Pulmonary and systemic inflammatory responses to intra-amniotic IL-1 in fetal sheep
Cincinnati Children's Hospital Medical Center, Univ. of Cincinnati, Division of Pulmonary Biology, 3333 Burnet Ave., Cincinnati, OH 45229-3039, USA. AJP Lung Cellular and Molecular Physiology
(Impact Factor: 4.08).
06/2011; 301(3):L285-95. DOI: 10.1152/ajplung.00446.2010
Clinical and epidemiological studies implicate IL-1 as an important mediator of perinatal inflammation. We tested the hypothesis that intra-amniotic IL-1α would induce pulmonary and systemic fetal inflammatory responses. Sheep with singleton fetuses were given an intra-amniotic injection of recombinant sheep IL-1α (100 μg) and were delivered 1, 3, or 7 days later, at 124 ± 1 days gestation (n=5-8/group). A separate group of sheep were given two intra-amniotic IL-1α injections (100 μg dose each): 7 days and again 1 day prior to delivery. IL-1α induced a robust increase in monocytes, neutrophils, lymphocytes, and IL-8 protein in bronchoalveolar lavage fluid. H(2)O(2) secretion was increased in inflammatory cells isolated from lungs of IL-1α-exposed lambs upon LPS challenge in vitro compared with control monocytes. T lymphocytes were recruited to the lung. IL-1β, cyclooxygenase-1, and cyclooxygenase-2 mRNA expression increased in the lung 1 day after intra-amniotic IL-1α exposure. Lung volumes increased 7 days after intra-amniotic IL-1α exposure, with minimal anatomic changes in air space morphology. The weight of the posterior mediastinal lymph node draining the lung and the gastrointestinal tract doubled, inducible nitric oxide synthase (NOSII)-positive cells increased, and Foxp3-positive T-regulatory lymphocytes decreased in the lymph node after IL-1α exposure. In the blood, neutrophil counts and plasma haptoglobin increased after IL-1α exposure. Compared with a single exposure, exposure to intra-amniotic IL-1α 7 days and again 1 day before delivery had a variable effect (increases in some inflammatory markers, but not pulmonary cytokines). IL-1α is a potent mediator of the fetal inflammatory response syndrome.
Available from: Peter G J Nikkels
- "In this study, we investigated the levels of sLAIR-1 in amniotic fluid. Intra-uterine inflammation, in absence of a fetal inflammatory response syndrome, promotes fetal lung maturation[9-12]. In a cohort of 761 preterm infants, chorioamnionitis protected against the development of chronic lung disease (CLD). "
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ABSTRACT: The soluble form of the inhibitory immune receptor leukocyte-Associated Ig-like Receptor-1 (sLAIR-1) is present in plasma, urine and synovial fluid and correlates to inflammation. We and others previously showed inflammatory protein expression in normal amniotic fluid at term. We hypothesized that sLAIR-1 is present in amniotic fluid during term parturition and is related to fetal lung function development. sLAIR-1 was detectable in all amniotic fluid samples (n=355) collected during term spontaneous deliveries. First, potential intra-uterine origins of amniotic fluid sLAIR-1 were explored. Although LAIR-1 was expressed on the surface of amniotic fluid neutrophils, LAIR-1 was not secreted upon ex vivo neutrophil stimulation with LPS, or PMA/ionomycin. Cord blood concentrations of sLAIR-1 were fourfold lower than and not related to amniotic fluid concentrations and placentas showed no or only sporadic LAIR-1 positive cells. Similarly, in post-mortem lung tissue of term neonates that died of non-pulmonary disorders LAIR-1 positive cells were absent or only sporadically present. In fetal urine samples, however, sLAIR-1 levels were even higher than in amniotic fluid and correlated with amniotic fluid sLAIR-1 concentrations. Second, the potential relevance of amniotic fluid sLAIR-1 was studied. sLAIR-1 concentrations had low correlation to amniotic fluid cytokines. We measured neonatal lung function in a convenient subset of 152 infants, using the single occlusion technique, at a median age of 34 days (IQR 30-39). The amniotic fluid concentration of sLAIR-1 was independently correlated to airway compliance (ρ=0.29, P=.001). Taken together, we show the consistent presence of sLAIR-1 in amniotic fluid, which originates from fetal urine. Concentrations of sLAIR-1 in amniotic fluid during term deliveries are independent from levels of other soluble immune mediators. The positive association between concentrations of amniotic fluid sLAIR-1 and neonatal lung compliance suggests that amniotic fluid sLAIR-1 may be useful as a novel independent marker of neonatal lung maturation.
- "In particular, IL-1a is a potent mediator of the fetal inflammatory response syndrome. Intra-amniotic IL-1a injections induced a robust increase in monocytes, neutrophils, lymphocytes, and IL-8 protein in bronchoalveolar lavage (BAL) fluid. It was hypothesized that after endotoxin injection, neutrophils producing oxidants cause a primary injury. "
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ABSTRACT: Bronchopulmonary dysplasia (BPD) is the major cause of pulmonary disease in infants. The pathophysiology and management of BPD changed with the improvement of neonatal intensive care unit (NICU) management and with the increase of survival rates. Despite the improvements made, BPD is still a public health concern, resulting in frequent hospitalizations with high rates of mortality, impaired weight and height growth, and neurodevelopmental disorders. Lung injury in the neonatal period has multiple etiologic factors - genetic, hemodynamic, metabolic, nutritional, mechanical, and infectious mechanisms - act in a cumulative and synergic way. Free radical (FR) generation is largely recognized as the major cause of lung damage. Oxidative stress (OS) is the final common endpoint for a complex convergence of events, some genetically determined and some triggered by in utero stressors. Inflammatory placental disorders and chorioamnionitis also play an important role due to the coexistence of inflammatory and oxidative lesions. In addition, the contribution of airway inflammation has been extensively studied. The link between inflammation and OS injury involves the direct activation of inflammatory cells, especially granulocytes, which potentiates the inflammatory reaction. Individualized interventions to support ventilation, minimize oxygen exposure, minimize apnea, and encourage growth should decrease both the frequency and severity of BPD. Future perspectives suggest supplementation with enzymatic and/or non-enzymatic antioxidants. The use of antioxidants in preterm newborns particularly exposed to OS and at risk for BPD represents a logical strategy to ameliorate FRs injury, but further studies are needed to support this hypothesis.
Available from: Graeme R Polglase
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ABSTRACT: The proinflammatory stimulus of chorioamnionitis is commonly associated with preterm delivery. Women at risk of preterm delivery receive antenatal glucocorticoids to functionally mature the fetal lung. However, the effects of the combined exposures of chorioamnionitis and antenatal glucocorticoids on the fetus are poorly understood. Time-mated ewes with singleton fetuses received an intra-amniotic injection of lipopolysaccharide (LPS) either preceding or following maternal intramuscular betamethasone 7 or 14 days before delivery, and the fetuses were delivered at 120 days gestational age (GA) (term = 150 days GA). Gestation matched controls received intra-amniotic and maternal intramuscular saline. Compared with saline controls, intra-amniotic LPS increased inflammatory cells in the bronchoalveolar lavage and myeloperoxidase, Toll-like receptor 2 and 4 mRNA, PU.1, CD3, and Foxp3-positive cells in the fetal lung. LPS-induced lung maturation measured as increased airway surfactant and improved lung gas volumes. Intra-amniotic LPS-induced inflammation persisted until 14 days after exposure. Betamethasone treatment alone induced modest lung maturation but, when administered before intra-amniotic LPS, suppressed lung inflammation. Interestingly, betamethasone treatment after LPS did not counteract inflammation but enhanced lung maturation. We conclude that the order of exposures of intra-amniotic LPS or maternal betamethasone had large effects on fetal lung inflammation and maturation.
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