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1.
Semin Fetal Neonatal Med ; 21(3): 162-73, 2016 06.
Article in English | MEDLINE | ID: mdl-26906338

ABSTRACT

Non-invasive respiratory support is increasingly used in lieu of intubated ventilator support for the management of neonatal respiratory failure, particularly in very low birth weight infants at risk for bronchopulmonary dysplasia. The optimal approach and mode for non-invasive support remains uncertain. This article reviews the application of high-frequency ventilation for non-invasive respiratory support in neonates, including basic science studies on mechanics of gas exchange, animal model investigations, and a review of current clinical use in human neonates.


Subject(s)
Bronchopulmonary Dysplasia/therapy , High-Frequency Ventilation/methods , Noninvasive Ventilation/methods , Respiratory Insufficiency/therapy , Humans , Infant, Newborn
2.
Cell Prolif ; 46(6): 654-64, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24460719

ABSTRACT

OBJECTIVE: Pulmonary arterial hypertension, characterized by pulmonary vascular remodelling and vasoconstriction, is associated with excessive proliferative changes in pulmonary vascular walls. However, the role of HDACs in the phenotypic alteration of pulmonary arterial smooth muscle cells (PASMC) is largely unknown. MATERIAL AND METHODS: Pulmonary arterial smooth muscle cells were isolated from newborn sheep. Cell cycle analysis was performed by flow cytometry. mRNA and protein expression were measured by real-time PCR and Western blot analysis. Wound-healing scratch assay was used to measure cell migration. Contractility of newborn PASMCs was determined by gel contraction assay. Chromatin immunoprecipitation was used to examine histone modifications along the p21 promoter region. Global DNA methylation was measured by liquid chromatography-mass spectroscopy. RESULTS: Inhibition of class I and class II HDACs by apicidin and HDACi VIII suppressed proliferation of newborn PASMC and induced cell cycle arrest in G1 phase. Acetyl H3 levels were higher in newborn PASMC treated with apicidin and HDACi VIII. This was accompanied by increased expression of p21 and reduced expression of CCND1 but not p53. HDAC inhibition altered histone codes around the p21 promoter region in NPASMC. Apicidin inhibited serum-induced cell migration, and modulated profiling of expression of genes encoding pro-oxidant and antioxidant enzymes. Contractility and global DNA methylation levels of newborn PASMCs were also markedly modulated by apicidin. CONCLUSION: Our results demonstrate that class I HDACs are clearly involved in phenotypic alteration of newborn PASMC.


Subject(s)
Histone Deacetylases/metabolism , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Pulmonary Artery/metabolism , Acetylation/drug effects , Animals , Antioxidants/metabolism , Cell Cycle Checkpoints/drug effects , Cell Cycle Checkpoints/genetics , Cell Movement/drug effects , Cell Movement/genetics , Cell Proliferation/drug effects , Cyclin D1/genetics , Cyclin D1/metabolism , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , DNA Methylation/drug effects , DNA Methylation/genetics , Familial Primary Pulmonary Hypertension , G1 Phase/drug effects , G1 Phase/genetics , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/genetics , Histones/genetics , Histones/metabolism , Humans , Hypertension, Pulmonary/genetics , Hypertension, Pulmonary/metabolism , Infant, Newborn , Muscle, Smooth, Vascular/drug effects , Phenotype , Promoter Regions, Genetic/drug effects , Promoter Regions, Genetic/genetics , Pulmonary Artery/drug effects , Sheep , Transcriptome/drug effects , Transcriptome/genetics , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
3.
J Anim Sci ; 88(13 Suppl): E216-22, 2010 Apr.
Article in English | MEDLINE | ID: mdl-19854998

ABSTRACT

Perinatal insults, including fetal undernutrition and hypoxia, are associated with an increased susceptibility to several adult-onset metabolic disorders. These include cardiovascular disease, insulin resistance, and obesity. However, the mechanisms driving the long-term phenotypic consequences have only recently begun to be elucidated. A primary mechanism accounting for perinatal adaptation is the epigenetic modification of chromatin. In this context, epigenetic modifications to chromatin are thought to arise in response to a perinatal insult in an effort to modulate gene expression and maximize fetal survival. In this symposium report, we discuss epigenetics as a mechanism by which perinatal adaptations can be made by the developing fetus. We examine the benefits of using multiple in vivo models to understand the interrelation of signals that come together and result in perinatal adaptation. Epigenetic effects on IGF-1 arising from a perinatal insult are discussed, as are the difficulties and challenges associated with this complex field. In conclusion, epigenetics provides a means of modulating gene transcription, thus allowing fetal adaptation to a broad variety of conditions.


Subject(s)
Adaptation, Physiological/physiology , Epigenesis, Genetic/physiology , Fetus/physiology , Animals , Animals, Domestic/physiology , Female , Fetal Development/genetics , Fetal Development/physiology , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/physiology , Pregnancy
4.
Anat Rec (Hoboken) ; 291(10): 1271-7, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18727105

ABSTRACT

All-trans retinoic acid (RA) is a potent modulator of lung development. Chorioamnionitis, which is frequently associated with preterm birth, causes fetal lung inflammation and improves lung function but also results in alveolar simplification and microvascular injury. Endotoxin-mediated chorioamnionitis reduces RA concentration in the fetal lung to 16% of control values. We hypothesized that administration of RA to the fetus before induction of chorioamnionitis would preserve septation of the distal airspaces. Time-mated ewes with singletons were assigned to receive a fetal intramuscular treatment with 20,000 IU of RA in olive oil (or olive oil only) 3 hr prior to intra-amniotic injection of endotoxin (20 mg, E. coli 055:B5) or saline, at 124-day gestational age and 7 days after the fetal treatment. The right cranial lung lobe was processed for morphometric analysis. RA treatment did not affect chorioamnionitis-induced fetal and systemic inflammation or interleukin-8 concentrations in lung tissue. RA administration alone did not alter lung structure. Relative to control lungs (5 +/- 3 mL/kg), lung volume increased similarly with endotoxin (22 +/- 4 mL/kg) or RA plus endotoxin (20 +/- 3 mL/kg; P < 0.05). Alveolar wall thickness was 4.2 +/- 0.3 mum after endotoxin-induced chorioamnionitis, 6.0 +/- 0.4 mum in controls (P < 0.05 versus endotoxin) and 5.5 +/- 0.2 mum after RA and endotoxin (P < 0.05 versus control, n.s. versus endotoxin). The ratio of airspace versus tissue was 4.6 +/- 0.3 in endotoxin-induced chorioamnionitis, 2.1 +/- 0.3 in controls and 4.1 +/- 0.5 after RA and endotoxin. We conclude that fetal treatment with RA did not prevent inflammation-induced alveolar simplification.


Subject(s)
Fetus/drug effects , Lung/drug effects , Lung/embryology , Tretinoin/pharmacology , Animals , Bronchopulmonary Dysplasia/chemically induced , Bronchopulmonary Dysplasia/metabolism , Bronchopulmonary Dysplasia/pathology , Chorioamnionitis/chemically induced , Chorioamnionitis/metabolism , Chorioamnionitis/pathology , Disease Models, Animal , Elastin/metabolism , Endotoxins , Female , Fetus/embryology , Humans , Infant, Newborn , Interleukin-8 , Lung/metabolism , Pregnancy , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/pathology , Sheep , Tretinoin/metabolism
5.
Am J Physiol Regul Integr Comp Physiol ; 293(1): R314-22, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17428897

ABSTRACT

Intrauterine growth restriction (IUGR) increases the incidence of chronic lung disease (CLD). The molecular mechanisms responsible for IUGR-induced acute lung injury that predispose the IUGR infant to CLD are unknown. p53, a transcription factor, plays a pivotal role in determining cellular response to stress by affecting apoptosis, cell cycle regulation, and angiogenesis, processes required for thinning of lung mesenchyme. Because thickened lung mesenchyme is characteristic of CLD, we hypothesized that IUGR-induced changes in lung growth are associated with alterations in p53 expression and/or modification. We induced IUGR through bilateral uterine artery ligation of pregnant rats. Uteroplacental insufficiency significantly decreased serine-15-phosphorylated (serine-15P) p53, an active form of p53, in IUGR rat lung. Moreover, we found that decreased phosphorylation of lung p53 serine-15 localized to thickened distal air space mesenchyme. We also found that IUGR significantly decreased mRNA for targets downstream of p53, specifically, proapoptotic Bax and Apaf, as well as Gadd45, involved in growth arrest, and Tsp-1, involved in angiogenesis. Furthermore, we found that IUGR significantly increased mRNA for Bcl-2, an antiapoptotic gene downregulated by p53. We conclude that in IUGR rats, uteroplacental insufficiency induces decreased lung mesenchymal p53 serine-15P in association with distal lung mesenchymal thickening. We speculate that decreased p53 serine-15P in IUGR rat lungs alters lung phenotype, making the IUGR lung more susceptible to subsequent injury.


Subject(s)
Fetal Growth Retardation/metabolism , Lung/metabolism , Placental Insufficiency/metabolism , Serine/metabolism , Tumor Suppressor Protein p53/metabolism , Animals , Animals, Newborn , Apoptosis/physiology , Blotting, Western , Cell Cycle/physiology , Female , Fetal Growth Retardation/pathology , Hyperplasia/pathology , Immunohistochemistry , Lung/pathology , Lung Diseases/congenital , Lung Diseases/metabolism , Lung Diseases/pathology , Neovascularization, Physiologic/genetics , Neovascularization, Physiologic/physiology , Phospholipids/metabolism , Phosphorylation , Pregnancy , Protein Kinases/metabolism , RNA/biosynthesis , RNA/genetics , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction
6.
J Perinatol ; 26 Suppl 2: S8-S12, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16801973

ABSTRACT

Pharmacologic study is needed in the extremely immature newborns who currently survive. Study is needed of both the drug treatment previously established in more mature neonates and of novel drug therapy. Carefully controlled studies are needed to identify accurately both beneficial and harmful drug therapy and the mechanisms of that toxicity. Careful pharmacologic study of drug disposition and its mechanisms might lead to dosing paradigms or patient selection that minimize toxicity and maximize efficacy. In vivo, translational models of neonatal diseases are limited, but can be used to identify novel treatments and study mechanisms of established, successful therapy. Findings from such studies can generate hypotheses for study in humans leading to a continuing scientific interchange from bedside to bench to bedside. Similarly, clinical observations can generate hypotheses for study in translational models where more invasive analyses are possible. Specific areas of drug treatment should focus on neonatal disorders with long-term, adverse outcomes, such as chronic lung disease, that is amenable to translational study with animal models. National data show a progressive decrease in the clinician-scientist pool entering biomedical research. The future of neonatal pharmacology studies requires an increase in training programs for the physician-scientist whose clinical education in neonatology can be complemented by rigorous basic-science training. Success as a clinician-scientist will require collaboration with full-time basic scientists who can continue studies during periods of clinical work and provide critical study methodology to the overall study design. Such a work environment must be supported by academic institutions and may require more flexibility in the promotion and tenure schedule and process, such as the nature of what it rewards. To complement this, the NIH could modify its grant reporting process to identify co-investigators in studies who may provide unique input to the study concepts and design, such as clinical correlations or clinical investigations.


Subject(s)
Disease Models, Animal , Infant, Newborn, Diseases/drug therapy , Neonatology , Pharmacology , Animals , Biomedical Research , Humans , Infant, Extremely Low Birth Weight , Infant, Newborn , Neonatology/education , Pharmacology/education , Research Support as Topic
7.
Physiol Genomics ; 25(1): 16-28, 2006 Mar 13.
Article in English | MEDLINE | ID: mdl-16380407

ABSTRACT

Intrauterine growth retardation (IUGR) increases the risk of neuroendocrine reprogramming. In the rat, IUGR leads to persistent changes in cerebral mRNA levels. This suggests lasting alterations in IUGR cerebral transcriptional regulation, which may result from changes in chromatin structure. Candidate nutritional triggers for these changes include altered cerebral zinc and one-carbon metabolite levels. We hypothesized that IUGR affects cerebral chromatin structure in neonatal and postnatal rat brains. Rats were rendered IUGR by bilateral uterine artery ligation; controls (Con) underwent sham surgery. At day of life 0 (d0), we measured cerebral DNA methylation, histone acetylation, expression of chromatin-affecting enzymes, and cerebral levels of one-carbon metabolites and zinc. At day of life 21 (d21), we measured cerebral DNA methylation and histone acetylation, as well as the caloric content of Con and IUGR rat breast milk. At d0, IUGR significantly decreased genome-wide and CpG island methylation, as well as increased histone 3 lysine 9 (H3/K9) and histone 3 lysine 14 (H3/K14) acetylation in the hippocampus and periventricular white matter, respectively. IUGR also decreased expression of the chromatin-affecting enzymes DNA methyltransferase 1 (DNMT1), methyl-CpG binding protein 2 (MeCP2), and histone deacetylase (HDAC)1 in association with increased cerebral levels of zinc. In d21 female IUGR rats, cerebral CpG DNA methylation remained lower, whereas H3/K9 and H3/K14 hyperacetylation persisted in hippocampus and white matter, respectively. In d21 male rats, IUGR decreased acetylation of H3/K9 and H3/K14 in these respective regions compared with controls. Despite these differences, caloric, fat, and protein content were similar in breast milk from Con and IUGR dams. We conclude that IUGR results in postnatal changes in cerebral chromatin structure and that these changes are sex specific.


Subject(s)
Brain/enzymology , Chromatin/chemistry , Epigenesis, Genetic , Fetal Growth Retardation/enzymology , Placental Insufficiency/enzymology , Acetylation , Animals , Animals, Newborn , Brain/ultrastructure , Chromatin/genetics , Chromatin/metabolism , CpG Islands , DNA/genetics , DNA/metabolism , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methylation , Female , Fetal Growth Retardation/genetics , Histone Deacetylases/genetics , Histone Deacetylases/metabolism , Histones/metabolism , Immunohistochemistry , Male , Methyl-CpG-Binding Protein 2/genetics , Methyl-CpG-Binding Protein 2/metabolism , Molecular Structure , Neurons/enzymology , Neurons/ultrastructure , Placental Insufficiency/genetics , Pregnancy , RNA, Messenger/metabolism , Rats , Sex Factors , Zinc/metabolism
8.
Am J Physiol Lung Cell Mol Physiol ; 287(4): L718-29, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15090366

ABSTRACT

Clinical studies have associated increased transforming growth factor (TGF)-alpha and EGF receptor with lung remodeling in diseases including bronchopulmonary dysplasia (BPD). BPD is characterized by disrupted alveolar and vascular morphogenesis, inflammation, and remodeling. To determine whether transient increases in TGF-alpha are sufficient to disrupt postnatal lung morphogenesis, we utilized neonatal transgenic mice conditionally expressing TGF-alpha. Expression of TGF-alpha from postnatal days 3 to 5 disrupted postnatal alveologenesis, causing permanent enlargement of distal air spaces in neonatal and adult mice. Lung volume-to-body weight ratios and lung compliance were increased in adult TGF-alpha transgenic mice, whereas tissue and airway elastance were reduced. Elastin fibers in the alveolar septae were fragmented and disorganized. Pulmonary vascular morphogenesis was abnormal in TGF-alpha mice, with attenuated and occasionally tortuous arterial branching. The ratios of right ventricle weight to left ventricle plus septal weight were increased in TGF-alpha mice, indicating pulmonary hypertension. Electron microscopy showed gaps in the capillary endothelium and extravasation of erythrocytes into the alveolar space of TGF-alpha mice. Hemorrhage and inflammatory cells were seen in distal air spaces at 1 mo of age. In adult TGF-alpha mice, alveolar remodeling, nodules, proteinaceous deposits, and inflammatory cells were seen. Immunostaining for pro-surfactant protein C showed that type II cells were abundant in the nodules, as well as neutrophils and macrophages. Trichrome staining showed that pulmonary fibrosis was minimal, apart from areas of nodular remodeling in adult TGF-alpha mice. Transient induction of TGF-alpha during early alveologenesis permanently disrupted lung structure and function and caused chronic lung disease.


Subject(s)
Lung Diseases/physiopathology , Lung/physiopathology , Transforming Growth Factor alpha/physiology , Animals , Crosses, Genetic , Disease Models, Animal , Gene Expression Regulation, Developmental , Lung/embryology , Mice , Mice, Inbred Strains , Mice, Transgenic , Morphogenesis , Transforming Growth Factor alpha/deficiency , Transforming Growth Factor alpha/genetics
9.
Am J Physiol Lung Cell Mol Physiol ; 287(1): L134-42, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15033636

ABSTRACT

To determine whether increased levels of VEGF disrupt postnatal lung formation or function, conditional transgenic mice in which VEGF 164 expression was enhanced in respiratory epithelial cells were produced. VEGF expression was induced in the lungs of VEGF transgenic pups with doxycycline from postnatal day 1 through 2 and 6 wk of age. VEGF levels were higher in bronchoalveolar lavage fluid (BALF) and lung homogenates of VEGF transgenic mice compared with endogenous VEGF levels in controls. Neonatal mortality was increased by 50% in VEGF transgenic mice. Total protein content in BALF was elevated in VEGF transgenic mice. Surfactant protein B protein expression was unaltered in VEGF transgenic mice. Although postnatal alveolar and vascular development were not disrupted by VEGF expression, VEGF transgenic mice developed pulmonary hemorrhage, alveolar remodeling, and macrophage accumulation as early as 2 wk of age. Electron microscopy demonstrated abnormal alveolar capillary endothelium in the VEGF transgenic mice. In many locations, the endothelium was discontinuous with segments of attenuated endothelial cells. Large numbers of hemosiderin-laden macrophages and varying degrees of emphysema were observed in adult VEGF transgenic mice. Overexpression of VEGF in the neonatal lung increased infant mortality and caused pulmonary hemorrhage, hemosiderosis, alveolar remodeling, and inflammation.


Subject(s)
Animals, Newborn , Hemorrhage/chemically induced , Hemosiderosis/chemically induced , Lung Diseases/chemically induced , Lung/pathology , Vascular Endothelial Growth Factor A/adverse effects , Aging , Animals , Animals, Newborn/growth & development , Animals, Newborn/metabolism , Blood Vessels/growth & development , Capillaries/ultrastructure , Capillary Permeability , Endothelium, Vascular/ultrastructure , Hemorrhage/metabolism , Hemorrhage/pathology , Hemosiderosis/metabolism , Hemosiderosis/pathology , Lung/blood supply , Lung/metabolism , Lung Diseases/metabolism , Lung Diseases/pathology , Mice , Mice, Inbred Strains , Mortality , Pulmonary Alveoli/physiopathology , Pulmonary Surfactant-Associated Protein B/metabolism
10.
Am J Physiol Lung Cell Mol Physiol ; 281(4): L1011-20, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11557605

ABSTRACT

Nitric oxide (NO), produced in lung vascular endothelium and airway epithelium, has an important role in regulating smooth muscle cell growth and tone. Chronic lung disease, a frequent complication of premature birth, is characterized by excess abundance, tone, and reactivity of smooth muscle in the pulmonary circulation and conducting airways, leading to increased lung vascular and airway resistance. Whether these structural and functional changes are associated with diminished pulmonary expression of endothelial nitric oxide synthase (eNOS) protein is unknown. Both quantitative immunoblot analysis and semiquantitative immunohistochemistry showed that there was less eNOS protein in the endothelium of small intrapulmonary arteries and epithelium of small airways of preterm lambs that were mechanically ventilated for 3 wk compared with control lambs born at term. No significant differences were detected for other proteins (inducible NOS, alpha-smooth muscle actin, and pancytokeratin). Lung vascular and respiratory tract resistances were greater in the chronically ventilated preterm lambs compared with control term lambs. These results support the notion that decreased eNOS in the pulmonary circulation and respiratory tract of preterm lambs may contribute to the pathophysiology of chronic lung disease.


Subject(s)
Endothelium, Vascular/enzymology , Nitric Oxide Synthase/metabolism , Pulmonary Circulation/physiology , Respiratory Insufficiency/metabolism , Respiratory Insufficiency/physiopathology , Airway Resistance/physiology , Animals , Animals, Newborn , Chronic Disease , Immunohistochemistry , Nitric Oxide Synthase/analysis , Nitric Oxide Synthase Type II , Nitric Oxide Synthase Type III , Respiration, Artificial , Respiratory Insufficiency/therapy , Sheep , Vascular Resistance/physiology
11.
Eur J Biochem ; 268(9): 2687-99, 2001 May.
Article in English | MEDLINE | ID: mdl-11322890

ABSTRACT

Previously, we reported cloning and characterization of the mouse gene, epitheliasin. In the present work we cloned the cDNA of the full-length human orthologue and characterized its gene including 2 kb of 5' flanking sequence. Analysis of epitheliasin gene expression in adult tissues shows that it is expressed as 3.4 kb and 2 kb transcripts. The major 3.4 kb transcript is observed in the following order: prostate > colon > small intestine > pancreas > kidney > lung > liver. Epitheliasin transcripts in fetal tissues are observed only in kidney and lung. In situ hybridization analysis of tissues revealed that epitheliasin was preferentially expressed in epithelial cells. The gene consists of 14 exons and 13 introns based on comparison with its cDNA sequence. In the 5' flanking region, we identified two transcription start sites and three CpG islands encompassing a number of potential regulatory elements including SP1, SREBP, GRE/PRE and ERE. The region upstream of the transcription sites lacks a TATA box but contains an initiator-like element as well as a downstream promoter-like element. In vitro experiments with lymph node carcinoma of prostate (LNCaP) cells revealed that the epitheliasin gene was induced by androgens and the induction was not blocked by cycloheximide indicating that the induction required no intermediate protein factors. Immunoprecipitation analysis showed that androgens strongly increased epitheliasin protein levels.


Subject(s)
DNA, Complementary/genetics , Serine Endopeptidases/genetics , Adult , Amino Acid Sequence , Animals , Base Sequence , Cloning, Molecular , DNA Primers/genetics , Exons , Female , Gene Expression Regulation, Enzymologic , Humans , Introns , Male , Mice , Molecular Sequence Data , Prostate/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sequence Homology, Amino Acid , Steroids/metabolism , Tissue Distribution
12.
J Histochem Cytochem ; 49(5): 667-8, 2001 May.
Article in English | MEDLINE | ID: mdl-11304807

ABSTRACT

As techniques evolve that allow molecular characterization of disease processes such as cancer, definition of "normal" at a molecular level becomes increasingly important. Increasingly large numbers of mutations are found at the genomic level, but whether all of those mutations contribute to the malignant state of a carcinoma cell is not clear. Without knowledge of what constitutes normality on the proteomic level in an organ or cell, we cannot determine what genomic changes are physiologically important. Traditionally, colon cancer is identified and classified by histological criteria. Margins of the colon are defined as "grossly uninvolved" when the histology is indistinguishable from that of normal (free from disease) colon. By using molecular pathology techniques and working backward from colon adenocarcinoma to hypoplastic polyps to presumably normal mucosa, we defined some of those protein differences. Our results may provide a molecular basis for identifying tumor formation and progression in situ.(J Histochem Cytochem 49:667-668, 2001)


Subject(s)
Adenocarcinoma/metabolism , Biomarkers, Tumor/metabolism , Colon/metabolism , Colonic Neoplasms/metabolism , Colonic Polyps/metabolism , DNA Topoisomerases, Type II , Trans-Activators , Antigens, Neoplasm , Antigens, Tumor-Associated, Carbohydrate/metabolism , Biomarkers, Tumor/classification , Cytoskeletal Proteins/metabolism , DNA Topoisomerases, Type II/metabolism , DNA-Binding Proteins , Gastric Mucins/metabolism , HSP70 Heat-Shock Proteins/metabolism , Humans , Immunohistochemistry , Intestinal Mucosa/metabolism , Isoenzymes/metabolism , Membrane Proteins/metabolism , Mucin-1/metabolism , Phosphoproteins/metabolism , Pilot Projects , Zonula Occludens-1 Protein , alpha Catenin , beta Catenin
13.
Am J Respir Cell Mol Biol ; 23(3): 320-6, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10970822

ABSTRACT

Elastin is a major component of the mammalian lung, predominantly found in the alveoli. Destruction of alveolar elastic fibers is implicated in the pathogenic mechanism of emphysema in adults. These data define a role for elastin in the structure and function of the mature lung, and suggest that elastin is important for alveogenesis. To investigate the role of elastin in lung development, we examined mice lacking elastin (Eln-/-). At birth, the distal air sacs of Eln-/- lungs dilate to form abnormally large cavities. This phenotype appears before the synthesis and deposition of alveolar elastin, a process mediated by myofibroblasts and initiated after postnatal Day 4. Morphometric analyses demonstrate that the perinatal development of terminal airway branches is arrested in Eln-/- mice. The branching defect is accompanied by fewer distal air sacs that are dilated with attenuated tissue septae, a condition reminiscent of emphysema. Elastin expression in the lung parenchyma before alveogenesis is localized to the mesenchyme surrounding the developing airways, supporting a role for elastin in airway branching. Thus, in addition to its role in the structure and function of the mature lung, elastin is essential for pulmonary development and is important for terminal airway branching.


Subject(s)
Gene Expression Regulation, Developmental/physiology , Pulmonary Alveoli/abnormalities , Pulmonary Alveoli/embryology , Tropoelastin/genetics , Actins/analysis , Animals , Animals, Newborn , Mesoderm/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Pulmonary Alveoli/chemistry , Tropoelastin/analysis
14.
Pediatr Res ; 48(1): 64-74, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10879802

ABSTRACT

Chronic lung disease of early infancy, or bronchopulmonary dysplasia, is a frequent complication of prolonged mechanical ventilation after premature birth. Pulmonary hypertension and edema are common features of this condition, which is often attributed to long-term, repetitive overinflation of incompletely developed lungs. The overall objective of this work was to examine the effects on the pulmonary circulation and lung fluid balance of different ventilation strategies using large versus small inflation volumes in an animal model of bronchopulmonary dysplasia. We studied 16 newborn lambs that were delivered prematurely (124+/-3 d gestation, term = 147 d) by cesarean section and mechanically ventilated for 3 to 4 wk. Ten lambs were ventilated at 20 breaths/min, yielding a tidal volume of 15+/-5 mL/kg, and six lambs were ventilated at 60 breaths/min, yielding a tidal volume of 6+/-2 mL/kg. All lambs received surfactant at birth and had subsequent surgery for closure of the ductus arteriosus and catheter placement to allow serial measurements of pulmonary vascular resistance and lung lymph flow. Chronic lung injury, documented by serial chest radiographs and postmortem pathologic examination, developed in all lambs irrespective of the pattern of assisted ventilation. Pulmonary vascular resistance, which normally decreases during the month after birth at term, did not change significantly from the first to the last week of study. Lung lymph flow, an index of net transvascular fluid filtration, increased with time in lambs that were ventilated at 20 breaths/min, but not in lambs ventilated at 60 breaths/min. Lymph protein concentration decreased with time, indicative of increased fluid filtration pressure, without evidence of a change in lung vascular protein permeability. Postmortem studies showed interstitial lung edema, increased pulmonary arteriolar smooth muscle and elastin, decreased numbers of small pulmonary arteries and veins, and decreased capillary surface density in distal lung of chronically ventilated lambs compared with control lambs that were killed either 1 d (same postconceptional age) or 3 wk (same postnatal age) after birth at term. Thus, chronic lung injury from prolonged mechanical ventilation after premature birth inhibits the normal postnatal decrease in pulmonary vascular resistance and leads to lung edema from increased fluid filtration pressure. These abnormalities of the pulmonary circulation may contribute to the abnormal respiratory gas exchange that often exists in infants with bronchopulmonary dysplasia.


Subject(s)
Bronchopulmonary Dysplasia/physiopathology , Lung/pathology , Lung/physiopathology , Pulmonary Circulation/physiology , Respiratory Mechanics/physiology , Animals , Animals, Newborn , Bronchopulmonary Dysplasia/pathology , Cesarean Section , Disease Models, Animal , Female , Humans , Infant, Newborn , Infant, Premature , Lung/embryology , Pregnancy , Respiration, Artificial , Sheep , Tidal Volume
15.
Thorax ; 55(2): 167-9, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10639537

ABSTRACT

A case of high altitude pulmonary oedema (HAPE) in a climber who made a rapid ascent on Mt McKinley (Denali), Alaska is described. The bronchoalveolar lavage (BAL) fluid contained increased numbers of red blood cells and an abundance of haemosiderin laden macrophages consistent with alveolar haemorrhage. The timing of this finding indicates that alveolar haemorrhage began early during the ascent, well before the onset of symptoms. Although evidence of alveolar haemorrhage has been reported at necropsy in individuals dying of HAPE, previous reports have not shown the same abundance of haemosiderin laden macrophages in the BAL fluid. These findings suggest that alveolar haemorrhage is an early event in HAPE.


Subject(s)
Altitude Sickness/complications , Hemorrhage/etiology , Pulmonary Alveoli/blood supply , Pulmonary Edema/etiology , Adult , Altitude Sickness/pathology , Bronchoalveolar Lavage Fluid , Erythrocyte Count , Hemorrhage/diagnosis , Hemosiderin , Humans , Macrophages, Alveolar , Male , Pulmonary Edema/pathology
16.
J Pediatr ; 136(4): 466-72, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10753244

ABSTRACT

BACKGROUND: The acute disappearance of neutrophils from the circulation can be associated with pulmonary leukostasis, lung injury, and respiratory distress. OBJECTIVE: To determine whether a low concentration of mature neutrophils in the peripheral blood soon after birth is associated with an increase in subsequent respiratory distress in premature infants. DESIGN: A cohort study performed by chart review at a tertiary medical center. SUBJECTS: Premature infants (birth weight 500 to 1250 g) who had a complete blood count obtained within 2 hours of delivery (n = 237). Patients in the lowest quartile of mature neutrophil concentrations (early neutropenia, < or =0.90 x 10(9) neutrophils/L blood) were compared with patients in the remaining 3 quartiles (control group). RESULTS: Low neutrophil concentrations were transient in the early neutropenia group. The concentration of mature circulating neutrophils rose from 0.49 +/- 0.25 x 10(9) cells/L at an average of 1 hour after delivery to 2.8 +/- 2.2 x 10(9) cells/L within 6 to 8 hours in the early neutropenia group and from 4.6 +/- 4.8 x 10(9) cells/L to 8.2 +/- 8. 0 x 10(9) cells/L in the control group during the same time period. Respiratory support immediately after birth was similar in both groups of infants, but by 12 hours patients who had early neutropenia required significantly greater inflation pressures and concentrations of inspired oxygen. By 1 week after birth patients who had early neutropenia were more likely to require mechanical ventilation and supplemental oxygen. Pulmonary interstitial emphysema, serious intraventricular hemorrhage, and chronic lung disease occurred more frequently in patients with early neutropenia. CONCLUSION: A low concentration of mature neutrophils in the systemic circulation of premature infants within 2 hours of birth is associated with more severe respiratory distress during the first postnatal week and with an increased risk of serious complications of prematurity.


Subject(s)
Neutrophils/cytology , Respiratory Distress Syndrome, Newborn/blood , Chi-Square Distribution , Cohort Studies , Female , Humans , Infant, Newborn , Infant, Premature , Leukocyte Count , Lung/pathology , Male , Neutropenia/blood , Neutropenia/pathology , Neutropenia/therapy , Respiratory Distress Syndrome, Newborn/pathology , Respiratory Distress Syndrome, Newborn/therapy , Risk Factors , Statistics, Nonparametric , Time Factors
19.
Blood ; 94(2): 600-9, 1999 Jul 15.
Article in English | MEDLINE | ID: mdl-10397727

ABSTRACT

Decreased adhesion of neutrophils to endothelial cells and delayed transendothelial cell migration of neutrophils have been consistently reported in neonatal animals and humans and contribute to their susceptibility to infection. The delayed transmigration of neutrophils is especially prevalent in premature neonates. To define the nature of this defect, we used an in vivo animal model of inflammation and found that radiolabeled leukocytes from adult rats transmigrated into the peritoneum of other adult rats 5 times more efficiently than they did in neonatal rats (P =.05). This indicated that defects in neonatal neutrophils could not completely account for the delayed transmigration. Delayed transmigration in the neonatal rats correlated with a defect in the expression of P-selectin on the surface of their endothelial cells. We found a similar P-selectin deficiency in endothelial cells lining mesenteric venules and umbilical veins of human premature infants when compared with term human infants. The decreased P-selectin in premature infants was associated with decreased numbers of P-selectin storage granules and decreased P-selectin transcription. Decreased P-selectin expression on the surface of endothelial cells in preterm infants may contribute to delayed neutrophil transmigration and increased susceptibility to infection.


Subject(s)
Endothelium, Vascular/metabolism , Infant, Premature/metabolism , P-Selectin/biosynthesis , Animals , Animals, Newborn , Cell Adhesion , Disease Susceptibility , Diseases in Twins , Fetal Death/pathology , Fetus/pathology , Gene Expression Regulation, Developmental , Gestational Age , Humans , Infant, Newborn , Infant, Premature/immunology , Infections/etiology , Intercellular Adhesion Molecule-1/analysis , Mesenteric Veins/chemistry , Neutrophils/cytology , P-Selectin/genetics , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley , Twins, Conjoined , Umbilical Veins/chemistry , von Willebrand Factor/analysis
20.
Am J Respir Crit Care Med ; 159(3): 945-58, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10051278

ABSTRACT

The cause of chronic lung disease of early infancy, often called bronchopulmonary dysplasia (BPD), remains unclear, partly because large-animal models that reliably reproduce BPD have not been available. We developed a model of BPD in lambs that are delivered prematurely and ventilated for 3 to 4 wk after birth to determine whether the histopathology of chronic lung injury in premature lambs mimics that which occurs in preterm infants who die with BPD, and to compare two ventilation strategies to test the hypothesis that differences in tidal volume (VT) influence histopathologic outcome. The two ventilation strategies were slow, deep ventilation (20 breaths/min, 15 +/- 2 ml/kg body weight VT; n = 5) or rapid, shallow ventilation (60 breaths/min, 6 +/- 1 ml/kg body weight VT; n = 5). Lambs were delivered at 125 +/- 4 d gestation (term = 147 d), treated with surfactant, and mechanically ventilated with sufficient supplemental oxygen to maintain normal arterial oxygenation (60 to 90 mm Hg). Quantitative histologic analysis revealed lung structural abnormalities for both groups of experimental lambs compared with lungs of control term lambs that were < 1 d old (matched for developmental age; n = 5) or 3 to 4 wk old (matched for postnatal age; n = 5). Compared with control lambs, chronically ventilated preterm lambs had pulmonary histopathology characterized by nonuniform inflation patterns, impaired alveolar formation, abnormal abundance of elastin, increased muscularization of terminal bronchioles, and inflammation and edema. Slow, deep ventilation was associated with less atelectasis, less alveolar formation, and more elastin when compared with rapid, shallow ventilation. We conclude that prolonged mechanical ventilation of preterm lambs disrupts lung development and produces pulmonary histopathologic changes that are very similar to those that are seen in the lungs of preterm infants who die with BPD. This chronic lung disease is not prevented by surfactant replacement at birth, does not appear to require arterial hyperoxia, and is influenced by VT.


Subject(s)
Bronchopulmonary Dysplasia/pathology , Animals , Animals, Newborn , Bronchopulmonary Dysplasia/etiology , Bronchopulmonary Dysplasia/therapy , Extracellular Matrix/pathology , Gestational Age , Humans , Infant, Newborn , Lung/pathology , Respiration, Artificial/adverse effects , Respiration, Artificial/methods , Sheep
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