fibrin and Bronchopulmonary-Dysplasia

Preeclampsia is a devastating medical complication of pregnancy that can lead to significant maternal and fetal morbidity and mortality. It is currently believed that there is abnormal placentation in as early as the first trimester in women destined to develop preeclampsia. Although the etiology of the abnormal placentation is being debated, numerous epidemiologic and experimental studies suggest that imbalances in circulating angiogenic factors released from the placenta are responsible for the maternal signs and symptoms of preeclampsia. In particular, circulating levels of soluble fms-like tyrosine kinase 1, an antiangiogenic factor, are markedly increased in women with preeclampsia, whereas free levels of its ligand, placental, growth factor are markedly diminished. Alterations in these angiogenic factors precede the onset of clinical signs of preeclampsia and correlate with disease severity. Recently, the availability of automated assays for the measurement of angiogenic biomarkers in the plasma, serum, and urine has helped investigators worldwide to demonstrate a key role for these factors in the clinical diagnosis and prediction of preeclampsia. Numerous studies have reported that circulating angiogenic biomarkers have a very high negative predictive value to rule out clinical disease among women with suspected preeclampsia. These blood-based biomarkers have provided a valuable tool to clinicians to accelerate the time to clinical diagnosis and minimize maternal adverse outcomes in women with preeclampsia. Angiogenic biomarkers have also been useful to elucidate the pathogenesis of related disorders of abnormal placentation such as intrauterine growth restriction, intrauterine fetal death, twin-to-twin transfusion syndrome, and fetal hydrops. In summary, the discovery and characterization of angiogenic proteins of placental origin have provided clinicians a noninvasive blood-based tool to monitor placental function and health and for early detection of disorders of placentation. Uncovering the mechanisms of altered angiogenic factors in preeclampsia and related disorders of placentation may provide insights into novel preventive and therapeutic options.

Topics: Biomarkers; Bronchopulmonary Dysplasia; Cardiovascular Diseases; Female; Fetal Death; Fetofetal Transfusion; Fibrin; Humans; Hydrops Fetalis; Placenta Diseases; Placenta Growth Factor; Placentation; Pre-Eclampsia; Pregnancy; Prognosis; Puerperal Disorders; Up-Regulation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Because therapeutic options are lacking for bronchopulmonary dysplasia (BPD), there is an urgent medical need to discover novel targets/drugs to treat this neonatal chronic lung disease. Metformin, a drug commonly used to lower blood glucose in type 2 diabetes patients, may be a novel therapeutic option for BPD by reducing pulmonary inflammation and fibrosis and improving vascularization. We investigated the therapeutic potential of daily treatment with 25 and 100 mg/kg metformin, injected subcutaneously in neonatal Wistar rats with severe experimental BPD, induced by continuous exposure to 100% oxygen for 10 days. Parameters investigated included survival, lung and heart histopathology, pulmonary fibrin and collagen deposition, vascular leakage, right ventricular hypertrophy, and differential mRNA expression in the lungs of key genes involved in BPD pathogenesis, including inflammation, coagulation, and alveolar development. After daily metformin treatment rat pups with experimental BPD had reduced mortality, alveolar septum thickness, lung inflammation, and fibrosis, demonstrated by a reduced influx of macrophages and neutrophils and hyperoxia-induced collagen III and fibrin deposition (25 mg/kg), as well as improved vascularization (100 mg/kg) compared with control treatment. However, metformin did not ameliorate alveolar enlargement, small arteriole wall thickening, vascular alveolar leakage, and right ventricular hypertrophy. In conclusion metformin prolongs survival and attenuates pulmonary injury by reducing pulmonary inflammation, coagulation, and fibrosis but does not affect alveolar development or prevent pulmonary arterial hypertension and right ventricular hypertrophy in neonatal rats with severe hyperoxia-induced experimental BPD.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents; Bronchopulmonary Dysplasia; Capillary Permeability; Collagen; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Elastin; Fibrin; Gene Expression; Hypertrophy, Right Ventricular; Lung; Metformin; Rats, Wistar

Intervening in angiotensin (Ang)-II type 2 receptor (AT2) signaling may have therapeutic potential for bronchopulmonary dysplasia (BPD) by attenuating lung inflammation and preventing arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). We first investigated the role of AT2 inhibition with PD123319 (0.5 and 2 mg·kg(-1)·day(-1)) on the beneficial effect of AT2 agonist LP2-3 (5 μg/kg twice a day) on RVH in newborn rats with hyperoxia-induced BPD. Next we determined the cardiopulmonary effects of PD123319 (0.1 mg·kg(-1)·day(-1)) in two models: early treatment during continuous exposure to hyperoxia for 10 days and late treatment starting on day 6 in rat pups exposed postnatally to hyperoxia for 9 days, followed by a 9-day recovery period in room air. Parameters investigated included lung and heart histopathology, fibrin deposition, vascular leakage, and differential mRNA expression. Ten days of coadministration of LP2-3 and PD123319 abolished the beneficial effects of LP2-3 on RVH in experimental BPD. In the early treatment model PD123319 attenuated cardiopulmonary injury by reducing alveolar septal thickness, pulmonary influx of inflammatory cells, including macrophages and neutrophils, medial wall thickness of small arterioles, and extravascular collagen III deposition, and by preventing RVH. In the late treatment model PD123319 diminished PAH and RVH, demonstrating that PAH is reversible in the neonatal period. At high concentrations PD123319 blocks the beneficial effects of the AT2-agonist LP2-3 on RVH. At low concentrations PD123319 attenuates cardiopulmonary injury by reducing pulmonary inflammation and fibrosis and preventing PAH-induced RVH but does not affect alveolar and vascular development in newborn rats with experimental BPD.

Topics: Angiotensin II Type 2 Receptor Blockers; Animals; Animals, Newborn; Bronchopulmonary Dysplasia; Fibrin; Heart Injuries; Hyperoxia; Hypertrophy, Right Ventricular; Imidazoles; Ligands; Lung Injury; Pneumonia; Pulmonary Alveoli; Pyridines; Rats; Rats, Wistar; Receptor, Angiotensin, Type 2

Preterm infants exposed to oxygen and mechanical ventilation are at risk for bronchopulmonary dysplasia (BPD), a multifactorial chronic lung disorder characterized by arrested alveolar development and nonsprouting, dysmorphic microvascular angiogenesis. The molecular regulation of this BPD-associated pathological angiogenesis remains incompletely understood. In this study, the authors used focused microarray technology to characterize the angiogenic gene expression profile in postmortem lung samples from short-term ventilated preterm infants (born at 24 to 27 weeks' gestation) and age-matched control infants. Microarray analysis identified differential expression of 13 of 112 angiogenesis-related genes. Genes significantly up-regulated in ventilated lungs included the antiangiogenic genes thrombospondin-1, collagen XVIII alpha-1, and tissue inhibitor of metalloproteinase-1 (TIMP1), as well as endoglin, transforming growth factor-alpha, and monocyte chemoattractant protein-1 (CCL2). Increased expression of thrombospondin-1 in ventilated lungs was verified by real-time polymerase chain reaction (PCR) and immunolocalized primarily to intravascular platelets and fibrin aggregates. Down-regulated genes included proangiogenic angiogenin and midkine, as well as vascular endothelial growth factor (VEGF)-B, VEGF receptor-2, and the angiopoietin receptor TEK/Tie-2. In conclusion, short-term ventilated lungs show a shift from traditional angiogenic growth factors to alternative, often antisprouting regulators. This angiogenic shift may be implicated in the regulation of dysmorphic angiogenesis and, consequently, deficient alveolarization characteristic of infants with BPD.

Topics: Antigens, CD; Blood Platelets; Bronchopulmonary Dysplasia; Chemokine CCL2; Chronic Disease; Collagen Type XVIII; Down-Regulation; Endoglin; Female; Fibrin; Gene Expression Profiling; Humans; Infant, Newborn; Infant, Premature; Lung; Male; Neovascularization, Physiologic; Receptor, TIE-2; Receptors, Cell Surface; Respiration, Artificial; Retrospective Studies; Thrombospondin 1; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor alpha; Up-Regulation; Vascular Endothelial Growth Factor B

Topics: Administration, Inhalation; Animals; Birth Weight; Bronchopulmonary Dysplasia; Clinical Trials as Topic; Fibrin; Humans; Infant, Newborn; Lung; Nitric Oxide

Oxidative stress is an important factor in the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants characterized by arrested alveolar and vascular development of the immature lung. We investigated differential gene expression with DNA microarray analysis in premature rat lungs exposed to prolonged hyperoxia during the saccular stage of development, which closely resembles the development of the lungs of premature infants receiving neonatal intensive care. Expression profiles were largely confirmed by real-time RT-PCR (27 genes) and in line with histopathology and fibrin deposition studied by Western blotting. Oxidative stress affected a complex orchestra of genes involved in inflammation, coagulation, fibrinolysis, extracellular matrix turnover, cell cycle, signal transduction, and alveolar enlargement and explains, at least in part, the pathological alterations that occur in lungs developing BPD. Exciting findings were the magnitude of fibrin deposition; the upregulation of chemokine-induced neutrophilic chemoattractant-1 (CINC-1), monocyte chemoattractant protein-1 (MCP-1), amphiregulin, plasminogen activator inhibitor-1 (PAI-1), secretory leukocyte proteinase inhibitor (SLPI), matrix metalloproteinase-12 (MMP12), p21, metallothionein, and heme oxygenase (HO); and the downregulation of fibroblast growth factor receptor-4 (FGFR4) and vascular endothelial growth factor (VEGF) receptor-2 (Flk-1). These findings are not only of fundamental importance in the understanding of the pathophysiology of BPD, but also essential for the development of new therapeutic strategies.

Topics: Animals; Animals, Newborn; Blood Coagulation Factors; Bronchopulmonary Dysplasia; Extracellular Matrix; Fibrin; Fibrinolysis; Gene Expression Profiling; Humans; Infant, Newborn; Inflammation; Lung; Oxidative Stress; Rats; Receptor, Fibroblast Growth Factor, Type 4; Receptors, Fibroblast Growth Factor; RNA, Messenger; Signal Transduction; Vascular Endothelial Growth Factor Receptor-2

Lung injury induced by 100% O2 over 6 days is characterized by markedly less alveolar fibrin and rare hyaline membranes in premature versus adult baboons. To determine the mechanism(s) underlying alveolar fibrin deposition in the evolution of hyaline membrane disease (HMD) through diffuse alveolar damage (DAD) and bronchopulmonary dysplasia (BPD), we measured procoagulant and fibrinolytic activities in lung lavage of premature baboons with HMD, those treated with 100% O2 for 6 days (DAD) or for 7 days followed by 14 days 80% O2 (BPD). Lavage procoagulant activity, mainly due to tissue factor associated with Factor VII, was increased by hyperoxia. Plasminogen-dependent fibrinolytic activity, due to both tissue plasminogen activator and urokinase, was stable or increased after hyperoxia. Plasminogen activator inhibitor 1 (PAI-1) was detectable in lavage of animals with HMD but not those with evolving DAD or BPD. Antiplasmin activity was stable or decreased. Although plasminogen was undetectable in lavage, D-dimer was increased in lavage of the groups exposed to hyperoxia versus HMD. The defect in plasminogen activator activity in lavage fluids of adult baboons with DAD induced by O2 does not occur in premature baboons with HMD, evolving DAD, or BPD. Expression of fibrinolytic activity in the lower respiratory tract of premature baboons is dependent on local access to plasminogen, which is present in relatively low concentrations in plasma of these animals.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Factor VII; Fibrin; Fibrinolysis; Humans; Hyaline Membrane Disease; Infant, Newborn; Male; Oxygen; Papio; Plasminogen Activator Inhibitor 1; Respiration, Artificial; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator

Premature infants who have self-limited respiratory distress syndrome (RDS) rapidly improve, whereas infants with a complicated respiratory course are more likely to develop bronchopulmonary dysplasia (BPD), a chronic lung disorder that is the result of prolonged lung injury and impaired healing. The balance of competing activities of coagulation and fibrinolysis may contribute to the premature lung's response to acute injury and determine, in part, whether there is early resolution or protracted alveolar inflammation. To determine the relative activities of the coagulation and fibrinolytic pathways in neonatal lung injury, procoagulant (PC) and plasminogen activator (PA) activities were measured in undiluted cell-free lung lavage samples obtained serially over the first 28 days of life from 11 infants with self-limited RDS, 11 infants with evolving BPD, and 5 mechanically ventilated control infants without lung disease. Lung lavage from all three groups contained readily detectable procoagulant activity due mainly to the tissue factor-Factor VII complex. Plasminogen activator activity was relatively high in control lavage samples but depressed on the first day of life in the two groups of infants with lung disease: median, 0.3814 IU/ml (control); 0.0541 IU/ml (RDS); and 0.0454 IU/ml (BPD), p < 0.05 in each case compared with control. Two infants with severe lung disease had no detectable plasminogen activator activity in lung lavage on the first day of life. Depressed fibrinolytic activity correlated with severity of lung disease assessed radiographically and by pulmonary function measurements. Plasminogen activator activity was due to both tissue plasminogen activator and urokinase.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Apgar Score; Baltimore; Birth Weight; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Evaluation Studies as Topic; Female; Fibrin; Fibrinolysis; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Intensive Care Units, Neonatal; Male; Plasminogen Activator Inhibitor 1; Plasminogen Activator Inhibitor 2; Predictive Value of Tests; Respiratory Distress Syndrome, Newborn; Risk Factors; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator