Diffuse Alveolar Damage in the Evolution of Bronchopulmonary Dysplasia in the Baboon

Coalson, Jacqueline J.; Kuehl, Thomas J.; Prihoda, T. J.; deLemos, Robert A.

doi:10.1203/00006450-198809000-00017

Cited by 77 publications

(35 citation statements)

References 25 publications

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“…This suggests that factors in addition t o surfactant deficiency contribute t o neonatal lung injury. Pathologic findings in B P D are consistent with a process of prolonged lung inflammation and impaired healing (2,3). In human infants with RDS (4)(5)(6) 49.4 ?…”

mentioning

confidence: 58%

Increased Activity of Interleukin-6 but not Tumor Necrosis Factor-α in Lung Lavage of Premature Infants is Associated with the Development of Bronchopulmonaiy Dysplasia

et al. 1994

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Although considerable evidence suggests that bronchopulmonary dysplasia (BPD) is the result of prolonged inflammation and impaired healing of the immature lung, the mediators that regulate inflammation in neonatal lung injury have not been completely elucidated. We examined whether the cytokines IL-6 and tumor necrosis factor-a (TNF) interact to modulate a cascade of cell-cell signaling events involved in inflammation contributing to the development of BPD. To determine the relative activities of these cytokines in neonatal lung injury, lung lavage samples were serially obtained from 1 to 28 d from 11 infants with self-limited respiratory distress syndrome (RDS), 19 infants with evolving BPD, and 10 control infants ventilated for nonpulmonary reasons. On the first day of life, there were no differences in antigenic IL-6 concentrations in lavage fluids among the BPD, RDS, and control groups, but IL-6 activity determined by the 7TD1 proliferation assay was 15-fold and 6.6-fold higher in lung lavage of infants who developed BPD compared with activities in lavage from control and RDS infants, respectively (control, Exogenous surfactant therapy has dramatically improved survival of very-low-birth-weight infants with RDS, but it has not affected the incidence of the neonatal chronic lung disorder B P D (1). This suggests that factors in addition t o surfactant deficiency contribute t o neonatal lung injury. Pathologic findings in B P D are consistent with a process of prolonged lung inflammation and impaired healing (2, 3). In human infants with RDS (4-6) 49.4 ? 17.6; RDS, 117.3 2 59.6; BPD, 779.5 2 212.6 x 10' hybridoma units/L, mean * SEM,p = 0.02). This suggests that pathways for inactivating or inhibiting IL-6 that may be present in the lungs of RDS and control infants may be deficient in BPD infants. IL-6 activity remained elevated in lavage of BPD infants for the first 2 wk and declined to low levels by d 28. There were no differences among groups on the first day of life for TNF antigen concentration or TNF activity determined by the L929 bioassay. Detectable but low TNF activity was found in BPD samples, with peak activity found in d-14 samples. Differences in complex interactions among these and other cytokines with their receptors and inhibitors may predispose some infants with RDS to develop BPD. (Pediuh. Res 36: 244-252, 1994) Abbreviations RDS, respiratory distress syndrome BPD, bronchopulmonary dysplasia TNF, tumor necrosis factor-a PROM, prolonged rupture of membranes and in primate models of acute lung injury (7), there is a rapid influx of neutrophils into the lung during the first 48 t o 96 h after initial injury followed b y a n increase in alveolar macrophages with subsequent resolution of airw a y inflammation. In contrast, in infants w h o develop BPD, the neutrophil influx is prolonged and the alveolar macrophage entry is delayed and blunted (5). nolysis (13), the mediators that regulate neonatal lung

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mentioning

confidence: 58%

Increased Activity of Interleukin-6 but not Tumor Necrosis Factor-α in Lung Lavage of Premature Infants is Associated with the Development of Bronchopulmonaiy Dysplasia

et al. 1994

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“…The results further show that this apoptotic cell death process is not dependent of significant pulmonary neutrophil accumulation and is promoted, at least in part, by ANG II receptor action in the meconium-contaminated lungs. Although the experimental lung injury in the present work was induced in fully developed lungs and the results therefore cannot be applied directly to neonatal pulmonary changes, the airway alterations in newborns tend to be more severe than those in adult lungs in response to a pulmonary insult (23). Our experimental approach further enables us to study the appearance of apoptosis in lungs with meconium aspiration without the involvement of the active process of programmed cell death during postnatal pulmonary remodeling (4).…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Receptor Blockade Inhibits Pneumocyte Apoptosis in Experimental Meconium Aspiration

et al. 2004

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Lung tissue inflammation and apoptosis are implicated in the pathogenesis of meconium aspiration-induced lung injury in the newborn, but the mechanisms of these reactions are still poorly known. We investigated the time-dependent leukocyte influx and appearance of apoptosis, as well as the contribution of angiotensin (ANG) II receptor action on these processes in the meconium-induced lung injury. Experimental meconium aspiration was induced by intratracheal instillation of human meconium in 18 rats, and eight rats were further pretreated with an unspecific ANG II receptor inhibitor saralasin. Rats were ventilated with 60% oxygen for 1, 3, or 5 h, and the lungs were then studied histologically for tissue injury and with DNA nick-end labeling and electron microscopy for apoptotic cell death. Lung tissue myeloperoxidase activity and expression of angiotensinogen mRNA and endothelial monocyte-activating polypeptide (EMAP) II protein were also analyzed. The meconium-instilled lungs showed increasing neutrophil migration and histologic injury after the first hour, whereas the number of epithelial apoptotic cells was elevated from the control level throughout the study. Myeloperoxidase activity was high, and the angiotensinogen mRNA and EMAP II protein was up-regulated at 5 h after the meconium insult. Pretreatment with saralasin significantly prevented the increase in lung tissue myeloperoxidase activity, EMAP II, and lung epithelial apoptosis. The results suggest that pulmonary meconium insult rapidly results in epithelial apoptosis, before significant neutrophil sequestration into the lungs. Perinatal aspiration of meconium frequently results in severe pulmonary failure with ventilation-perfusion mismatching in the lungs, hypoxemia, and increase in pulmonary vascular resistance, associated with high morbidity and mortality in fullor postterm newborn infants. The pathophysiology of the neonatal meconium aspiration syndrome (MAS) is complex, but inflammation with accumulation of polymorphonuclear leukocytes in the pulmonary tissue is believed to be a central event in the development of acute tissue damage (1, 2). This inflammatory reaction is associated with increased pulmonary vascular permeability leading to proteinaceous exudation into the alveolar spaces and inactivation of the pulmonary surfactant and may together with direct toxic effects of meconium significantly contribute to the lung injury process (1, 2). Still, the clinical effects of anti-inflammatory therapeutic approaches and surfactant replacement treatment have often been unsatisfactory and have not consistently improved the outcome of severe complications of this disease (1-3). New advances in the pathophysiology of MAS therefore are needed.Apoptosis, programmed cell death, is usually regarded as a physiologic mechanism in organ remodeling (4) but has been

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“…To investigate the effects of hyperoxia on p53, oxidant DNA damage and VEGF expression, we used a well-described model of moderately premature baboons delivered at 140 d of gestation (75% of term) that were treated with ventilation and either 100% oxygen or oxygen as needed (PRN oxygen) for up to 10 d. Baboons treated with 100% oxygen are known to have decreased endothelial cells (34). We hypothesized that ventilation of these animals with 100% oxygen would result in oxidant DNA damage, increased p53, and decreased VEGF expression.…”

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confidence: 99%

Hyperoxic Ventilated Premature Baboons Have Increased p53, Oxidant DNA Damage and Decreased VEGF Expression

et al. 2005

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Diffuse Alveolar Damage in the Evolution of Bronchopulmonary Dysplasia in the Baboon

Cited by 77 publications

References 25 publications

Increased Activity of Interleukin-6 but not Tumor Necrosis Factor-α in Lung Lavage of Premature Infants is Associated with the Development of Bronchopulmonaiy Dysplasia

Increased Activity of Interleukin-6 but not Tumor Necrosis Factor-α in Lung Lavage of Premature Infants is Associated with the Development of Bronchopulmonaiy Dysplasia

Angiotensin II Receptor Blockade Inhibits Pneumocyte Apoptosis in Experimental Meconium Aspiration

Hyperoxic Ventilated Premature Baboons Have Increased p53, Oxidant DNA Damage and Decreased VEGF Expression

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