elastin and Premature-Birth

The aim of this review was to identify the underlying relationship between preterm birth and the development of cardiovascular diseases. Preterm birth significantly affects the elastin content and viscoelastic properties of the vascular extracellular matrix in human arteries. Inadequate elastin synthesis during early development may cause a permanent increase in arterial stiffness in adulthood.. Early and permanent alterations in viscoelastic properties may lead to hypertension and cardiovascular disease development in adults born prematurely.

Topics: Adaptation, Physiological; Aorta; Elastin; Humans; Hypertension; Premature Birth; Vascular Stiffness

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that occurs in very premature infants and is characterized by impaired alveologenesis. This ultimate phase of lung development is mostly postnatal and allows growth of gas-exchange surface area to meet the needs of the organism. Alveologenesis is a highly integrated process that implies cooperative interactions between interstitial, epithelial, and vascular compartments of the lung. Understanding of its underlying mechanisms has considerably progressed recently with identification of structural, signaling, or remodeling molecules that are crucial in the process. Thus, the pivotal role of elastin deposition in lung walls has been demonstrated, and many key control-molecules have been identified, including various transcription factors, growth factors such as platelet-derived growth factor, fibroblast growth factors, and vascular endothelial growth factor, matrix-remodeling enzymes, and retinoids. BPD-associated changes in lung expression/content have been evidenced for most of these molecules, especially for signaling pathways, through both clinical investigations in premature infants and the use of animal models, including the premature baboon or lamb, neonatal exposure to hyperoxia in rodents, and maternal-fetal infection. These findings open therapeutic perspectives to correct imbalanced signaling. Unraveling the intimate molecular mechanisms of alveolar building appears as a prerequisite to define new strategies for the prevention and care of BPD.

Topics: Animals; Bronchopulmonary Dysplasia; Cell Differentiation; Cell Proliferation; Elastin; Fibroblast Growth Factors; Humans; Hypoxia; Infant, Newborn; Lung; Models, Biological; Platelet-Derived Growth Factor; Premature Birth; Pulmonary Alveoli; Pulmonary Gas Exchange; Retinoids; Signal Transduction; Vascular Endothelial Growth Factor A

Extremely preterm infants often receive mechanical ventilation (MV), which can contribute to bronchopulmonary dysplasia (BPD). However, the effects of MV alone on the extremely preterm lung and the lung's capacity for repair are poorly understood.. To characterise lung injury induced by MV alone, and mechanisms of injury and repair, in extremely preterm lungs and to compare them with very preterm lungs.. Extremely preterm lambs (0.75 of term) were transiently exposed by hysterotomy and underwent 2 h of injurious MV. Lungs were collected 24 h and at 15 d after MV. Immunohistochemistry and morphometry were used to characterise injury and repair processes. qRT-PCR was performed on extremely and very preterm (0.85 of term) lungs 24 h after MV to assess molecular injury and repair responses.. 24 h after MV at 0.75 of term, lung parenchyma and bronchioles were severely injured; tissue space and myofibroblast density were increased, collagen and elastin fibres were deformed and secondary crest density was reduced. Bronchioles contained debris and their epithelium was injured and thickened. 24 h after MV at 0.75 and 0.85 of term, mRNA expression of potential mediators of lung repair were significantly increased. By 15 days after MV, most lung injury had resolved without treatment.. Extremely immature lungs, particularly bronchioles, are severely injured by 2 h of MV. In the absence of continued ventilation these injured lungs are capable of repair. At 24 h after MV, genes associated with injurious MV are unaltered, while potential repair genes are activated in both extremely and very preterm lungs.

Topics: Animals; Blood Gas Analysis; Body Weight; Bronchioles; Cell Proliferation; Collagen; DNA; Elastin; Electrolytes; Fetal Blood; Gene Expression Regulation, Developmental; Lung; Myofibroblasts; Necrosis; Organ Size; Premature Birth; Respiration, Artificial; RNA, Messenger; Ventilator-Induced Lung Injury; Wound Healing

Preterm birth affects 8-12% of live births and is associated with the development of elevated arterial blood pressure and aortic narrowing in later life; this suggests that preterm birth may alter the development of arteries. Our objective was to determine the effects of preterm birth, accompanied by antenatal corticosteroid administration, on the structure of the aorta and pulmonary artery, which experience different alterations in pressure flow at birth.. At 11 wk, preterm lambs had significantly thicker aortic walls and a smaller lumen, whereas the morphometry of the pulmonary artery was unaffected. Elastin deposition was markedly increased in the aorta and pulmonary artery and smooth muscle content was reduced in the aorta only. In preterm lambs we found injury in the aorta only; controls were unaffected.. We conclude that moderate preterm birth after antenatal betamethasone can cause injury and persistent alterations in the structure and composition of the aorta, with lesser effects in the pulmonary artery. Our findings suggest that preterm birth may increase the risk of atherosclerosis and aortic aneurysms in later life.. Using an established ovine model of preterm birth, lambs were born at 0.9 of gestation and underwent necropsy at 11 wk after birth; controls were born at term.

Topics: Adrenal Cortex Hormones; Androstenols; Animals; Aorta; Betamethasone; Cardiovascular Diseases; Collagen; Disease Models, Animal; Drug Administration Schedule; Elastin; Female; Gestational Age; Pregnancy; Premature Birth; Pulmonary Artery; Sheep

Mechanical ventilation (MV) of very premature infants contributes to lung injury and bronchopulmonary dysplasia (BPD), the effects of which can be long-lasting. Little is currently known about the ability of the very immature lung to recover from ventilator-induced lung injury. Our objective was to determine the ability of the injured very immature lung to repair in the absence of continued ventilation and to identify potential mechanisms. At 125 days gestational age (days GA, 0.85 of term), fetal sheep were partially exposed by hysterotomy under anesthesia and aseptic conditions; they were intubated and ventilated for 2 h with an injurious MV protocol and then returned to the uterus to continue development. Necropsy was performed at either 1 day (short-term group, 126 days GA, n = 6) or 15 days (long-term group, 140 days GA, n = 5) after MV; controls were unventilated (n = 7-8). At 1 day after MV, lungs displayed signs of injury, including hemorrhage, disorganized elastin and collagen deposition in the distal airspaces, altered morphology, significantly reduced secondary septal crest density, and decreased airspace. Bronchioles had thickened epithelium with evidence of injury and sloughing. Relative mRNA levels of early response genes (connective tissue growth factor, cysteine-rich 61, and early growth response-1) and proinflammatory cytokines [interleukins (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, and transforming growth factor-β] were not different between groups 1 day after MV. At 15 days after MV, lung structure was normal with no evidence of injury. We conclude that 2 h of MV induces severe injury in the very immature lung and that these lungs have the capacity to repair spontaneously in the absence of further ventilation.

Topics: Actins; Animals; Autopsy; Blood Gas Analysis; Bronchioles; Cell Proliferation; Collagen; Elastin; Epithelium; Female; Gene Expression Profiling; Hysterotomy; Lung; Lung Volume Measurements; Mucins; Myofibroblasts; Organ Size; Pregnancy; Premature Birth; Pulmonary Alveoli; Recovery of Function; Respiration, Artificial; Sheep; Ventilator-Induced Lung Injury

Neonatal chronic lung disease is characterized by failed formation of alveoli and capillaries, and excessive deposition of matrix elastin, which are linked to lengthy mechanical ventilation (MV) with O(2)-rich gas. Vitamin A supplementation has improved respiratory outcome of premature infants, but there is little information about the structural and molecular manifestations in the lung that occur with vitamin A treatment. We hypothesized that vitamin A supplementation during prolonged MV, without confounding by antenatal steroid treatment, would improve alveolar secondary septation, decrease thickness of the mesenchymal tissue cores between distal air space walls, and increase alveolar capillary growth. We further hypothesized that these structural advancements would be associated with modulated expression of tropoelastin and deposition of matrix elastin, phosphorylated Smad2 (pSmad2), cleaved caspase 3, proliferating cell nuclear antigen (PCNA), VEGF, VEGF-R2, and midkine in the parenchyma of the immature lung. Eight preterm lambs (125 days' gestation, term approximately 150 days) were managed by MV for 3 wk: four were treated with daily intramuscular Aquasol A (vitamin A), 5,000 IU/kg, starting at birth; four received vehicle alone. Postmortem lung assays included quantitative RT-PCR and in situ hybridization, immunoblot and immunohistochemistry, and morphometry and stereology. Daily vitamin A supplementation increased alveolar secondary septation, decreased thickness of the mesenchymal tissue cores between the distal air space walls, and increased alveolar capillary growth. Associated molecular changes were less tropoelastin mRNA expression, matrix elastin deposition, pSmad2, and PCNA protein localization in the mesenchymal tissue core of the distal air space walls. On the other hand, mRNA expression and protein abundance of VEGF, VEGF-R2, midkine, and cleaved caspase 3 were increased. We conclude that vitamin A treatment partially improves lung development in chronically ventilated preterm neonates by modulating expression of tropoelastin, deposition of elastin, and expression of vascular growth factors.

Topics: Animals; Animals, Newborn; Chronic Disease; Dietary Supplements; Elastin; Female; Gestational Age; Lung; Lung Diseases; Pregnancy; Premature Birth; Pulmonary Alveoli; Pulmonary Gas Exchange; Respiration, Artificial; Sheep; Tropoelastin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Vitamin A; Vitamins

Retinoids regulate elastin synthesis by alveolar myofibroblasts and affect angiogenesis pathways, both of which are processes critical for alveolar development. Retinoids accelerate alveolarization in rodents and are now used therapeutically in premature infants at risk of bronchopulmonary dysplasia (BPD). This study examined the effects of retinoid supplementation on alveolar elastin expression and deposition and angiogenesis-related signaling in a primate model of BPD. Premature baboons delivered at 125 d of gestation after maternal steroid treatment were given surfactant and ventilated with minimal supplemental oxygen for 14 d with (n = 5) and without (n = 5) supplemental vitamin A (5000 U/kg/d) and compared with 140-d unventilated controls. Ventilatory efficiency index (VEI) and oxygenation index (OI) were not statistically different between ventilated treatment groups. Expression of vascular endothelial growth factor A (VEGF-A), fms-related tyrosine kinase 1 (Flt-1), and tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE-1) was repressed by premature delivery and mechanical ventilation and was not altered by retinoid supplementation. Retinoid supplementation did not enhance alveolar angiogenesis. Elastin expression was repressed by premature delivery and extended ventilation, and retinoid supplementation increased elastin expression specifically in alveolar myofibroblasts within alveolar walls. These results suggest that the small decrease in mortality among premature infants receiving retinoid supplementation may not be mediated through enhanced alveolar development.

Topics: Animals; Capillaries; Elastin; Gene Expression; Lung; Neovascularization, Physiologic; Papio; Platelet Endothelial Cell Adhesion Molecule-1; Premature Birth; Pulmonary Alveoli; Pulmonary Ventilation; Receptor, TIE-1; Retinoids; Up-Regulation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Our objective was to determine whether postnatal respiratory function, lung growth, and lung structure are affected by preterm birth which did not require neonatal respiratory support. Two groups of preterm (P) lambs were delivered 2 weeks before term, at 133 days of gestational age (GA). Tissue was collected at term equivalent age (TEA, 147 days GA) in one P group and at 6 weeks post-TEA in the other. Tissue was also collected from control (C) lambs soon after term birth (TEA) and at 6 weeks post-TEA. Lung function was assessed at TEA and 6 weeks post-TEA. Respiratory system compliance (Crs/kg BWT) was not different between P and C groups at TEA, but was higher (P = 0.02) in P lambs at 6 weeks post-TEA. Pulmonary resistance was 62% higher in P lambs than controls (P = 0.07) at TEA, and remained higher at 6 weeks post-TEA. Lung weights (wet and dry) were greater (P < 0.05) in preterm animals at both ages; when adjusted for body weight, only dry lung weight remained higher at 6 weeks post-TEA. Alveoli were more numerous (P = 0.05) and smaller (P = 0.05) in preterm lambs compared to controls at both ages. Alveolar septa were 33% thicker and the blood-air barrier was 26% thicker in P lambs than in controls at TEA, and remained thicker at 6 weeks post-TEA. In P lambs, the airway epithelium was thicker at TEA and 6 weeks post-TEA. At TEA, pulmonary tropoelastin expression was 27% lower in P lambs. At 6 weeks post-TEA, dry lung weight and lung protein content were approximately 50% greater in preterm lambs than in controls (P < 0.05), whereas lung DNA, elastin, and collagen contents were similar in the two groups. We conclude that mild preterm birth per se leads to both transient and persistent changes in lung development. Persistent increases in lung protein content and in the thickness of the airway epithelium, and a greater number of smaller alveolar, may alter later lung function.

Topics: Animals; Collagen; DNA; Elastin; Epithelium; Female; Humans; Infant, Newborn; Infant, Premature; Lung; Lung Compliance; Organ Size; Pregnancy; Premature Birth; Pulmonary Alveoli; Sheep; Tropoelastin