Elsevier

Early Human Development

Volume 53, Issue 1, 1 November 1998, Pages 81-94
Early Human Development

Mechanisms initiating lung injury in the preterm

https://doi.org/10.1016/S0378-3782(98)00045-0Get rights and content

Abstract

Bronchopulmonary dysplasia (BPD)/chronic lung disease occurs primarily in very low birth weight infants (VLBW) often without antecedent severe respiratory distress syndrome. The BPD in these VLBW infants results in less fibrosis than the traditional BPD but the normal process of alveolarization seems to be disrupted. This review develops the thesis that BPD in VLBW infants results from inflammatory mediators interfering with the signaling required for normal late gestational lung development. Proinflammatory mediators may be elevated because of fetal exposure, postnatal infection or by release from preterm lungs ventilated at either low or high lung volumes. The preterm lung is highly susceptible to injury during resuscitation or more chronic mechanical ventilation because the gas volumes/kg body weight of the lungs are small. An understanding of what causes cytokine release and how cytokines influence lung development is necessary to develop targeted therapies to minimize BPD. However, care strategies that minimize inflammation and ventilator-induced lung injury should help decrease BPD.

Section snippets

“Old” verses “new” bronchopulmonary dysplasia (BPD)

This review will bring together a number of recent observations of why infants are at risk for BPD with several of our ideas about care strategies that might decrease BPD. We will use the terms BPD and chronic lung disease (CLD) interchangeably to refer to preterm infants with abnormal lung function and abnormal chest films late in their postnatal course. BPD traditionally occurred primarily in infants recovering from respiratory distress syndrome (RDS) or other lung problems after prolonged

RDS to BPD

Most of the emphasis on VLBW infants at risk of BPD has been on the infants that progress from RDS to BPD. There have been several scoring systems developed to predict those infants with RDS who will develop BPD, with the goal being to identify infants for evaluations of new therapies 10, 11. Representative incidences of BPD at 28 days for infants with RDS severe enough to receive surfactant treatment in recent trials were about 40% [12]. BPD occurred in 51% and 35% of all survivors with birth

CO2 partial pressure (PCO2) and BPD

Avery et al. [14] pointed out in 1987 that the incidences of BPD varied widely between different neonatal units. That wide variance in BPD has been striking in large data bases from neonatal networks [15]. Although not fully understood, different incidences of BPD between neonatal units correlate with neonatal care practices [16]. Kraybill et al. [17] evaluated factors associated with BPD in infants less than 1 kg in ten neonatal units and found that BPD rates were inversely related to PCO2

Fetal inflammation and BPD

Other paths to BPD are antenatal or postnatal inflammation/infection. Rojas et al. [19] noted that the major association other than birth weight and gestational age with BPD for infants without lung disease at birth was postnatal sepsis. Perhaps 45% of fetuses delivered after preterm labor have been exposed to low grade ascending infection [20]. These fetuses are exposed to elevated cytokines and inflammatory mediators in association with chorioamnionitis and may or may not be overtly infected.

How ventilators injure lungs

Mechanical ventilation can injure the preterm lungs and multiple ventilation strategies have been tried to reduce injury and improve outcomes. Because outcomes of ventilated adults with acute RDS have been so poor, major research efforts have been directed at better understanding ventilator-associated lung injury. Dreyfuss and Saumon [32] recently reviewed the compelling information demonstrating that lungs are injured if they are inflated to volumes that exceed total lung capacity. Regional or

Lung volumes of the preterm

Lung volumes can be evaluated from the perspectives of gas volumes measured with pressure–volume curves, volumes measured using gas washout techniques and plethysmography, and volumes and alveolarization measured morphometrically. Gribetz et al. [39] used pressure–volume curves in 1959 to measure a total lung gas volume of 7 ml/kg for infants that died of RDS and a volume of 27 ml/kg for preterm infants dying of other causes. Preterm monkeys who died of RDS had total lung gas volumes measured

Lung injury with the initiation of ventilation

Vyas et al. [48] measured lung expansion after term birth and observed high negative esophageal pressures with inspiration and high positive esophageal pressures with expiration. Adequate tidal volumes and functional residual capacities were achieved most effectively in asphyxiated term infants when long inspiratory times (5 s) were used to initiate ventilation [49]. The long inspiratory times and relatively high pressures overcome the resistance of fluid movement down the airways, a process

Lung injury from continued mechanical ventilation

Relative to infants without lung disease, ventilation of preterm infants with RDS results in an increase in macrophages and an influx of granulocytes into the airspaces [54]. Infants that progress to BPD have a persistence of leukocytes in alveolar lavages 55, 56. These airway samples contain high levels of the same cytokines/chemokines identified in amniotic fluid for infants at risk for BPD. Airway samples also contain elevations of other factors that can promote leukocyte migration to the

The new BPD in VLBW infants

There is increasing evidence that antenatal exposure of the fetus to proinflammatory cytokines can predispose to the development of BPD, independently of severity of RDS (Fig. 1). Resuscitation and the initiation of ventilation of the VLBW infant is likely to initiate lung injury [53]. There is overwhelming evidence that ventilation of the VLBW infant is associated with increases of proinflammatory mediators in airspace samples [55]. In very preterm ventilated animals, injury causes a delay in

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