transforming-growth-factor-beta and Chorioamnionitis

Various pre- and postnatal risk factors, which act additively or synergistically induce an injurious inflammatory response in the airways and the pulmonary interstitium of preterm infants with bronchopulmonary dysplasia. This inflammatory response is characterized by an accumulation of neutrophils and macrophages as well as an arsenal of proinflammatory mediators that affect the endothelium and alveolar-capillary integrity. Besides proinflammatory cytokines and toxic oxygen radicals, lipid mediators as well as potent proteases may be responsible for acute lung injury. There is increasing evidence that an imbalance between pro- and anti-inflammatory factors, which should protect the alveoli and lung tissue, are key features in the pathogenesis of bronchopulmonary dysplasia. In addition, a subnormal generation of growth factors may affect alveolarization and vascular development in preterm infants with bronchopulmonary dysplasia. In this condensed review article, the current concepts on the possible role of inflammation in the evolution of bronchopulmonary dysplasia will be summarized.

Topics: Blood-Air Barrier; Bronchopulmonary Dysplasia; Chemotaxis; Chorioamnionitis; Cytokines; Endothelium; Female; Humans; Hyperoxia; Infant, Newborn; Infant, Premature; Inflammation Mediators; Intercellular Signaling Peptides and Proteins; Macrophages; Neutrophils; Oxygen; Peptide Hydrolases; Pneumonia; Pregnancy; Pulmonary Alveoli; Respiration, Artificial; Transforming Growth Factor beta

Pulmonary inflammation is a key feature in the pathogenesis of bronchopulmonary dysplasia (BPD). This inflammatory process, induced by multiple risk factors, is characterized by the presence of inflammatory cells, cytokines and an arsenal of additional humoral mediators in the airways and pulmonary tissue of preterm infants with the condition. Several mediators have a direct detrimental effect on pulmonary structures by affecting cell integrity and inducing apoptosis. An imbalance between pro-inflammatory and anti-inflammatory factors can generally be considered to be a hallmark of lung injury. Intrauterine exposure to pro-inflammatory cytokines or antenatal infection may prime the fetal lung such that minimally injurious postnatal events provoke an excessive pulmonary inflammatory response that most certainly affects normal alveolization and pulmonary vascular development in preterm infants with BPD.

Topics: Animals; Bronchopulmonary Dysplasia; Chorioamnionitis; Cytokines; Female; Humans; Infant, Newborn; Inflammation; Leukocyte Elastase; Models, Immunological; Pregnancy; Respiration, Artificial; Risk Factors; Transforming Growth Factor beta

Chorioamnionitis is a gestational pathological condition characterized by acute inflammation of the amniochorionic membranes and placentas leading to high concentrations of IL-1β, Il-6, Il-8 and TGF-β in the amniotic fluid. In normal conditions, the permeability of foeto-maternal barrier is due to the assembly and maintenance of different cellular junctional domains.. In the present study, first we aimed to evaluate the protein expression (by immunohistochemistry and western blotting) and mRNA (by real time PCR) levels of the molecular components of tight junctions (Zonula occludens-1 and occludin), and of adherent junctions (VE-cadherin and β-catenin) in placentas from chorioamnionitis compared to that in normal pregnancies.. Western blotting results showed a significant down-regulation of occludin in placentas affected with chorioamnionitis. No differences were detected for the other proteins analysed. We evaluated whether occludin expression was regulated by IL-1β, IL-6, IL-8 and TGF-β by means of in vitro studies using HUVEC cultures and demonstrated a key role of IL-1β and TGF-β in the disappearance of occludin at cellular border.. We conclude by suggesting a pivotal role of these two cytokines in facilitating intra-placental infection via para-cellular way due to the disassembly of tight junctions at trophoblastic and endothelial cells in placental tissues.

Topics: Antigens, CD; beta Catenin; Cadherins; Case-Control Studies; Cell Membrane Permeability; Chorioamnionitis; Cytokines; Female; Human Umbilical Vein Endothelial Cells; Humans; Immunohistochemistry; Interleukin-1beta; Maternal-Fetal Exchange; Occludin; Placenta; Pregnancy; RNA, Messenger; Tight Junctions; Transforming Growth Factor beta; Zonula Occludens-1 Protein

Bronchopulmonary dysplasia (BPD) is one of the most common complications after preterm birth and is associated with intrauterine exposure to bacteria. Transforming growth factor-β (TGFβ) is implicated in the development of BPD.. We hypothesized that different and/or multiple bacterial signals could elicit divergent TGFβ signaling responses in the developing lung.. Time-mated pregnant Merino ewes received an intra-amniotic injection of lipopolysaccharide (LPS) and/or Ureaplasma parvum serovar 3 (UP) at 117 days' and/or 121/122 days' gestational age (GA). Controls received an equivalent injection of saline and or media. Lambs were euthanized at 124 days' GA (term = 150 days' GA). TGFβ1, TGFβ2, TGFβ3, TGFβ receptor (R)1 and TGFβR2 protein levels, Smad2 phosphorylation and elastin deposition were evaluated in lung tissue.. Total TGFβ1 and TGFβ2 decreased by 24 and 51% after combined UP+LPS exposure, whereas total TGFβ1 increased by 31% after 7 days' LPS exposure but not after double exposures. Alveolar expression of TGFβR2 decreased 75% after UP, but remained unaltered after double exposures. Decreased focal elastin deposition after single LPS exposure was prevented by double exposures.. TGFβ signaling components and elastin responded differently to intrauterine LPS and UP exposure. Multiple bacterial exposures attenuated TGFβ signaling and normalized elastin deposition.

Topics: Amnion; Animals; Chorioamnionitis; Disease Models, Animal; Elastin; Female; Gestational Age; Inflammation; Lipopolysaccharides; Lung; Phosphorylation; Pregnancy; Pregnancy Complications; Receptors, Transforming Growth Factor beta; Sheep; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Transforming Growth Factor beta3; Ureaplasma

Genome-wide screening studies of the chorioamniotic membranes unexpectedly identified an increase in the expression of bone morphogenetic protein 2 in spontaneous labor at term. The objective of this study was to determine whether bone morphogenetic protein 2 messenger RNA and protein expression are altered in the chorioamniotic membranes of patients with term labor, preterm labor, and preterm premature rupture of membranes.. Chorioamniotic membranes were obtained from patients at term (with and without labor), with preterm labor (with and without histologic chorioamnionitis), and with preterm premature rupture of membranes (with and without histologic chorioamnionitis). The expression of bone morphogenetic protein 2 was studied by real-time quantitative reverse transcriptase-polymerase chain reaction (n = 88) and immunohistochemistry (n = 124). Nonparametric statistics were used for analysis. Primary amnion cells obtained from women at term not in labor were treated with bone morphogenetic protein 2 to examine whether there was increased prostaglandin E2 expression.. The median bone morphogenetic protein 2 messenger RNA and protein expression were significantly higher in the membranes of patients with spontaneous labor at term than in those of patients not in labor at term (P < .001 for both). Bone morphogenetic protein 2 messenger RNA and protein expression were increased in patients with preterm labor with histologic chorioamnionitis than in those without histologic chorioamnionitis (P < .05 and P < .001, respectively). There was no difference in bone morphogenetic protein 2 messenger RNA and protein expression in patients with preterm premature rupture of membranes, regardless of chorioamnionitis (P = .13 and P = .08, respectively). There was a correlation between bone morphogenetic protein 2 and cyclooxygenase 2 protein expression in chorioamniotic membranes (R = .34; P < .001).. Bone morphogenetic protein 2 messenger RNA and protein expression are increased in the chorioamniotic membranes of patients with spontaneous labor at term and patients with preterm labor associated with histologic chorioamnionitis. Its expression pattern and biologic effects strongly suggest that bone morphogenetic protein 2 is involved in human parturition.

Topics: Amnion; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Cells, Cultured; Chorioamnionitis; Chorion; Cross-Sectional Studies; Female; Fetal Membranes, Premature Rupture; Humans; Immunohistochemistry; Labor, Obstetric; Obstetric Labor, Premature; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta; Up-Regulation; Uterine Contraction

Inflammatory mediators that are induced by gram-negative bacteria in the course of intrauterine infections threaten successful pregnancy. To compare the effect of two different routes of cytokine induction, bacterial lipopolysaccharide (LPS) was administered in vivo either into the cord vein or into the amniotic cavity of pig fetuses in the second half of gestation for 20 h and cytokines were detected in the amnion.Tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) were induced in the amniotic epithelium after intra-amniotic but not after intra-venous administration of LPS. The presence of IL-8 was confirmed by RT-PCR. In contrast, transforming growth factor-beta1 (TGF-beta1) was expressed constitutively and was found in all samples of the amniotic epithelium. Amniotic fluid contained only minute levels of TNF-alpha. IL-8 levels in amniotic fluid increased after the treatment with LPS and the highest IL-8 levels were found in dead LPS-treated fetuses.

Topics: Amnion; Animals; Chorioamnionitis; Female; Fetus; Immunohistochemistry; Interleukin-8; Lipopolysaccharides; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Swine; Swine Diseases; Swine, Miniature; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha