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Biomedical subjects

Alan H Jobe

Publications and source records attributed to Alan H Jobe.

At least 37 records · Page 2Linked to original sources
PubMed2004

Vascular changes after intra-amniotic endotoxin in preterm lamb lungs.

Chorioamnionitis is associated with preterm delivery and bronchopulmonary dysplasia (BPD), characterized by impaired alveolar and pulmonary vascular development and vascular dysfunction. To study the vascular effects in a model of chorioamnionitis, preterm lambs were exposed to 20 mg of intra-amniotic endotoxin or saline for 1, 2, 4, or 7 days and delivered at 122 days gestational age (term = 150 days). This intra-amniotic endotoxin dose was previously shown to induce lung maturation. The effect of intra-amniotic endotoxin on expression of endothelial proteins was evaluated. Muscularization of the media and collagen deposition in adventitia of small pulmonary arteries was used to assess vascular remodeling. Compared with controls, bronchoalveolar lavage fluid protein content was increased 2 days after intra-amniotic endotoxin exposure. Vascular endothelial growth factor (VEGF) 165 isoform mRNA decreased 2-4 days after intra-amniotic endotoxin. VEGF, VEGF receptor-2, endothelial nitric oxide synthase (eNOS), platelet endothelial cell adhesion molecule-1, and Tie-2 protein expression in the lung coordinately decreased 1-7 days after intra-amniotic endotoxin. Intra-amniotic endotoxin appeared to selectively decrease eNOS expression in small pulmonary vessels compared with large vessels. Medial smooth muscle hypertrophy and increased adventitial fibrosis were observed 4 and 7 days after intra-amniotic endotoxin. These results demonstrate that, in the preterm lamb lung, antenatal inflammation inhibits endothelial cell protein expression followed by vascular remodeling changes in small pulmonary arteries. Exposure to antenatal inflammation may cause vascular remodeling and contribute to the development of BPD.

Amnion↗
PubMed2004

Variability in preterm lamb lung mechanics after intra-amniotic endotoxin is associated with changes in surfactant pool size and morphometry.

Antenatal exposure to intra-amniotic (i.a.) endotoxin initiates a complex series of events, including an inflammatory cascade, increased surfactant production, and alterations to lung structure. Using the low frequency forced oscillation technique as a sensitive tool for measurement of respiratory impedance, we aimed to determine which factors contributed most to measured changes in lung mechanics. Respiratory impedance data obtained from sedated preterm lambs exposed to either i.a. injection with saline or 20 mg of endotoxin 1, 2, 4, and 15 days before delivery at 125 days gestation were studied, and association with indexes of standard lung morphometry, inflammatory response, and alveolar surfactant-saturated phosphatidylcholine (Sat PC) pool size was demonstrated. Reduction in tissue impedance with increasing interval between exposure and delivery was evident as early as 4 days after i.a. endotoxin injection, coinciding with resolution of inflammatory reaction, increased alveolar surfactant pools, and contribution of alveolar ducts to the parenchymal fraction, and a later decrease in the tissue component of the parenchymal fraction. Decreases in tissue damping (resistance) were more marked than decreases in tissue elastance. Log alveolar Sat PC accounted for most variability in tissue damping (88.9%) and tissue elastance (73.4%), whereas tissue fraction contributed 2 and 6.4%, respectively. The alveolar Sat PC pool size was the sole factor contributing to change in tissue hysteresivity. No changes were observed in airway resistance. Despite the complex cascade of events initiated by antenatal endotoxin exposure, variability in lung tissue mechanics is associated primarily with changes in alveolar Sat PC pool and lung morphology.

Animals↗
PubMed2004

Antenatal betamethasone changes cord blood monocyte responses to endotoxin in preterm lambs.

Corticosteroids are routinely administered to women at risk for preterm delivery to induce fetal lung maturation. Antenatal corticosteroids have immunomodulatory effects on fetal immune cells that are poorly understood. We hypothesized that maternal betamethasone would alter in fetal monocytes both the initiation of inflammation in response to pro-inflammatory stimuli and the resolution of inflammation by phagocytosis of apoptotic neutrophils. Preterm lambs at 124 d gestation were delivered 15 h, 1 d, 2 d, or 7 d after 0.5 mg/kg maternal intramuscular betamethasone. Monocytes from cord blood were isolated and cultured and results were compared with monocytes from preterm lambs exposed to maternal saline or monocytes from adult sheep. Phagocytosis of Escherichia coli was not changed, however, phagocytosis of apoptotic neutrophils was low in fetal monocytes but increased after 7 d exposure to maternal betamethasone to the level found in adult monocytes. Hydrogen peroxide production after endotoxin stimulus was significantly reduced to 7.1 +/- 2.2 micromol at 5 h, 8.7 +/- 2.9 micromol at 24 h, and 4.1 +/- 1.9 micromol at 48 h versus 16.4 +/- 3.6 micromol in control animals; at 7 d, the hydrogen peroxide production increased to 74.3 +/- 19.7 micromol (p < 0.05, per 10(6) monocytes). IL-6 production was reduced at 15 h after maternal betamethasone but at no other time point. Maternal betamethasone initially suppressed several fetal monocyte functions, however, at 7 d, measurements of initiation and resolution of inflammation were increased to levels similar to monocytes from adult sheep. The time-dependent changes in maternal betamethasone modulation of the responses of fetal monocytes may influence immune function of the preterm lamb after delivery.

Adrenal Cortex Hormones↗
PubMed2004

Lung inflammatory responses to intratracheal interleukin-1alpha in ventilated preterm lambs.

Interleukin-1alpha is an early response proinflammatory cytokine that has been associated with chorioamnionitis and preterm labor, brain injury, and bronchopulmonary dysplasia. However, IL-1alpha also can increase expression of surfactant proteins and induce lung maturation in the preterm fetus. We measured the effects of IL-1alpha given by intratracheal instillation (IT) and compared the responses with injection of i.v. IL-1alpha in surfactant-treated and ventilated premature lambs. IT recombinant ovine IL-1alpha at doses of 5 and 50 microg/kg caused a similar large recruitment of neutrophils into the bronchoalveolar lavage fluid. The neutrophils expressed CD11b, CD14, and CD44, but did not produce increased amounts of H(2)O(2). Cells from the bronchoalveolar lavage fluid had increased expression of proinflammatory cytokines, which also were increased in mRNA from lung tissue. The IT IL-1alpha also suppressed the expression of surfactant protein-C mRNA. Systemic effects were decreased neutrophils in blood, decreased lung function, increased heart rate, and hypotension or death in the 50 microg/kg IL-1alpha IT group and only decreased neutrophils in the blood in the 5 microg/kg IL-1alpha IT group. The i.v. IL-1alpha caused no lung inflammation or injury but did result in severe neutropenia and hypotension leading to early death. IT IL-1alpha can cause intense lung inflammation and systemic shock in ventilated preterm lungs.

Animals↗
PubMed2004

Choice and dose of corticosteroid for antenatal treatments.

Although antenatal glucocorticoids are standard of care for women at risk of preterm delivery before 32 to 34 weeks' gestation, the choice and dosing of the corticosteroid has not been standardized. An analysis of the trial data demonstrates that the risk of neonatal death is decreased with betamethasone, but not dexamethasone. Other clinical data also indicate that betamethasone is the drug of choice for antenatal treatment. The pharmacology of the corticosteroids suggests that a lower total glucocorticoid dose per treatment may be as effective as the current treatment recommendations. However, a change from current practice will require further randomized controlled trials.

Betamethasone↗
PubMed2004

Prenatal glucocorticoid exposure and postnatal adaptation in premature newborn baboons ventilated for six days.

OBJECTIVE: Renal and cardiovascular function is improved during the first 24 hours of life in preterm ventilated baboons exposed to prenatal betamethasone (BETA). We hypothesized BETA-induced effects would be sustained through day 6 of life. Study design Pregnant baboons received saline or BETA (6 mg) 48 and 24 hours before preterm delivery at 125 days' gestation. The newborn baboons were ventilated for 6 days, and assessed for renal, cardiovascular, and endocrine function. RESULTS: Mean arterial blood pressure (MAP) and glomerular filtration rate (GFR) values 24 hours after delivery were higher in the BETA group. Kidney Na, K-ATPase activity was higher in the BETA group by day 6. All other measures were similar in both groups by day 6. CONCLUSION: Prenatal BETA exposure in the premature baboon: (1) increases MAP and GFR on day 1 without measurable effects by day 6 and (2) increases kidney Na, K-ATPase activity.

Adaptation, Physiological↗
PubMed2003

Initial responses to ventilation of premature lambs exposed to intra-amniotic endotoxin 4 days before delivery.

Preterm delivery is frequently preceded by chorioamnionitis, resulting in exposure of the fetal lung to inflammation. We hypothesized that ventilation of the antenatally inflamed lung would result in amplification of the lung injury. Therefore, we induced fetal lung inflammation with intra-amniotic endotoxin (10 mg of Escherichia coli 055:B5) 4 days before premature delivery at 130 days of gestation. Lung function and lung inflammation after surfactant treatment and 4 h of mechanical ventilation were evaluated. Inflammatory cell numbers in amniotic fluid were increased >10-fold by antenatal endotoxin exposure. Antenatal endotoxin exposure had minimal effects on blood pressure, heart rate, lung compliance, and blood gas values. The endotoxin-exposed lungs required higher ventilation pressures. Ventilation did not increase the number of inflammatory cells or the protein in bronchoalveolar lavage fluid of the endotoxin-exposed animals above that measured in endotoxin-exposed fetuses that were not ventilated. IL-1beta, IL-6, and IL-8 mRNA in cells from bronchoalveolar lavage fluid were increased by antenatal endotoxin exposure but not changed by ventilation. IL-1beta and IL-8 protein was increased in lung tissue by 4 h of ventilation. Very little inflammation was induced by ventilation in this premature lamb model of surfactant treatment and gentle ventilation. After lung inflammation was induced by intra-amniotic endotoxin injection, ventilation did not increase lung injury.

Animals↗
PubMed2003

Monocyte function in preterm, term, and adult sheep.

The preterm infant has functionally immature monocytes. The effects of common clinical interventions and exposures that might modulate inflammation were evaluated using monocytes isolated from blood of preterm lambs [130 d gestational age (GA)], near-term lambs (141 d GA), and adult sheep. Endotoxin stimulated hydrogen peroxide production by adult monocytes, but monocytes from 130-d and 141-d GA lambs had a reduced and delayed hydrogen peroxide production. Endotoxin did not decrease apoptosis of monocytes from 130-d and 141-d GA lambs but decreased apoptosis of adult monocytes. Dexamethasone increased the phagocytosis of bacteria and apoptotic cells by adult monocytes by 35% but not by monocytes from 130-d and 141-d GA lambs. Synthetic and natural surfactants and dipalmitoylphosphatidylcholine increased phagocytosis of apoptotic cells by monocytes from preterm, term, and adult sheep. Monocytes from preterm and term lambs differ from adult monocytes in tests of both the initiation and the resolution of inflammation. The reduced phagocytosis of apoptotic cells by monocytes from the preterm may contribute to prolonged inflammation in diseases such as bronchopulmonary dysplasia.

Age Factors↗
PubMed2003

Increased IP-10 and MIG expression after intra-amniotic endotoxin in preterm lamb lung.

Subtraction hybridization was performed to explore changes in gene expression in the fetal lung after 20 mg of intra-amniotic (IA) endotoxin. Interferon-gamma-inducible 10-kd protein (IP-10) and monokine induced by interferon-gamma (MIG) constituted 20% of 102 endotoxin-induced clones identified in the preterm lamb lung. IP-10 (CXCL10) and MIG (CXCL9) are T-cell chemoattractants that have angiostatic properties. Both IP-10 and MIG mRNA were induced 30- to 40-fold in the fetal lung at 1 to 2 days after IA endotoxin. Intense IP-10 mRNA expression was detected by in situ hybridization in the bronchiolar and peribronchiolar areas and the vascular endothelium after IA endotoxin at all time points tested. MIG mRNA expression was detected initially focally in infiltrating neutrophils (15 hours after IA endotoxin) and later in the bronchiolar and peribronchiolar areas and vascular endothelium (1 day after IA endotoxin). In contrast to endotoxin, IA tumor necrosis factor-alpha or interleukin-1 alpha did not induce IP-10 or MIG mRNA in the lung. IA endotoxin also caused a modest induction of IP-10 and MIG mRNA in the jejunum, liver, and spleen. The IP-10 and MIG receptor CXCR3 was detected in the bronchiolar epithelium of preterm lambs by immunostaining. IP-10 and MIG are potent angiostatic chemokines that may contribute to lung injury and altered pulmonary vascular development in the preterm exposed to chorioamnionitis.

Amnion↗
PubMed2003

Minimal lung and systemic responses to TNF-alpha in preterm sheep.

TNF-alpha has been associated with chorioamnionitis and the subsequent development of bronchopulmonary dysplasia in preterm infants. We asked whether bioactive recombinant ovine TNF-alpha could induce chorioamnionitis, lung inflammation, lung maturation, and systemic effects in fetal sheep. We compared the responses to IL-1alpha, a cytokine known to induce these responses in preterm sheep. Intra-amniotic TNF-alpha caused no chorioamnionitis, no lung maturation, and a very small increase in inflammatory cells in the fetal lung after 5 h, 2 days (d), and 7 d. In contrast, IL-1alpha induced inflammation and lung maturation. TNF-alpha given into the airways at birth increased granulocytes in the bronchoalveolar lavage fluid of ventilated preterm lungs and decreased the mRNA for surfactant protein C but did not adversely effect postnatal lung function. An intravascular injection of IL-1alpha caused a systemic inflammatory response in fetal sheep, whereas there was no fetal response to intravascular TNF-alpha. Fetal and newborn preterm sheep are minimally responsive to TNF-alpha. Therefore, the presence of a mediator such as TNF-alpha in a developing animal does not necessarily mean that it is causing the responses anticipated from previous results in adult animals.

Amniotic Fluid↗
PubMed2003

Intraamniotic endotoxin increases lung antioxidant enzyme activity in preterm lambs.

Proinflammatory stimulation resulting from intraamniotic endotoxin improves lung function, increases surfactant protein mRNA expression and protein content, increases alveolar and lung saturated phosphatidylcholine pools, and accelerates lung morphometric maturation in fetal sheep. The mechanism for induction of lung maturation does not involve an increase in fetal cortisol. The effect of endotoxin on the maturation of a different lung system, the antioxidant enzyme (AOE) system, has not been examined. Therefore, we hypothesized that intraamniotic endotoxin would produce acceleration of AOE activity in fetal sheep at similar doses and schedule of administration to those producing lung functional and surfactant maturation. In a dose-response study, intraamniotic injections of 1, 4, 20, or 100 mg of Escherichia coli 055:beta5 endotoxin were administered 7 d before preterm delivery of sheep at 125 d gestation. In a study examining time interval of administration before delivery, 20 mg of endotoxin was injected at either 1-, 2-, 4-, 7-, or 15-d intervals before preterm delivery at 125 d. Doses of 1-100 mg of endotoxin produced significant increases in glutathione peroxidase activity; doses of 4-100 mg significantly increased catalase activity, whereas doses of 20-100 mg resulted in significant increases in total superoxide dismutase activity. Glutathione peroxidase activity was elevated within 2 d, whereas superoxide dismutase was increased by 4 d and catalase activity increased by 7 d after endotoxin. No AOE increases were sustained for 15 d. Endotoxin increased fetal lung AOE activity at similar dosing amounts and intervals to those producing maturation of lung function and surfactant. Thus, mechanisms involving proinflammatory stimulation, unrelated to glucocorticoid hormones, can induce maturation of the AOE system of the fetal lung.

Amniotic Fluid↗
PubMed2003

Chorioamnionitis induced by subchorionic endotoxin infusion in sheep.

OBJECTIVE: This study was undertaken to determine whether subchorionic endotoxin infusion causes chorioamnionitis and preterm lung maturation, as occurs after intra-amniotic endotoxin. STUDY DESIGN: From day 118 of pregnancy, sheep received infusions of endotoxin (subchorionic 7.5 mg/d, n=11; intra-amniotic 2.5 mg/d, n=9) until delivery of lambs at 120 or 124 days. Other sheep received a single intra-amniotic injection of endotoxin (10 mg, n=7) at 118 days before delivery at 124 days. Controls (n=9) received equivalent saline solution treatments. RESULTS: Chorioamnionitis accompanied all endotoxin treatments. Lung inflammation occurred after intra-amniotic endotoxin infusion or injection but not after subchorionic endotoxin. Umbilical arterial pH was lower and Pco(2) was higher than control after subchorionic endotoxin. Lung compliance and surfactant were increased after intra-amniotic endotoxin infusion or injection but not after subchorionic endotoxin. CONCLUSION: Chorioamnionitis may result from inflammatory stimuli at various intrauterine sites, with different sites causing different fetal effects and not all cases of chorioamnionitis being accompanied by enhanced lung maturation.

Amnion↗
PubMed2003

The multiple negative randomized controlled trials in perinatology--why?

Many of the multicenter trials in perinatal medicine have been negative in that they have shown no benefit for the intervention relative to the control. Although a negative trial can improve patient care by the avoidance of an unnecessary treatment, most trials are designed with the intent of the intervention improving outcomes. We selectively reviewed a number of recent trials in order to identify why the trials were negative. In general, the preliminary information on which the trials were based, which was a small trial or a meta-analysis of multiple small trials, was not robust or predictive. The weak preliminary information together with limited numbers of patients, problematic primary outcomes and a poor understanding of the biology of neonatal diseases has limited the ability to reliably design trials with positive outcomes.

Humans↗
PubMed2003

Antenatal factors and the development of bronchopulmonary dysplasia.

The lung of the preterm fetus is often exposed to antenatal glucocorticoids, and histologic chorioamnionitis is frequent. Clinically and experimentally, antenatal glucocorticoids and/or chorioamnionitis are associated with early lung maturation, but in experimental models, both glucocorticoids and intra-uterine inflammation decrease alveolarization. Experimental chorioamnionitis also can amplify the inflammatory response of the preterm lung to mechanical ventilation. In this article, the hypothesis developed is that bronchopulmonary dysplasia occurs because of repetitive adverse lung exposures, or hits, and that the initial hits may be antenatal glucocorticoid exposure and/or antenatal inflammation.

Animals↗
PubMed2003

Single and multiple prenatal glucocorticoid exposures improve preterm newborn lamb cardiovascular and renal function similarly.

OBJECTIVE: Renal and cardiovascular function improves in preterm newborn lambs after a single prenatal betamethasone treatment. We hypothesized that multiple betamethasone exposures would further improve renal and cardiovascular adaptation. STUDY DESIGN: Pregnant ewes were chosen randomly to receive saline solution, one dose of 0.5 mg/kg betamethasone at 104 days of gestation, or three doses of 0.5 mg/kg betamethasone at 104, 111, and 118 days of gestation. Lambs were delivered at 125 days of gestation (preterm) or 145 days of gestation (term). Renal and cardiovascular responses to phenylephrine were evaluated at 2 hours of age. RESULTS: The preterm single and multiple betamethasone-treated lambs comparably increased glomerular filtration rate, urinary flow and osmolar clearance, and sodium excretion in response to phenylephrine. Term responses were similar and not influenced by betamethasone exposure. CONCLUSION: Multiple courses of betamethasone do not further improve renal and cardiovascular responses from a single betamethasone dose. Renal and cardiovascular function at term is not affected by early prenatal betamethasone exposure.

Aldosterone↗
PubMed2003

Differential effects of maternal betamethasone and cortisol on lung maturation and growth in fetal sheep.

OBJECTIVES: We asked whether maternal or fetal cortisol treatments induced fetal lung maturation and growth restriction compared with betamethasone and whether medroxyprogesterone (MPA) influenced lung maturation. STUDY DESIGN: Pregnant sheep were randomized to receive MPA or saline solution at 100 days of gestation. At 117 days of pregnancy, ewes were randomized to receive maternal or fetal treatments with 0.5 mg/kg betamethasone, four injections of hydrocortisone given over 4.5 hours or saline solution. Body weight and lung maturation were evaluated at 125 days. RESULTS: Maternal betamethasone decreased in birth weight by 16% and induced lung maturation. Fetal cortisol or betamethasone induced only lung maturation. Maternal cortisol caused neither growth restriction nor lung maturation. MPA did not alter lung function in control lambs or in betamethasone-treated preterm lambs. CONCLUSIONS: Maternal cortisol treatments had no apparent effects on the fetus, suggesting that growth restriction caused by betamethasone may result from unidentified effects on the maternal-placental unit.

Animals↗