelopmental outcomes in early infancy more accurately than other definitions.

Bronchopulmonary Dysplasia↗
PubMed2004

Surfactant and physiologic responses of preterm lambs to continuous positive airway pressure.

Although continuous positive airway pressure (CPAP) is used frequently for preterm infants, the relationships between the amount of surfactant and lung physiologic and injury responses to CPAP are unknown. Therefore, saturated phosphatidylcholine (Sat PC) was measured to quantify the surfactant necessary for preterm lambs to breathe successfully on a CPAP of 5 cm H(2)O (CPAP 5). Five of 21 lambs delivered at 130-136 days gestation failed to keep PCO(2) below 100 mm Hg by 2 hours. The lambs that failed had less than 1.9 micromol/kg Sat PC in bronchoalveolar fluid (approximately 3% the pool size at term), less surfactant secretion, and less large aggregate surfactant. Physiologic responses of other 132-day preterm lambs after 2 or 6 hours of CPAP 5, 8 cm H(2)O CPAP (CPAP 8), or mechanical ventilation were then characterized. At 6 hours, oxygenation and lung gas volumes were higher with CPAP 8 relative to the other groups and VE was decreased with CPAP 8 relative to CPAP 5. Lung dry/wet ratios were greater for the CPAP groups than for the mechanical ventilation group. A small amount of endogenous Sat PC is required for preterm lambs to breathe successfully with CPAP. CPAP 8 improves early newborn respiratory transition relative to CPAP 5.

Age Factors↗
PubMed2004

Endotoxin-induced chorioamnionitis modulates innate immunity of monocytes in preterm sheep.

The preterm fetus is immune naive and has immature innate immune function. Although the preterm fetus is frequently exposed to chorioamnionitis, the effects of exposure of the fetal lung to inflammation on innate immune responses are unknown. Using the fetal sheep model of chorioamnionitis, cord blood monocytes were isolated from preterm lambs 1 to 14 days after intra-amniotic endotoxin injection, cultured for approximately 16 hours, and challenged with endotoxin in vitro. Compared with monocytes from adult sheep, the preterm monocytes produced less H(2)O(2) and interleukin-6, and toll-like receptor 4 expression was decreased. Three days after intra-amniotic endotoxin exposure, preterm monocyte responses to in vitro endotoxin challenge demonstrated decreased H(2)O(2) and interleukin-6 production and decreased CD14 and major histocompatibility complex class II expression. Preterm monocyte responses 7 to 14 days after endotoxin tended to exceed those of adults and preterm control animals indicating augmented function. In contrast, a second intra-amniotic endotoxin injection 7 days after the initial endotoxin exposure suppressed monocyte function at 14 days. The fetal monocytes demonstrated patterns of responses consistent with endotoxin tolerance (immune paralysis) as well as maturation of function. Modulation of fetal innate immune responses by exposure to inflammation may alter subsequent immune adaptation after birth.

Amnion↗