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ABSTRACT: Hyperoxia is closely linked with the development of chronic lung disease of prematurity (CLD), but the exact mechanisms whereby hyperoxia alters the lung architecture in the developing lung remain largely unknown. We developed a fetal human lung organ culture model to investigate (a) the morphologic changes induced by hyperoxia and (b) whether hyperoxia resulted in differential cellular responses in the epithelium and interstitium. The effects of hyperoxia on lung morphometry were analyzed using computer-assisted image analysis. The lung architecture remained largely unchanged in normoxia lasting as long as 4 d. In contrast, hyperoxic culture of pseudoglandular fetal lungs resulted in significant dilatation of airways, thinning of the epithelium, and regression of the interstitium including the pulmonary vasculature. Although there were no significant differences in Ki67 between normoxic and hyperoxic lungs, activated caspase-3 was significantly increased in interstitial cells, but not epithelial cells, under hyperoxic conditions. These changes show that exposure of pseudoglandular lungs to hyperoxia modulates the lung architecture to resemble saccular lungs.
Pediatric Research 04/2006; 59(3):383-8. · 2.70 Impact Factor
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ABSTRACT: Recent investigations demonstrating that pseudoglandular-stage airspaces contract spontaneously suggest that the production of contractile proteins by airway wall smooth muscle (ASM) is an important factor in the functional and structural differentiation of ASM.
Ouraim was to determine if smooth muscle (SM)-myosin heavy chain (MHC) myofilaments, the 'motor' underlying SM contraction, and SM-alpha-actin myofilaments were distributed simultaneously in pseudoglandular-stage human lungs and to further define the nature of fetal airway contractions.
Immunohistochemically stained sections of fetal lung (14 fetuses, 10.1-17 weeks gestation) were analysed by computer-assisted morphometry to determine airspace dimensions and detect SM-MHC- and SM-alpha-actin-ASM. Lung tissue from the same fetuses was also placed in explant culture to observe airway contractions using videomicroscopy. We found that the smallest airspaces were just as likely to be invested by a layer of SM-MHC-positive ASM as by a layer of SM-alpha-actin-positive ASM. In addition, larger airways or airways from more mature fetal lungs were more likely to be invested by either SM-MHC- or SM-alpha-actin-positive ASM. Spontaneous airspace contractions were peristalsis-like and variable in amplitude. The time interval between contractions was temperature dependent (mean+/-SEM, 44+/-7.5 s at 37 degrees C), shortened by carbachol and increased by nitric oxide (NO)-donating drugs.
These observations suggest that ASM differentiation is characterised by the simultaneous production of SM-alpha-actin and SM-MHC myofilaments and that the presence of these proteins is likely to be responsible for cholinergic- and NO-sensitive spontaneous contractions of fetal human airspaces.
Biology of the Neonate 02/2006; 89(4):211-9. · 1.90 Impact Factor
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ABSTRACT: Although antenatal infection is thought to play an important role in the pathogenesis of preterm labor and neonatal diseases, the exact mechanisms are largely unknown. We sought to clarify the relationship between antenatal infection and intrauterine and neonatal inflammation. Samples were obtained from 41 preterm infants of <33 wk gestation delivered to 36 mothers and analyzed for the presence of 16s ribosomal RNA (16s rRNA) genes using PCR and for the proinflammatory cytokines IL-6 and IL-8. In 16 (44%) mother-baby pairings, at least one sample was found to be positive for the presence of 16s rRNA genes. All but one of the positive samples were from mothers presenting with preterm prelabor rupture of membranes (pPROM) or in spontaneous idiopathic preterm labor. A strong association was found between the presence of 16s rRNA genes and chorioamnionitis and with funisitis. A marked increase in IL-6 and IL-8 was noted in all tissues positive for 16s rRNA genes, including placenta, fetal membranes, cord blood serum, and, where samples were available, in bronchoalveolar lavage fluid (BAL) and in amniotic fluid. Interestingly, gastric fluid was always positive for 16s rRNA genes if any other intrauterine or BAL sample was positive, suggesting that this sample may provide an alternative to amniotic fluid to identify antenatal infection. In conclusion, we have found that microbial genes are particularly prevalent in pPROM and spontaneous preterm labor groups and that their presence is strongly associated with a marked intrauterine inflammatory response.
Pediatric Research 04/2005; 57(4):570-7. · 2.70 Impact Factor
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ABSTRACT: To investigate the safety and feasibility of using mild hypothermia in neonates receiving extracorporeal membrane oxygenation (ECMO). Study design A prospective, nonrandomized pilot study of 25 neonates referred for ECMO. Whole body cooling was achieved by adjustment of the temperature of the extracorporeal circuit water bath. Five groups (N=5 per group) were each studied for the first 5 days of ECMO. The first group was maintained at 37 degrees C throughout the study period. Subsequent groups were cooled to 36 degrees C, to 35 degrees C, and, finally, to 34 degrees C, respectively, for 24 hours and the final group to 34 degrees C for 48 hours before being rewarmed to 37 degrees C. Patients were carefully assessed clinically and biologically. In addition to routine laboratory tests, cytokines (IL-6 and IL-8), complement (C3a), and molecular markers of coagulation (thrombin/antithrombin III [TAT], antithrombin III, and plasmin-alpha2plasminogen) were measured.
No major clinical or circuit problems were noted during cooling or rewarming. In particular, there were no problems of bleeding or cardiac arrhythmia. No significant difference was found between groups in terms of molecular markers of coagulation, complement, cytokines, and platelet transfusions.
Applying mild hypothermia (34 degrees C) for 24 or 48 hours to neonates receiving ECMO is both feasible and safe.
Journal of Pediatrics 04/2004; 144(3):301-8. · 4.11 Impact Factor
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ABSTRACT: Previously, we have reported marked pulmonary inflammation in infants who develop chronic lung disease of prematurity. We revisited these infants who did not have clinical or laboratory evidence of infection and searched for Ureaplasma urealyticum, group B streptococci, and other microbes by reverse transcription-PCR performed on RNA extracted from 93 bronchoalveolar lavage samples. From infants ventilated for respiratory distress syndrome, 6 (gestation, 28 wk; birthweight, 880 g) were positive for U. urealyticum and 11 (25 wk, 800 g) were negative. Five (83%) positive and four (36%) negative infants developed chronic lung disease. Each infant was colonized with either biovar 1 or biovar 2 but not both. U. urealyticum was very weakly detectable in two infants on d 1 but was detected in five of six infants at d 10. Furthermore, pulmonary neutrophils, alveolar macrophages, soluble intercellular adhesion molecule-1, and IL-1beta on d 10 and IL-6 and IL-8 at d 1 were significantly increased in the positive group. A variety of organisms were identified in six samples between 14 and 21 d of age, but all samples were negative for group B streptococci. Our data suggest that U. urealyticum colonization is associated with the development of pulmonary inflammation in infants who subsequently develop chronic lung disease.
Pediatric Research 02/2004; 55(1):61-8. · 2.70 Impact Factor
