Hyperoxia-derived lung damage in preterm infants

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Summary

Hyperoxia-induced lung injury is characterized by an influx of inflammatory cells, increased pulmonary permeability, endothelial and epithelial cell death. This review highlights the mechanistic aspects of inflammation, vascular leak and cell death. The focus will be on agents that contribute to hyperoxia-induced lung injury in developmentally appropriate animal models, and those that have been detected in human premature neonates.

Introduction

Exposure to high concentrations of oxygen is known to cause significant damage to the developing lung. Acute pulmonary injury secondary to hyperoxia is characterized by an inflammatory response with destruction of the alveolar–capillary barrier, followed by cell death.1

Section snippets

Pathology

Morphologic studies in animal models have demonstrated that toxic concentrations of oxygen initially induce focal endothelial cell injury and, with continued exposure, necrosis of epithelial cells.2, 3 After acute oxygen exposure, pulmonary microvascular endothelial cells rapidly die, leaving areas of denuded capillary basement membrane. Disruption of the alveolar–capillary membrane leads to flooding of the alveoli, causing significant perturbations in pulmonary mechanics and impairment of gas

Inflammatory cells

The inflammatory cell influx is orchestrated and amplified by chemotactic factors.12 Monocytes/macrophages and lymphocytes are not the only source of these chemotactic agents, as stromal, epithelial and endothelial cells can generate significant chemokine levels.12 In such a scenario, alveolar or interstitial macrophages can respond to the exposure to hyperoxia with the expression of the early-response cytokines. These cytokines can then activate resident lung endothelial cells, epithelial

Cell death

It has been postulated that tissue injury on exposure to hyperoxia occurs as a result of reactive oxygen species (ROS). Lung cells poison themselves by producing an excess of ROS.13 Inflammatory cells are also a potent source of ROS.14 Thus, inflammation and lung injury are frequently juxtaposed in animal models of hyperoxia-induced lung injury. This has led to studies investigating the mechanisms of hyperoxia-induced inflammation and the relationship between injury and inflammation in this

Putative mediators of hyperoxia-induced lung injury in premature infants

Investigators have mostly adopted two approaches to identify mediators that may be involved in the process of hyperoxia-induced lung injury in premature neonates. The bench approach is to utilize in-vitro/in-vivo modeling systems and ascertain their responses to hyperoxia exposure. The bedside approach has been to access various compartments (tracheal, blood, urine, postmortem lung tissue) in premature human neonates and measure a variety of analytes, and report their association with long-term

Bombesin-like peptide (BLP)

BLP has been shown to impact on alveolar development in neonatal animals.29 Using the baboon model, postnatal administration of anti-BLP antibody attenuated clinical and pathological features of hyperoxia-induced lung injury.30 Urine BLP levels have correlated with the development of BPD in both the baboon model30 and humans.31

Hepatocyte growth factor (HGF)

Exposure of neonatal rats to 60% O2 led to an upregulation of lung HGF.32 However, anti-HGF treatment led to a simplified alveolar structure in neonatal rat pups in room air.32 By contrast, other investigators reported that rHGF partially protected against the inhibition of alveolarization and improved functional abnormality in a hyperoxia-induced neonatal mice model of BPD.33 In preterm humans, lower tracheal aspirate levels of HGF were associated with more severe lung disease.34

IL-1

The three known constituents of the IL-1 family, IL-1α, IL-1β and IL-1 receptor antagonist (IL-1RA), are structurally related to one another and bind with similar affinities to IL-1 receptors (IL-1R) on cells.12 IL-1α and IL-1β are potent agonists that elicit broad-ranging biological responses in various cells, which are blocked by IL-1RA. Nearly all cell types that produce IL-1α and IL-1β also produce IL-1RA.12 Both isoforms of IL-1 recruit cells to sites of inflammation and stimulate the

Keratinocyte growth factor (KGF)

In neonatal rats exposed to hyperoxia, KGF treatment was protective against lethality, but did not impact on the impaired alveolarization (the pathologic hallmark of BPD).42, 43 Tracheal aspirate KGF concentrations were higher in survivors without BPD, compared to those with BPD.44

Monocyte chemoattractant protein-1 (MCP-1)

MCP-1 is one of the ligands for CCR2.12 It is a chemoattractant for monocytes, lymphocytes and basophils. It is produced by a variety of cells in response to inflammatory stimuli.12

On gene expression profiling with confirmation by real-time reverse transcriptase–polymerase chain reaction (RT–PCR), premature rat lungs exposed to prolonged hyperoxia (10 days) had an upregulation of MCP-1.39 Newborn rats were exposed at birth to hyperoxia or room air and given anti-MCP-1 or IgG control injections

Matrix metalloproteinase 9 (MMP9)

MMP9 has been found to be increased in neonatal rat lungs exposed to hyperoxia in one study,46 whereas another reported a decrease.47 Consistent with the former, MMP9 was found increased in the baboon model of BPD.48 By contrast, MMP9 null mutant neonatal mice were protected from hyperoxia-induced lung injury,49 whereas in the IL-1β transgenic model of BPD, absence of MMP9 worsened the phenotype.50 Most of the preterm human studies support the contention that hyperoxia leads to increased MMP9

Transforming growth factor beta (TGFβ)

TGFβ and/or constituents of its signaling pathways have been noted to be upregulated on exposure to hyperoxia in neonatal rats53 and mice.54, 55 Lung overexpression models of TGFβ in neonatal rodents also have features consistent with BPD.56, 57 Preterm infants who developed BPD had significantly increased levels of TGFβ1 in tracheal aspirates, when compared with controls.27

Tumor necrosis factor alpha (TNFα)

TNFα was increased in the lungs of neonatal rat6 and mice9 pups exposed to hyperoxia. In human neonates, tracheal aspirate levels of TNFα were increased in neonates who subsequently developed BPD.27

Vascular endothelial growth factor (VEGF)

VEGF is a widely expressed dimeric glycoprotein, but the highest level of expression in normal tissues is in the lung.12 The biological activity of VEGF is dependent upon its interaction with specific transmembrane receptor tyrosine kinase (RTK) receptors; the two well-defined ones are VEGFR1/Flt-1 and KDR/Flk-1/VEGFR2.12 A wide variety of cells express VEGF receptors, including activated macrophages, neutrophils, vascular endothelial cells, and Type II cells.4 VEGF promotes endothelial cell

Conclusions

Inflammatory cells produce cytokines and chemoattractants for augmentation of the inflammatory response, in an attempt to curb the damage of the initial and ongoing insults secondary to hyperoxia. Subsequent disruption of the alveolar capillary unit with increased vascular permeability, and cell death result in decreased pulmonary tissue integrity. This injurious process, with a simultaneous attempt at repair, mediated via a variety of factors, results in lung pathology that culminates with

Conflict of interest statement

None declared.

Funding sources

Supported in part by grants 0755843T from the American Heart Association, ATS-07-005 from the American Thoracic Society, HL-074195, and HL-085103 from the NHLBI of the National Institutes of Health, USA.

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