transforming-growth-factor-beta and Infant--Newborn--Diseases

Necrotizing enterocolitis (NEC) yet remains a leading cause of morbidity and mortality in premature infants. The developmental deficiency of transforming growth factor-Beta (TGF-β) in the intestine is a risk factor for NEC in premature infants.We aimed to investigate the potential utility of serum TGF-β1 in the early diagnosis and severity assessment of NEC. This prospective case-control study was conducted on 102 VLBW neonates aging less than 32 weeks and weighing less than 1500 gm. They were divided into NEC group of 52 preterm neonates with symptoms and signs of NEC and 50 age and sex-matched neonates without NEC as a control group. All neonates underwent full medical history taking, clinical examination, radiological and laboratory investigations including CBC, CRP, fecal occult blood, and serum TGF-β1. Serum TGF-β1 was tested in NEC patients at the onset of symptoms and signs and 7 days later. Serum TGF-β1 was significantly lower in NEC patients at the onset of symptoms than the control group (P = 0.004) while after 7 days of onset serum TGF-β1 was significantly higher than at the onset of symptoms (P < 0.001). In NEC patients with stage I, TGF-β1 was significantly higher than in NEC patients with stage ≥II (P = 0.027).In conclusion serum TGF-β1 is downregulated in neonatal necrotizing enterocolitis and can be used as a useful biomarker for early diagnosis of NEC and to assess disease severity.

Topics: Case-Control Studies; Enterocolitis, Necrotizing; Female; Fetal Diseases; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature; Transforming Growth Factor beta; Transforming Growth Factor beta1

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in children worldwide. The understanding of neonatal RSV pathogenesis depends on using an animal model that reproduces neonatal RSV disease. Previous studies from us and others demonstrated that the neonatal lamb model resembles human neonatal RSV infection. Here, we provide an extensive and detailed characterization of the histopathology, viral load, cellular infiltration, and cytokine production in lungs and tracheobronchial lymph nodes of lambs inoculated with human RSV strain A2 over the course of infection. In the lung, RSV titers were low at day 3 postinfection, increased significantly by day 6, and decreased to baseline levels at day 14. Infection in the lung was associated with an accumulation of macrophages, CD4(+) and CD8(+) T cells, and a transcriptional response of genes involved in inflammation, chemotaxis, and interferon response, characterized by increased IFNγ, IL-8, MCP-1, and PD-L1, and decreased IFNβ, IL-10, and TGF-β. Laser capture microdissection studies determined that lung macrophage-enriched populations were the source of MCP-1 but not IL-8. Immunoreactivity to caspase 3 occurred within bronchioles and alveoli of day 6-infected lambs. In lung-draining lymph nodes, RSV induced lymphoid hyperplasia, suggesting an ability of RSV to enhance lymphocytic proliferation and differentiation pathways. This study suggests that, in lambs with moderate clinical disease, RSV enhances the activation of caspase cell death and Th1-skewed inflammatory pathways, and complements previous observations that emphasize the role of inflammation in the pathogenesis of RSV disease.

Topics: Animals; Animals, Newborn; Child; Humans; Infant, Newborn; Infant, Newborn, Diseases; Inflammation; Interleukin-8; Lung; Macrophages; Receptors, CCR2; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Sheep; Transcription, Genetic; Transforming Growth Factor beta

There is no effective intervention to prevent or treat bronchopulmonary dysplasia (BPD). Curcumin has potent antioxidant and anti-inflammatory properties, and it modulates signaling of peroxisome proliferator-activated receptor-γ (PPARγ), an important molecule in the pathobiology of BPD. However, its role in the prevention of BPD is not known. We determined 1) if curcumin enhances neonatal lung maturation, 2) if curcumin protects against hyperoxia-induced neonatal lung injury, and 3) if this protection is mediated by blocking TGF-β. Embryonic day 19 fetal rat lung fibroblasts were exposed to 21% or 95% O(2) for 24 h following 1 h of treatment with curcumin. Curcumin dose dependently accelerated e19 fibroblast differentiation [increased parathyroid hormone-related protein (PTHrP) receptor, PPARγ, and adipocyte differentiation-related protein (ADRP) levels and triolein uptake] and proliferation (increased thymidine incorporation). Pretreatment with curcumin blocked the hyperoxia-induced decrease (PPARγ and ADRP) and increase (α-smooth muscle actin and fibronectin) in markers of lung injury/repair, as well as the activation of TGF-β signaling. In a separate set of experiments, neonatal Sprague-Dawley rat pups were exposed to 21% or 95% O(2) for 7 days with or without intraperitoneal administration of curcumin. Analysis for markers of lung injury/repair [PTHrP receptor, PPARγ, ADRP, fibronectin, TGF-β receptor (activin receptor-like kinase 5), and Smad3] and lung morphology (radial alveolar count) demonstrated that curcumin effectively blocks TGF-β activation and hyperoxia-induced lung injury. Therefore, curcumin accelerates lung maturation by stimulating key alveolar epithelial-mesenchymal interactions and prevents hyperoxia-induced neonatal lung injury, possibly by blocking TGF-β activation, suggesting that it is a potential intervention against BPD.

Topics: Animals; Animals, Newborn; Blotting, Western; Bronchopulmonary Dysplasia; Cell Differentiation; Curcumin; Female; Fibroblasts; Gene Expression Regulation; Humans; Hyperoxia; Infant, Newborn; Infant, Newborn, Diseases; Lung; Parathyroid Hormone-Related Protein; Peroxisome Proliferator-Activated Receptors; PPAR gamma; Pregnancy; Rats; Rats, Sprague-Dawley; Receptor, Parathyroid Hormone, Type 1; Signal Transduction; Transforming Growth Factor beta

The expression of neuron-type glutamate transporters (EAAC-1), AMPA glutamate receptor subunits (GluR1 and GluR2/3), polyadenosine (5'diphosphate-ribose) polymerase (PARP), and transforming growth factor-beta1 was investigated in 20 cases of neonatal pontosubicular neuron necrosis and 12 gestational-age matched controls. Developmental immunoreactivities of EAAC-1, GluR1, and GluR2/3 appeared in the neurons of the pontine nuclei at 29 to 30 weeks' gestation in controls, and then gradually increased with age. However, these activities were decreased in the pontine nucleus of patients with pontosubicular neuron necrosis. Decreases in these immunoreactivities might indicate early degeneration of neurons. Although PARP and transforming growth factor-beta1 immunoreactivity was insignificant or very weak in the pontine nuclei at any age in controls, PARP was markedly expressed in karyorrhectic neurons of the pontine nucleus in patients with pontosubicular neuron necrosis. Transforming growth factor-beta1 immunoreactivity was observed in nonkaryorrhectic neurons of the pontine nuclei. PARP could contribute to the pathogenesis of pontosubicular neuron necrosis more than EAAC-1 or GluR1 or GluR2/3. Transforming growth factor-beta1 could play a role in the protection and repair of damaged neurons.

Topics: Amino Acid Transport System X-AG; Apoptosis; ATP-Binding Cassette Transporters; Brain Stem Hemorrhage, Traumatic; Case-Control Studies; Enzyme Activation; Female; Gene Expression; Gestational Age; Humans; Immunoblotting; Immunohistochemistry; Infant, Newborn; Infant, Newborn, Diseases; Male; Necrosis; Neurons; Poly(ADP-ribose) Polymerases; Receptors, AMPA; Survival Analysis; Transforming Growth Factor beta

Biliary atresia and paucity of intrahepatic bile ducts are the main causes of neonatal cholestasis leading to hepatic fibrosis. Fibrotic evolution is slow in paucity of bile ducts as compared to the rapid progression to biliary cirrhosis in biliary atresia when cholestasis persists despite hepatoportoenterostomy. Our aim was to compare the expression of collagens type I and IV, alpha-smooth muscle actin, osteonectin and transforming growth factor beta1 in biliary atresia and paucity of bile ducts.. Liver biopsies were obtained in 12 children with biliary atresia and in five with paucity of bile ducts. Collagens type I and IV, alpha-smooth muscle actin were detected with immunostaining. Collagens type I and IV, osteonectin and transforming growth factor beta1 mRNAs were detected by in situ hybridization.. Expression of mRNA and proteins was roughly parallel. In ductular proliferation areas of biliary atresia: (1) the expression of collagens type I and IV and osteonectin was increased, and was localized to periductular myofibroblasts; (2) transforming growth factor beta1 was expressed around biliary ductules, probably in inflammatory cells, and also in biliary cells. Osteonectin expression was also increased in the lobules. In paucity of bile ducts, there was no overexpression of collagens type I and IV and transforming growth factor beta1, except in the only child with marked fibrosis. However, osteonectin expression was enhanced at the periphery of the lobules, even when fibrosis was mild or absent.. These findings suggest that in biliary atresia ductular proliferation areas are the site of a marked production of extracellular matrix proteins in periductular myofibroblasts, probably secondary to transforming growth factor beta1 production by inflammatory cells and by biliary cells. The weak expression of transforming growth factor beta1 could explain the slow progression of fibrosis in paucity of bile ducts.

Topics: Actins; Bile Duct Diseases; Bile Ducts, Intrahepatic; Biliary Atresia; Collagen; Female; Humans; Immunohistochemistry; In Situ Hybridization; Infant; Infant, Newborn; Infant, Newborn, Diseases; Male; Muscle, Smooth, Vascular; Osteonectin; RNA, Messenger; Transforming Growth Factor beta