The role of neutrophil apoptosis in the resolution of acute lung injury in newborn infants

Kotecha, Sailesh; Mildner, Reinout J; Prince, Lynne R.; Vyas, Julian; Currie, Andrew; Lawson, Roderick; Whyte, Moira K. B.

doi:10.1136/thorax.58.11.961

Cited by 64 publications

(58 citation statements)

References 40 publications

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“…[11][12][13] Most recently, a prolonged survival of neonatal neutrophils owing to an inappropriate suppression of neutrophil apoptosis has been described. [14][15][16] Before neutrophil migration, cellular attachment to endothelial cells is mediated through a complex interaction of adhesion molecules. Increased concentrations of various cellular and endothelial adhesion molecules such as intercellular adhesion molecule (ICAM-1) and selectins have been detected in airway secretions and the circulation of preterm infants with BPD.…”

Section: Inflammatory Cells Endothelial Interactions and Chemotaxismentioning

confidence: 99%

Pulmonary inflammation and bronchopulmonary dysplasia

Speer

2006

J Perinatol

131

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Various pre-and postnatal risk factors, which act additively or synergistically induce an injurious inflammatory response in the airways and the pulmonary interstitium of preterm infants with bronchopulmonary dysplasia. This inflammatory response is characterized by an accumulation of neutrophils and macrophages as well as an arsenal of proinflammatory mediators that affect the endothelium and alveolar-capillary integrity. Besides proinflammatory cytokines and toxic oxygen radicals, lipid mediators as well as potent proteases may be responsible for acute lung injury. There is increasing evidence that an imbalance between pro-and anti-inflammatory factors, which should protect the alveoli and lung tissue, are key features in the pathogenesis of bronchopulmonary dysplasia. In addition, a subnormal generation of growth factors may affect alveolarization and vascular development in preterm infants with bronchopulmonary dysplasia. In this condensed review article, the current concepts on the possible role of inflammation in the evolution of bronchopulmonary dysplasia will be summarized.

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Section: Inflammatory Cells Endothelial Interactions and Chemotaxismentioning

confidence: 99%

Pulmonary inflammation and bronchopulmonary dysplasia

Speer

2006

J Perinatol

131

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“…Post-natal inflammatory response dominated by persistent neutrophil activity [25] and the presence of oxidative stress, may play a major role in this process since both are known to alter eNO [7,8]. Neutrophil activity and oxidative stress both promote the oxygenation of NO to soluble peroxy-nitrites, nitrites and nitrates.…”

Section: Interpretation Of the Findingsmentioning

confidence: 99%

Alterations of exhaled nitric oxide in pre-term infants with chronic lung disease

Roiha

Kuehni²,

Zanolari³

et al. 2006

Eur Respir J

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Animal models suggest that reduced nitric oxide (NO) synthase activity results in lower values of exhaled NO (eNO) present at birth in those individuals who are going to develop chronic lung disease of infancy (CLDI).Online tidal eNO was measured in 39 unsedated pre-term infants with CLDI (mean gestational age (GA) 27.3 weeks) in comparison with 23 healthy pre-term (31.6 weeks) and 127 term infants (39.9 weeks) at 44 weeks post-conceptional age, thus after the main inflammatory response. NO output (NO output (V9NO)5eNO6flow) was calculated to account for tidal-flow-related changes. Sex, maternal atopic disease and environmental factors (smoking, caffeine) were controlled for.The mean eNO was not different (14.9 ppb in all groups) but V9NO was lower in CLDI compared with healthy term infants (0.52 versus 0.63 nL?s ). Values for healthy pre-term infants were between these two groups (0.58 nL?s -1 ). Within all pre-term infants (n562), V9NO was reduced in infants with low GA, high clinical risk index for babies scores and longer duration of oxygen therapy but not associated with post-natal factors, such as ventilation or corticosteroid treatment. After accounting for flow, the lower nitric oxide output in premature infants with chronic lung disease of infancy is consistent with the hypothesis of nitric oxide metabolism being involved in chronic lung disease of infancy.KEYWORDS: Chronic lung disease, infants, lung function, nitric oxide, prematurity R ecent evidence supports the hypothesis that chronic lung disease of infancy (CLDI) is the result of arrested or disturbed alveolar and vascular development [1]. The insult leading to this disturbed lung development may occur due to intra-uterine and postnatal infections, prematurity with surfactant deficiency or as a consequence of ventilation, hyperoxia (oxidative stress) or other factors. An inflammatory response with a peak at the age of ,10 days followed by a progressive decline [2] has been observed in this condition; however, little is known about the ongoing effects of these mechanisms after the acute phase during the first month of life.Various inflammatory processes, with a dominance of neutrophilic inflammation and oxidative stress, are involved in the pathogenesis of CLDI. Premature infants exhibit an immature response to oxidative stress [3], immature interleukin-10-mediated inflammatory responses [4,5], persistence of neutrophilic inflammation and an imbalance of a 1 -protease inhibitor activity [6]. Nitric oxide (NO) metabolism plays a crucial role in many of these inflammatory processes. Exhaled NO (eNO) is altered during both oxidative stress [7] and neutrophilic inflammation [8]. There is also increasing evidence that NO is involved in lung development and growth, as well as in angiogenesis [9,10]. Recently, it has been demonstrated that premature baboons, in which CLDI subsequently develops, show pre-existing alterations of NO metabolism at birth [11]. These animals have decreased levels of constitutive forms of NO synthase (endothelial nitr...

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“…The etiology of this CLD of premature infants is unclear and has been associated with a myriad of risk factors (14,15). Persistence of lung PMN is one characteristic associated with CLD; however, whether a delay in the apoptosis of these PMN contributes to their persistence, as has been suggested, has not been established (16,17).…”

mentioning

confidence: 99%

“…Several recent studies have shown delayed apoptosis of lung PMN in premature neonates at risk for developing CLD (16,17), although the involved mechanisms remain to be defined. In previous in vitro studies, we observed that neonatal PMN had an intrinsic delay in both spontaneous and Fasmediated apoptosis (18), which was associated with decreased activity of caspase-3 (52), a critical downstream mediator of PMN apoptosis (53).…”

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confidence: 99%

Neonatal Neutrophils with Prolonged Survival Exhibit Enhanced Inflammatory and Cytotoxic Responsiveness

et al. 2005

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Apoptosis is critical to the resolution of inflammation, as it promotes the removal of neutrophils (PMN) by the reticuloendothelial system. In contrast, PMN persistence characterizes the early stages of chronic inflammation. Adult PMN with delayed senescence retain some functionality, although this has not been described for neonatal PMN. We hypothesized that neonatal PMN with prolonged survival retain cytotoxic and inflammatory function. To test one aspect of inflammatory function, we determined surface CD11b expression on 0-h and 24-h PMN after chemotactic formyl-methionine-leucine-phenylalanine (fMLP) stimulation. Although fMLP induced a greater percentage upregulation of CD11b on 0-h adult PMN, this was similar between nonapoptotic cord blood and adult PMN at 24 h. Furthermore, percentage up-regulation of CD11b was more robust for 24-h than for 0-h cord blood PMN. In contrast, there was no difference in responsiveness between 0-h and 24-h adult PMN. In studies of cytotoxic potential, we determined the expression of reactive oxygen intermediates (ROI) in phorbol 12-myristate 13-acetatestimulated cord blood and adult PMN at 0 h and in 24-h nonapoptotic PMN, using the dihydrorhodamine 123 assay.Stimulated cord blood PMN generated more ROI than did adult PMN at both 0 h and 24 h; in addition, ROI levels in 24-h cord blood PMN were similar to those of 0-h adult PMN. We conclude that PMN with prolonged survival retain specific cytotoxic and inflammatory functions, and these are enhanced in cord blood PMN. We speculate that neonatal PMN with prolonged survival have the functional capacity to contribute to the pathogenesis of inflammatory disorders. Abbreviations CLD, chronic lung disease DHR, dihydrorhodamine 123 fMLP, formyl-methionine-leucine-phenylalanine PE, phycoerythrin PMA, phorbol 12-myristate 13-acetate PMN, neutrophil(s) ROI, reactive oxygen intermediates 7-AAD, 7-aminoactinomycin PMN serve as the primary line of host defense during the early stages of sepsis and inflammation (1). After activation by systemic or local factors, primed endothelial cells interact with PMN through adhesion molecules that include selectins and integrins (2). These adhesive interactions initiate a process that allows the extravasation of PMN into inflamed tissue with the goal of neutralizing the inciting stimulus. In the case of inflammation mediated by bacterial or fungal microorganisms, phagocytosis and subsequent killing of these invaders occurs through mechanisms that partly involve ROI and proteases (3,4).The concept that apoptosis of inflammatory PMN and their timely removal by resident macrophages are critical to the resolution of inflammation has been well established (5,6). During the resolution phase, PMN typically undergo the phenotypic changes associated with apoptosis, which promotes their removal by resident macrophages (7). PMN can also undergo necrosis and lysis, a process that induces cytotoxicity in surrounding tissues (8), although apoptosis is the more common and physiologically preferable route. All cells a...

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The role of neutrophil apoptosis in the resolution of acute lung injury in newborn infants

Cited by 64 publications

References 40 publications

Pulmonary inflammation and bronchopulmonary dysplasia

Pulmonary inflammation and bronchopulmonary dysplasia

Alterations of exhaled nitric oxide in pre-term infants with chronic lung disease

Neonatal Neutrophils with Prolonged Survival Exhibit Enhanced Inflammatory and Cytotoxic Responsiveness

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