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Glucocorticoids, inflammation and the perinatal lung
Semin Neonatol 2001; 6: 331–342 doi:10.1053/siny.2001.0068, available online at http://www.idealibrary.com on
Glucocorticoids, inflammation and the perinatal lung Alan H. Jobe
Children’s Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, OH, USA
Key words: RDS, BPD, alveolarization, cytokines, endotoxin, betamethasone, chorioamnionitis
Many women delivering preterm infants at less than 30 weeks gestation have subclinical chorioamnionitis. Based on current guidelines, maternal glucocorticoid treatment is given to induce lung maturation. Fetal exposure to proinflammation can cause acute and chronic injury, but inflammation also can induce fetal lung maturation. Both antenatal glucocorticoids and inflammation modulate lung development, by inducing the surfactant system, inducing structural maturation, and inhibiting alveolarization. The opportunities for the future are to develop new safer strategies to mature the preterm foetus, and the risks are potential adverse interactions of repetitive glucocorticoid exposures and unrecognized fetal exposure to inflammation. 2002 Elsevier Science Ltd
An overview Traditionally inflammation resulting from infection or injury and lung maturation have been considered separately. However, fetal exposure to chorioamnionitis followed by early gestational preterm labour may be the rule rather than the exception [1]. Similarly, once preterm delivery has occurred at 26 weeks in the example in Figure 1, then the initiation of ventilation, subsequent ventilatory support and supplemental oxygen will promote inflammation [2]. Against this background of proinflammatory events antenatal glucocorticoids are used to induce early lung maturation and postnatal glucocorticoids are used to decrease the risk or severity of lung injury. Both inflammation and glucocorticoids are acting on a fetal or neonatal lung at 26 weeks gestation that has just transitioned from the canalicular stage to the saccular stage of lung anatomic development [3]. This lung is 4 to 6 weeks from the initiation of alveolarization. Glucocorticoids and inflammatory exposures can each cause both clinical lung maturation and alterations in lung development indicative of Correspondence to: Alan H. Jobe, MD, PhD, Children’s Hospital Medical Center, Division of Pulmonary Biology, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA. Tel.: +1 (513) 636 8563; Fax: +1 (513) 636 8691; E-mail: jobeaØ@chmcc.org
1084–2756/01/$-see front matter
injury. This chapter will begin to explore the relationships between inflammation and steroids in the developing lung. The fact that the exposures may be antenatal, postnatal, or both probably is more situational than biologically distinct in terms of lung development. The widespread use of repetitive courses of antenatal glucocorticoids and the frequent use of high-dose, long duration postnatal glucocorticoid treatments are not supported by clinical data of either efficacy or safety [4]. This chapter will begin with a discussion of inflammation, then a review of glucocorticoid effects on lung maturation, and finally will link these two important factors in outcomes of very preterm infants.
Fetal inflammation Fetal exposures to inflammation Traditionally chorioamnionitis was thought to be an acute infection of the fetal membranes, amniotic fluid and potentially the fetus, primarily by high virulence organisms ascending from the lower genital tract. Organisms such as E. coli, Listeria monocytogenes, and Group B Streptococci certainly can cause acute infection resulting in preterm labour and severe complications for the newborn. © 2002 Elsevier Science Ltd
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Figure 1. Diagram emphasizing antenatal and postnatal inflammatory events that may influence lung development of a preterm infant delivered at 26 weeks gestational age. The potential glucocorticoid exposures also are indicated. The lung of the human fetus at 26 weeks gestation is in the saccular stage of lung structural development.
A recent pathologic series demonstrated that 27% of infants with birth weights <1 kg that came to autopsy died from or with severe infection in the lungs acquired antenatally [5]. However, the more commonly low grade, indolent chorioamnionitis that is present but clinically silent over weeks and perhaps months ultimately results in preterm labour between 20 and 30 weeks gestation [1]. Histologic chorioamnionitis and fetal membranes that are culture positive with organisms such as Ureaplasma urealyticum, Mycoplasma and Gardnerella are very frequently associated with preterm deliveries before 30 weeks gestation. Amniotic fluid from women in preterm labour often is culture-positive for the same organisms and that amniotic fluid contains increased numbers of granulocytes and increased levels of pro-inflammatory cytokines such as IL-1, IL-6, IL-8, and TNF [6,7]. Most women at risk of preterm labour are now receiving antenatal glucocorticoids and many will have subclinical chorioamnionitis. Preterms born after chorioamnionitis may have elevated plasma
levels of indicators of pro-inflammatory exposure such as IL-6 [8]. These infants can also have tracheal aspirates positive for Ureaplasma urealyticum, and elevated white blood cells and cytokines in tracheal aspirates but initial blood cultures are rarely positive.
Consequences of fetal exposure to inflammation Severe fetal infection with invasive organisms will cause fetal death or severe pneumonia/sepsis after birth. Preterm infants exposed to elevated proinflammatory cytokines in amniotic fluid or who have a systemic inflammatory response as indicated by elevated IL-6 in cord blood may have more severe RDS and have an increased risk of developing BPD [8,9]. However, the outcomes of many very preterm fetuses exposed to chorioamnionitis is quite different. Infants born at less than 26 weeks
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gestation in the United Kingdom had higher overall survival rates if they were exposed to histologic chorioamnionitis [10]. In selected series, infants born after exposure to chorioamnionitis or who were tracheal aspirate culture positive for Ureaplasma urealyticum were less likely to have RDS but were more likely to develop BPD [11,12]. A number of reports identify a population of infants that have minimal or no RDS after birth but who develop BPD despite minimal mechanical ventilation or supplemental oxygen [13,14]. The explanation for the decreased incidence of RDS may be antenatal exposure to chorioamnionitis while the later progression to BPD may result from progression of the antenatal pro-inflammatory exposure. We have hypothesized that the newborn lung exposed to fetal inflammation may respond with an augmented and prolonged inflammatory response to subsequent newborn care practices such as the use of supplemental oxygen and mechanical ventilation with the result being BPD [15]. The clinical observations that chorioamnionitis may initially be good for the preterm fetus by decreasing RDS are consistent with some experimental results. A decrease in RDS means clinically ‘induced lung maturation’ in very preterm infants. Does the ‘induced lung maturation’ from chorioamnionitis have elements in common with lung maturation induced by antenatal glucocorticoid treatments? Pro-inflammatory stimuli certainly can increase indicators of surfactant and improve lung mechanics. Bry et al. [16] found that intra-amniotic IL-1 increased the mRNAs for the surfactant proteins and improved lung compliance of rabbits delivered preterm. Subsequently Glumoff et al. [17] noted that IL-1 induced surfactant protein mRNAs in lung explants from early gestation rabbits but suppressed the same mRNAs in explants from rabbits close to term. These results demonstrate a direct effect of IL-1 on the fetal lung, which appears to be gestation-dependent. We recently found that recombinant ovine IL-1 or IL-1 when given by intra-amniotic injection at 118 days gestation to fetal sheep induced chorioamnionitis. At delivery 7 days later at 125 days gestation (term=150 days), the lung had increased numbers of white blood cells, indicating inflammation, and improved lung mechanics and increased surfactant lipids and proteins [18]. Therefore, a single pro-inflammatory cytokine can induce fetal-lung maturation, but that maturation was associated with chorioamnionitis.
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Figure 2. Patterns of responses of the fetal sheep to intra-amniotic exposure to endotoxin before preterm delivery at 125 days gestation at the intervals indicated on the horizontal axis. Inflammation indicated by the increased expression of IL-1 mRNA in amnion/chorion and lung tissue increases within 5 hours. The mRNA for SP-A increased by 1 day after endotoxin exposure and remained elevated for 15 days. The amount of SP-A and saturated phosphatidylcholine (Sat PC) were increased significantly by 4 to 7 days. Please note log scales for the inflammation and surfactant measurements. Lung function after preterm delivery also was improved by 4 to 7 days after intra-amniotic endotoxin. Data from [20,21,22].
To model a general pro-inflammatory stimulus, we gave intra-amniotic injections of E. coli endotoxin to sheep in various doses and durations before preterm delivery [19,20]. The endotoxin recruits granulocytes, which express proinflammatory cytokine mRNA, to the amnion/ chorion and amniotic fluid within 5 h (Fig. 2) [21]. The same cytokine expression is highest in the lung at 1 to 2 days. Pro-inflammatory cells also accumulate rapidly in the lungs but are minimally activated within 4 days of the intra-amniotic exposure. The first indication of a maturational stimulus is an increase in the mRNAs for the surfactant proteins within 24 h, although lung mechanics and surfactant proteins and lipids in alveolar washes do
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not increase for 4 to 7 days after the intra-amniotic endotoxin [22]. The mRNAs for the surfactant proteins and other indicators of lung maturation are elevated relative to controls even when the endotoxin was given 15 or 25 days before delivery at 125 days gestation. Fetal cord cortisol values do not increase very much after the inflammation induced by endotoxin or IL-1, indicating that the maturational effect was not dependent on endogenous cortisol [20].
Neonatal inflammation Neonatal exposure to inflammation Once preterm birth has occurred, much of what is standard neonatal care has a pro-inflammatory component. In the mature lung ventilation from tidal volumes below normal functional residual capacity causes injury with the expression of proinflammatory cytokines [23]. Similarly, ventilation of the normal lung to volumes that approach or exceed total lung capacity causes injury and cytokine expression. Ventilation of the injured lung can cause the release of pro-inflammatory mediators, endotoxin and bacteria into the systemic circulation [24]. We evaluated the initiation of mechanical ventilation in preterm lambs and found that recruitment of activated granulocytes and expression of IL-1, IL-6 and IL-8 occurred despite the use of surfactant treatment before the first breath, positive end expiratory pressure, and low tidal volumes to avoid hyperventilation (Fig. 3) [25]. The initiation of ventilation without positive end expiratory pressure resulted in larger proinflammatory responses. Ventilation of preterm lungs that contain endotoxin in the surfactant results in loss of the endotoxin to the systemic circulation [26]. There is no information about how the preterm lung responds to the spontaneous initiation of ventilation using continuous positive airway pressure only. However, our results indicate that any mechanical ventilation can initiate an inflammatory response. If that newborn were exposed to chorioamnionitis, then the lung would already be manifesting an inflammatory response and ventilation could amplify that response and cause pro-inflammatory mediators to spill from the lungs into the systemic circulation. There is an extensive literature based on airway aspirates from ventilated preterm infants demon-
Figure 3. Inflammatory responses of preterm lamb lungs to the initiation of mechanical ventilation. Preterm lambs were treated with surfactant and mechanical ventilation was initiated with tidal volumes of 10 ml/kg using PEEP values of 0, 4, or 7 cmH2O. Neutrophils in alveolar washes and IL-1 mRNA in lung tissues were measured after 2 hours of ventilation. All styles of ventilation resulted in increased expression of IL-1 mRNA and recruitment of neutrophils to the lungs. Data from [25].
strating elevations in white blood cells, proinflammatory cytokines, leukotrienes, and other mediators and indicators of inflammation [27]. In general, infants with elevated indicators of inflammation/injury in airway aspirates progress to BPD. The three factors thought to contribute to this pro-inflammatory response of the preterm lung are ventilation (stretch, barotrauma, volutrauma), supplemental oxygen, and pneumonia/sepsis [28]. In experimental models, each factor can injure the lung and all three commonly occur in the very preterm infant.
Consequences of neonatal exposures to inflammation The pathologic characteristics of the lungs of preterm infants dying of BPD have changed as
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increasingly smaller infants survive, and techniques to ventilate infants have improved. The fibrotic parenchymal and inflammatory airway disease that resulted primarily from barotrauma and oxygen now are less frequent [29]. The pathology more commonly indicates an interference in the ability of the preterm lung to alveolarize and vascularize [30]. Multiple factors can inhibit alveolarization in experimental models. Mice that over-express the pro-inflammatory cytokines TNF, TGF, IL-6 and IL-11 have an arrest in alveolar development [15]. Inflammatory stimuli such as mechanical ventilation, chronic elevated oxygen exposure, and colonization of the lung with low pathogenic organisms have been associated with an arrest in alveolar development in humans and experimental animals [31–33]. Starvation can augment the alveolar arrest as can chronic maternal nicotine exposure in fetal monkeys [34]. Thus there are multiple adverse exposures that have in common the ability to interfere with lung development. Many of these factors that can inhibit lung development are inflammatory.
Fetal and neonatal exposures to glucocorticoids Single- and multiple-dose glucocorticoid effects on the fetal lung in experimental animals Since this article focuses on the very preterm infant, the discussion is limited primarily to glucocorticoid effects on the pre-alveolarized lung. Glucocorticoid exposure of the fetal lung upregulates numerous genes and down-regulates others, and for some genes such as SP-A low doses upregulate and high doses suppress gene expression [35]. In the mid-to-late gestation monkey, maternal glucocorticoid treatments have both acute and chronic effects on the fetal lung. A dose of 0.3 mg/kg betamethasone for 3 days or for 13 days before preterm delivery at 133 days gestation caused mesenchymal thinning and a large increase in maximal lung gas volumes but with minimal effects on surfactant phospholipids (Fig. 4) [36,37]. When fetuses that were exposed to 0.3 mg/kg betamethasone from 120 to 132 days gestation were subsequently delivered at 160 days gestation, the alveolar number, lung surface area and lung gas volumes expressed per kg body weight were
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Figure 4. Effect of maternal betamethasone (Beta) treatments (0.3 mg/kg for 13 days from 120 to 132 days gestation) on fetal lung gas volumes for monkeys that were delivered at 133 or 165 days gestation. At 133 days gestation betamethasone increased lung volumes while by 165 days gestation the early gestational treatment with betamethasone resulted in lower lung volumes. Data from [37].
decreased. These results demonstrate acute increases in lung gas volumes induced by maternal glucocorticoids but an adverse effect on subsequent alveolarization and lung growth. Bunton and Plopper [38] found that 3 days of maternal treatment with high dose triamcinolone acetonide during the pseudoglandular (63–65 days gestation) or canalicular (110–112 days gestation) stages of monkey lung development caused loss of lung interstitial tissue resulting in more mature appearing lungs after preterm delivery. However, when delivery was close to term a severe interference with alveolarization was apparent. These results indicate that the fetal primate lung is sensitive to a ‘lung maturational’ stimulus by mid-gestation. However, high or prolonged fetal exposures cause an inhibition of subsequent lung development. Newborn mice and rats are born with saccular lungs at term, and postnatal glucocorticoid treatments cause a delay in alveolar and vascular development that persists as the animals age [39]. In fetal sheep a single maternal or fetal dose of glucocorticoids at 120 days gestation when the lung is beginning to alveolarize will increase fetal lung gas volumes within 24 hours but with an inhibition in alveolar number [40,41]. If delivery occurs at term, lung gas volumes and lung anatomy are normal [42]. The information from single fetal exposures in sheep suggest no long term adverse
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effects on lung structure. Experimental results in monkeys and sheep demonstrate acute effects of glucocorticoids primarily on lung structure with minimal effects on the surfactant system. There is much less information available about repetitive doses or courses of antenatal glucocorticoids at intervals that are relevant to clinical practice. Although repetitive doses of maternal betamethasone when given to mice cause lung structural maturation and when given to rabbits increase surfactant proteins A and B more than single doses, the short gestations and rapid growth rates complicate the interpretation [43,44]. There is no information on repetitive doses or courses at weekly intervals in primates. In fetal sheep lung structural changes, improvements in lung function after preterm delivery, and increases in mRNA for the surfactant proteins occur within 15 to 24 hours [40]. Surfactant lipid and protein pools in alveolar washes do not increase until 4 to 7 days after fetal glucocorticoid exposure, and the glucocorticoid induced improvements in lung function persist for at least 7 days [45]. The improvements in lung function after a single dose of glucocorticoids result in decreased severity of RDS, and do not prevent the clinical disease in sheep. Therefore we evaluated if a further augmentation of lung function could be achieved with repeated doses of glucocorticoids given at 1 week intervals (Fig. 5). Fetal sheep were given 0.5 mg/kg betamethasone at 7 days intervals prior to preterm delivery and evaluation at 125 days gestation [46]. For all indicators of lung function, surfactant pools in alveolar washes, and antioxidant protection, the lungs seemed to benefit cumulatively from the weekly exposures [47,48]. Alveolar volume increased and alveolar number decreased more after 3 doses than after 1 dose of betamethasone when assessed at 125 days gestation, but lung structure was not altered when delivery was delayed until term [49]. A curious observation was that the lung maturational effects of betamethasone were greater when the betamethasone was given to the ewe rather than when the foetus was treated directly, although fetal plasma betamethasone levels were lower after the maternal treatments [50]. The experimental data demonstrate that lung function after preterm delivery can be improved by repetitive glucocorticoid exposures. The results in monkeys indicate that there may be persistent effects on alveolar development if the glucocorticoids are given before alveolarization has begun or are given in repetitive high doses.
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Antenatal single- and multiple-dose glucocorticoid effects on clinical pulmonary outcomes The multiple clinical trials of antenatal glucocorticoid treatments from the initial trial of Liggins and Howie in 1972 through the 1990s had as the primary outcome a decrease in the incidence of RDS. The Crowley meta-analysis demonstrated definitively that antenatal glucocorticoids decreased the incidence of RDS by about 50% without much impact on the other major respiratory outcome of BPD [51]. This lack of effect of antenatal glucocorticoid treatment on BPD probably results from the increased survival of infants most at risk for BPD. A limitation of the clinical trials is that there is minimal information for infants less than 28 weeks gestation. Garite et al. [52] found no decrease in RDS at earlier gestations, but their results clearly demonstrated benefit because of a decreased severity of RDS and a much lower incidence of severe intraventricular haemorrhage. The results from animal models indicate that the fetal lung should be responsive at gestations as early as 20 weeks [53], although the risks for interfering with subsequent normal development are higher. No adverse long term outcomes after a single course of antenatal glucocorticoids have been reported. Dessens et al. [54] evaluated young adults at an average age of 20 years after randomization to antenatal glucocorticoids and delivery at an average gestation of 32 weeks. There were no differences in growth, blood pressure, cognitive function or educational achievements. Another follow-up report of 14-year-old children with a birth weight average of 1200 g and a gestational age average of 29 weeks found that the children exposed to a single course of glucocorticoids were taller and had better cognitive function than did the comparison group, although the antenatal glucocorticoid exposure was not randomized [55]. There were no differences in lung function at 14 years of age. There is no new information since 1994 to alter the recommendations of the Consensus Conference on Antenatal Steroids that virtually all women at risk of preterm delivery should receive a single course of glucocorticoids. New information does suggest that 2 doses of 12 mg betamethasone given at a 24 h interval are preferable to other dosing schedules or to dexamethasone [56]. A question left unresolved by the Consensus Conference in 1994 was the value of using repetitive courses of antenatal glucocorticoids for
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Figure 5. Effect of repetitive fetal exposures to 0.5 mg/kg betamethasone given at weekly intervals before preterm delivery at 125 days gestation. In comparison to saline-treated controls, lung function as assessed by compliance and lung gas volumes increased with repetitive doses of betamethasone. Surfactant as indicated by saturated phosphatidylcholine (Sat PC) and SP-A in alveolar washes also increased with repetitive doses of betamethasone. The antioxidant enzyme superoxide dismutase increased and, the protein carbonyls as indicators of oxidant injury decreased with increasing doses of betamethasone given at weekly intervals. Data from [46,47,48].
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women at continued risk of preterm delivery but who had not delivered within 7 to 10 days of the initial treatment [57]. A single course of antenatal glucocorticoid decreases the incidence of RDS by only 50%, and the results with fetal sheep demonstrate added benefit to subsequent courses. In explant cultures of human lungs, glucocorticoids induce the surfactant system only when they are present [58]. The stimulation of the mRNAs for the surfactant proteins disappears when glucocorticoids are removed. This same effect occurs in fetal sheep where the increase in mRNAs for the surfactant proteins persists for only a few days after the fetal glucocorticoid exposure [59]. The clinical data suggest a loss of glucocorticoid effects about 7 days after antenatal glucocorticoid treatments [51]. Also, in animal models, larger improvements in lung function after preterm delivery may occur with treatments at later gestational ages [50]. The experimental results clearly support cumulative benefit from repeated doses of antenatal glucocorticoids when given at a 7 days interval. However, the experimental literature also indicates potential risks – with the major risks being decreased fetal growth and concerns about the long term adverse effects on lung and brain development [37,60,61] (see other articles in this issue). Repetitive courses of antenatal glucocorticoids have been rapidly accepted into clinical practice despite a lack of clinical data demonstrating benefit. Numerous abstracts and a few complete papers have been published demonstrating either benefit or no benefit and either risk or no risk using retrospective analyses of data bases that did not randomize for repetitive courses of glucocorticoids. As is common in this situation, the reports with the most adverse outcomes probably are preferentially published. French et al. [62] found that both birth weight and head circumference decreased as number of courses of antenatal glucocorticoids increased without any benefit of less RDS for more than 1 course of treatment. There was a tendency to increased BPD for infants exposed to 3 or more courses of antenatal glucocorticoids. Of more concern, Banks et al. [63] found no decrease in RDS for repetitive courses of glucocorticoids relative to a single course but decreased fetal size and increased death as adverse outcomes. In contrast, Abbasi et al. [64] reported a significant decrease in RDS for infants exposed to 2 or more compared to 1 course of antenatal glucocorticoids. In support of a pulmonary benefit, McEvoy et al. [65] found improved lung mechanics after preterm birth in infants that
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had been exposed to repetitive glucocorticoids relative to infants not exposed or exposed more than 7 days from the time of delivery. This inconsistent information and the potential risks resulted in the Consensus Statement from the Antenatal Corticosteroids Revisited: Repeat Courses Conference in 2000 that repetitive courses should be used only within the context of randomized clinical trials [4]. The option to give a second course only if preterm delivery is imminent (the ‘rescue’ dosing strategy) was also not recommended outside of trials. This latter approach is logical based on what is known about the biology of glucocorticoid effects, although safety or benefit have not been demonstrated.
Effects of glucocorticoids on the newborn lung The postnatal use of glucocorticoids has been primarily to prevent or treat BPD. The rationale for the multiple clinical trials of various treatment, doses, durations, and ages at initiating treatments is that the inflammation and injury associated with ventilation and oxygen exposure can be minimized and thus BPD can be minimized [66]. Based on aspirates from the airways of preterm infants, it is clear that glucocorticoid treatments can suppress a number of indicators of inflammation/injury. The clinical trials demonstrate that glucocorticoid treatments can acutely improve lung function, facilitate extubation and have modest effects on the incidence of BPD defined as oxygen at 36 weeks [67–69]. There is virtually no experimental literature on the effects of glucocorticoids on the injured preterm lung. As noted above, the major effect of glucocorticoids on the pre-alveolarized postnatal rodent lung is to decrease alveolar and vascular development [39].
The combined responses of the developing lung to glucocorticoids and inflammation The experimental models demonstrate that the normal fetal lung responds in predictable and somewhat similar ways to pro-inflammatory stimuli and glucocorticoids. Both induce lung maturation and inhibit alveolar development. However, the clinical situation is much more complex. Women
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Figure 6. Effect of exposure of the fetal sheep to maternal betamethasone (Beta) and/or intra-amniotic endotoxin (Endo) 7 days before preterm delivery at 125 days gestation. Chord blood white blood cells and cells in the alveolar washes were similar for animals exposed to endotoxin or betamethasone plus endotoxin. Lung gas volume increased more with endotoxin plus betamethasone than with betamethasone alone, and all three treatment groups had more saturated phosphatidylcholine (Sat PC) than did the control group, although the amounts tended to be higher in the endotoxin exposed groups (data from Newnham et al. [72].
with fetuses experiencing preterm labour are not normal. As emphasized above, many preterm fetuses destined to be born before 30 weeks are exposed to inflammation from chorioamnionitis, and the process of labour itself has inflammatory characteristics [1]. Gravett et al. [70] recently showed that cortisol levels were elevated in the amniotic fluid of infants exposed to chorioamnionitis, indicating activation of the fetal adrenal axis. Watterberg [71] noted also that cortisol levels were higher for preterm infants delivered after chorioamnionitis and hypothesized that the decreased risks of RDS resulted from the induction of cortisol in the infants exposed to chorioamnionitis. In unstressed ‘normal’ fetal sheep inflammation is associated with lung maturation independently of fetal cortisol [20]. However, the human fetus may have a chronic inflammatory stimulus, elevated cortisol from fetal stress, preterm labour, and other unidentified stimuli. Furthermore, the recommendation that all women at risk of preterm delivery receive glucocorticoids means that many fetuses
exposed to the clinically silent chorioamnionitis before 30 weeks gestation will also be exposed to glucocorticoids, perhaps even repetitive courses of glucocorticoids. In fetal sheep the simultaneous exposure to intra-amniotic endotoxin and maternal betamethasone 7 days before preterm delivery results in an elevation of chord blood white cells similar to the increase caused by endotoxin (Fig. 6) [72]. The addition of the glucocorticoids did not suppress the number of inflammatory cells in peripheral blood, alveolar washes, or change the amount of saturated phosphatidylcholine recovered by alveolar wash. Lung function after preterm delivery tended to be better after the combined fetal exposure to betamethasone and endotoxin than to either stimulus alone. Far more needs to be known about possible interactions, but empirically very preterm infants exposed to chorioamnionitis and antenatal glucocorticoids seem to do better than those exposed to neither factor [10]. We view postnatal glucocorticoids in principle as a continuation of the fetal effects superimposed
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on the lung inflammation/injury sequence resulting from mechanical ventilation and oxygen exposure. The major difference is the much higher dose and longer duration of exposure to glucocorticoids. The concern is that both inflammatory stimuli and glucocorticoid exposures of the fetal or neonatal lung before and during the stage of alveolarization could disrupt subsequent alveolar and vascular development. The combination of both stimuli, especially when present in the developing lung for prolonged periods, has not been evaluated. We speculate that much of the new pathology of an arrest in lung development resulting in the new BPD results from these interactions. Acknowledgements This work was supported and depends on research from the National Institute of Health grants HD-12714 and HL-65397.
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10 Costeloe K, Hennessy E, Gibson AT, Marlow N, Wilkinson AR. The EPICure study: outcomes to discharge from hospital for infants born at the threshold of viability. Pediatrics 2000; 106: 659–671. 11 Watterberg KL, Demers LM, Scott SM, Murphy S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 1996; 97: 210–215. 12 Hannaford K, Todd DA, Jeffery H, John E, Blyth K, Gilbert GL. Role of ureaplasma urealyticum in lung disease of prematurity. Archives of Disease in Childhood, Fetal and Neonatal Edition 1999; 81: F162–167. 13 Bancalari E, Gonzalez A. Clinical course and lung function abnormalities during development of neonatal chronic lung disease. In: Bland RD, Coalson JJ (eds) Chronic Lung Disease in Early Infancy. New York: Marcel Dekker, Inc., 2000; 41–64. 14 Charafeddine L, D’Angio CT, Phelps DL. Atypical chronic lung disease patterns in neonates. Pediatrics 1999; 103: 759–765. 15 Jobe AH. The New BPD: An arrest of lung development. Pediatric Research 1999; 46: 641–643. 16 Bry K, Lappalainen U, Hallman M. Intraamniotic interleukin-1 accelerates surfactant protein synthesis in fetal rabbits and improves lung stability after premature birth. Journal of Clinical Investigation 1997; 99: 2992–2999. 17 Glumoff V, Vayrynen O, Kangas T, Hallman M. Degree of lung maturity determines the direction of the interleukin-1-induced effect on the expression of surfactant proteins. American Journal of Respiratory Cell and Molecular Biology 2000; 22: 280–288. 18 Willet K, Kramer BW, Kallapur SG, Ikegami M, Newnham J, Moss T, Sly P, Jobe A. Intra-amniotic injection of IL-1 induces inflammation and maturation in fetal sheep lung. American Journal of Physiology 2001; 282: L411–420. 19 Jobe AH, Newnham JP, Willet KE, Sly P, Ervin MG, Backurski C, Possmayer F, Hallman M, Ikegami M. Effects of antenatal endotoxin and glucocorticoids on the lungs of preterm lambs. American Journal of Obstetrics and Gynecology 2000; 182: 401–408. 20 Jobe AH, Newnham JP, Willet KE, Moss TJ, Ervin MG, Padbury JF, Sly PD, Ikegami M. Endotoxin induced lung maturation in preterm lambs is not mediated by cortisol. Am J Respirt Crit Care Med 2000; 162: 1656–1661. 21 Kallapur SG, Willet KE, Jobe AH, Ikegami M, Bachurski C. Intra-amniotic endotoxin: Chorioamnionitis precedes lung maturation in preterm lambs. American Journal of Physiology 2001; 280: L527–L536. 22 Bachurski CJ, Ross GF, Ikegami M, Kramer BW, Jobe AH. Intra-amniotic endotoxin increases pulmonary surfactant components and induces SP-B processing in fetal sheep. American Journal of Physiology 2001; 280: L279–L285. 23 Tremblay LN, Slutsky AS, Dreyfuss D, Saumon G. Ventilator-induced lung injury: Mechanisms and clinical correlates. In: Marini JJ, Slutsky AS (eds) Physiological Basis of Ventilatory Support. New York: Marcel Dekker Inc., 1998; 395–451. 24 Murphy DB, Cregg N, Tremblay L, Engelberts D, Laffey JG, Slutsky AS, Romaschin A, Kavanagh BP. Adverse ventilatory strategy causes pulmonary-to-systemic translocation of endotoxin. American Journal of Respiratory and Critical Care Medicine 2000; 162: 27–33.
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25 Naik AS, Kallapur SG, Bachurski CJ, Jobe AH, Michna J, Kramer BW, Ikegami M. Effects of ventilation with different positive end-expiratory pressures on cytokine expression in the preterm lamb lung. American Journal of Respiratory and Critical Care Medicine 2001; in press. 26 Kramer BW, Jobe AH, Ikegami M. Systemic inflammation following intratracheal endotoxin that leaks into the circulation despite gentle ventilation of preterm lambs. American Journal of Respiratory and Critical Care Medicine 2001; 163: A209. 27 Speer CP, Groneck P. Oxygen radicals, cytokines, adhesion molecules and lung injury in neonates. Seminars in Neonatology 1998; 3: 219–228. 28 Bancalari E. Neonatal chronic lung disease. In: Fanaroff AA, Martin RJ (eds) Neonatal–Perinatal Medicine. St Louis: Mosby, 1997; 1074–1089. 29 Hussain NA, Siddiqui NH, Stocker JR. Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia. Hum Pathol 1998; 29: 710–717. 30 Thibeault DW, Mabry SM, Ekekezie II, Truog WE. Lung elastic tissue maturation and perturbations during the evolution of chronic lung disease. Pediatrics 2000; 106: 1452–1459. 31 Albertine KH, Jones GP, Starcher BC, Bohnsack JF, Davis PL, Cho S, Carlton DP, Bland RD. Chronic lung injury in preterm lambs. American Journal of Respiratory and Critical Care Medicine 1999; 159: 945–958. 32 Warner BB, Stuart LA, Papes RA, Wispe JR. Functional and pathological effects of prolonged hyperoxia in neonatal mice. American Journal of Physiology 1998; 275: L110–117. 33 Coalson JJ, Winter VT, Siler-Khodr T, Yoder BA. Neonatal chronic lung disease in extremely immature baboons. American Journal of Respiratory and Critical Care Medicine 1999; 160: 1333–1346. 34 Sekhon HS, Jia Y, Raab R, Kuryatov A, Pankow JF, Whitsett JA, Lindstrom J, Spindel ER. Prenatal nicotine increases pulmonary alpha7 nicotinic receptor expression and alters fetal lung development in monkeys. Journal of Clinical Investigation 1999; 103: 637–647. 35 Liley HG, White RT, Benson BJ, Ballard PL. Glucocorticoids both stimulate and inhibit production of pulmonary surfactant protein A in fetal human lung. Proceedings of the National Academy of Science of the United States of America 1988; 85: 9096–9100. 36 Johnson JWC, Mitzner W, London WT, Palmer AE, Scott R, Kearney K. Glucocorticoids and the rhesus fetal lung. American Journal of Obstetrics and Gynecology 1978; 130: 905–916. 37 Johnson JWC, Mitzner W, Beck JC, London WT, Sly DL, Lee PA, Khouzami VA, Cavalieri RL. Long-term effects of betamethasone on fetal development. American Journal of Obstetrics and Gynecology 1981; 141: 1053–1061. 38 Bunton TE, Plopper CG. Triamcinolone-induced structural alterations in the development of the lung of the fetal rhesus macaque. American Journal of Obstetrics and Gynecology 1984; 148: 203–215. 39 Massaro DJ, Massaro GD. The regulation of the formation of pulmonary alveoli. In: Bland RD, Coalson JJ (eds) Chronic Lung Disease in Early Infancy. New York: Marcel Dekker, Inc., 2000; 137: 479–492.
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40 Ikegami M, Polk D, Jobe A. Minimum interval from fetal betamethasone treatment to postnatal lung responses in preterm lambs. American Journal of Obstetrics and Gynecology 1996; 174: 1408–1413. 41 Willet K, Jobe A, Ikegami M, Sly P. Lung morphometry in preterm sheep following antenatal endotoxin exposure. Pediatric Research 2000; 48: 782–788. 42 Jobe AH, Polk DH, Ervin MG, Padbury JF, Rebello CM, Ikegami M. Preterm betamethasone treatment of fetal sheep: Outcome after term delivery. J Soc Gynecol Invest 1996; 3: 250–258. 43 Stewart JD, Sienko AE, Gonzalez CL, Christensen HD, Rayburn WF. Placebo-controlled comparison between a single dose and a multidose of betamethasone in accelerating lung maturation of mice offspring. American Journal of Obstetrics and Gynecology 1998; 179: 1241–1257. 44 Pratt L, Magness RR, Phernetton T, Hendricks SK, Abbott DH, Bird IM. Repeated use of betamethasone in rabbits: effects of treatment variation on adrenal suppression, pulmonary maturation, and pregnancy outcome. American Journal of Obstetrics and Gynecology 1999; 180: 995–1005. 45 Ikegami M, Polk DH, Jobe AH, Newnham J, Sly P, Kohan R, Kelly R. Effect of interval from fetal corticosteroid treatment to delivery on postnatal lung function of preterm lambs. Journal of Applied Physiology 1996; 80: 591–597. 46 Ikegami M, Jobe AH, Newnham J, Polk DH, Willet KE, Sly P. Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs. American Journal of Respiratory and Critical Care Medicine 1997; 156: 178–184. 47 Ballard PL, Ning Y, Polk D, Ikegami M, Jobe A. Glucocorticoid regulation of surfactant components in immature lambs. American Journal of Physiology 1997; 273: L1048–L1057. 48 Walther FJ, Jobe AH, Ikegami M. Repetitive prenatal glucocorticoid therapy reduces oxidative stress in the lungs of preterm lambs. Journal of Applied Physiology 1998; 85: 273–278. 49 Willet KE, Jobe AH, Ikegami M, Kovar J, Sly PD. Lung morphometry after repetitive antenatal glucocorticoid treatment in preterm sheep. American Journal of Respiratory and Critical Care Medicine 2001; 163: 1437–1443. 50 Jobe AH, Newnham J, Willet K, Sly P, Ikegami M. Fetal Versus Material and Gestational Age Effects of Repetitive Antenatal Glucocorticoids. Pediatrics 1998; 102: 1116– 1125. 51 Crowley P. Antenatal corticosteroid therapy: A metaanalysis of the randomized trials—1972–1994. American Journal of Obstetrics and Gynecology 1995; 173: 322–335. 52 Garite TJ, Rumney PJ, Briggs GG, Harding JA, Nageotte MP, Towers CV, Freeman RK. A randomized placebocontrolled trial of betamethasone for the prevention of respiratory distress syndrome at 24 to 28 weeks’ gestation. American Journal of Obstetrics and Gynecology 1992; 166: 646–651. 53 Jobe AH, Ikegami M. Fetal Responses to Glucocorticoids. In: Mendelson CR (ed.) Endocrinology of the Lung. Humana Press, 2000; 45–57. 54 Dessens AB, Haas HS, Koppe JG. Twenty-year follow-up of antenatal corticosteroid treatment. Pediatrics 2000; 105: E77.
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55 Doyle LW, Ford GW, Rickards AL, Kelly EA, Davis NM, Callanan C, Olinsky A. Antenatal corticosteroids and outcome at 14 years of age in children with birth weight less than 1501 grams. Pediatrics 2000; 106: E2. 56 Baud O, Foix-L’Helias L, Kaminski M, Audibert F, Jarreau PH, Papiernik E, Huon C, Lepercq J, Dehan M, LacazeMasmonteil T. Antenatal glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants. New England Journal of Medicine 1999; 341: 1190– 1196. 57 Consensus development panel on the effects of corticosteroids for fetal maturation on perinatal outcomes. Journal of the American Medical Association 1995; 273: 413–418. 58 Gonzales LW, Ballard PL, Ertsey R, Williams MC. Glucocorticoids and thyroid hormones stimulate biochemical and morphological differentiation of human fetal lung in organ culture. J Clin Endocrinol Metab 1986; 62: 678–691. 59 Tan RC, Ikegami M, Jobe AH, Possmayer F, Ballard PL. Developmental and glucocorticoid regulation of surfactant protein mRNAs in preterm lambs. American Journal of Physiology 1999; 277: L1142–1148. 60 Jobe AH, Wada N, Berry LM, Ikegami M, Ervin MG. Single and repetitive maternal glucocorticoid exposures reduce fetal growth in sheep. American Journal of Obstetrics and Gynecology 1998; 178: 880–885. 61 Uno H, Lohmiller L, Thieme C, Kemnitz JW, Engle MJ, Roecker EB, Farrell PM. Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques. Dev Brain Res 1990; 53: 157–167. 62 French NP, Hagan R, Evans SF, Godfrey M, Newnmham JP. Repeated antenatal corticosteroids: size at birth and subsequent development. American Journal of Obstetrics and Gynecology 1999; 180: 114–121. 63 Banks BA, Cnaan A, Morgan MA, Parer JT, Merrill JD, Ballard PL, Ballard RA. Multiple courses of antenatal corticosteroids and outcome of premature neonates. Am J Obstet Gynecol 1999; 181: 709–717.
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64 Abbasi S, Hirsch D, Davis J, Tolosa J, Stouffer N, Debbs R, Gerdes JS. Effect of single versus multiple courses of antenatal corticosteroids on maternal and neonatal outcome. American Journal of Obstetrics and Gynecology 2000; 182: 1243–1249. 65 McEvoy C, Bowling S, Williamson K, Collins J, Tolaymat L, Maher J. Timing of antenatal corticosteroids and neonatal pulmonary mechanics. American Journal of Obstetrics and Gynecology 2000; 183: 895–899. 66 Bancalari E. Corticosteroids and neonatal chronic lung disease. European Journal of Pediatrics 1998; 157: S31–S37. 67 Halliday HL, Ehrenkranz RA. Delayed (>3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants. The Cochrane Library 1999. 68 Halliday HL, Ekrenkranz RA. Moderately early (7–14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants (Cochrane Review). The Cochrane Library 1999; Oxford Update Software. 69 Halliday HL, Ehrenkranz RA. Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants (Cochrane Review). The Cochrane Library 1999. 70 Gravett MG, Hitti J, Hess DL, Eschenbach DA. Intrauterine infection and preterm delivery: evidence for activation of the fetal hypothalamic-pituitary-adrenal axis. American Journal of Obstetrics and Gynecology 2000; 182: 1404–1413. 71 Watterberg KL, Scott SM, Naeye RL. Chorioamnionitis, cortisol, and acute lung disease in very low birth weight infants. Pediatrics 1997; 99: E6. 72 Newnham JP, Moss TJ, Padbury JF, Willet KE, Ikegami M, Ervin MG, Sly P, Jobe AH. The interactive effects of endotoxin with prenatal glucocorticoids on short-term lung functions in sheep. American Journal of Obstetrics and Gynecology 2001; 185: 190–197.
Glucocorticoids, inflammation and the perinatal lung Alan H. Jobe
Children’s Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, OH, USA
Key words: RDS, BPD, alveolarization, cytokines, endotoxin, betamethasone, chorioamnionitis
Many women delivering preterm infants at less than 30 weeks gestation have subclinical chorioamnionitis. Based on current guidelines, maternal glucocorticoid treatment is given to induce lung maturation. Fetal exposure to proinflammation can cause acute and chronic injury, but inflammation also can induce fetal lung maturation. Both antenatal glucocorticoids and inflammation modulate lung development, by inducing the surfactant system, inducing structural maturation, and inhibiting alveolarization. The opportunities for the future are to develop new safer strategies to mature the preterm foetus, and the risks are potential adverse interactions of repetitive glucocorticoid exposures and unrecognized fetal exposure to inflammation. 2002 Elsevier Science Ltd
An overview Traditionally inflammation resulting from infection or injury and lung maturation have been considered separately. However, fetal exposure to chorioamnionitis followed by early gestational preterm labour may be the rule rather than the exception [1]. Similarly, once preterm delivery has occurred at 26 weeks in the example in Figure 1, then the initiation of ventilation, subsequent ventilatory support and supplemental oxygen will promote inflammation [2]. Against this background of proinflammatory events antenatal glucocorticoids are used to induce early lung maturation and postnatal glucocorticoids are used to decrease the risk or severity of lung injury. Both inflammation and glucocorticoids are acting on a fetal or neonatal lung at 26 weeks gestation that has just transitioned from the canalicular stage to the saccular stage of lung anatomic development [3]. This lung is 4 to 6 weeks from the initiation of alveolarization. Glucocorticoids and inflammatory exposures can each cause both clinical lung maturation and alterations in lung development indicative of Correspondence to: Alan H. Jobe, MD, PhD, Children’s Hospital Medical Center, Division of Pulmonary Biology, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA. Tel.: +1 (513) 636 8563; Fax: +1 (513) 636 8691; E-mail: jobeaØ@chmcc.org
1084–2756/01/$-see front matter
injury. This chapter will begin to explore the relationships between inflammation and steroids in the developing lung. The fact that the exposures may be antenatal, postnatal, or both probably is more situational than biologically distinct in terms of lung development. The widespread use of repetitive courses of antenatal glucocorticoids and the frequent use of high-dose, long duration postnatal glucocorticoid treatments are not supported by clinical data of either efficacy or safety [4]. This chapter will begin with a discussion of inflammation, then a review of glucocorticoid effects on lung maturation, and finally will link these two important factors in outcomes of very preterm infants.
Fetal inflammation Fetal exposures to inflammation Traditionally chorioamnionitis was thought to be an acute infection of the fetal membranes, amniotic fluid and potentially the fetus, primarily by high virulence organisms ascending from the lower genital tract. Organisms such as E. coli, Listeria monocytogenes, and Group B Streptococci certainly can cause acute infection resulting in preterm labour and severe complications for the newborn. © 2002 Elsevier Science Ltd
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Figure 1. Diagram emphasizing antenatal and postnatal inflammatory events that may influence lung development of a preterm infant delivered at 26 weeks gestational age. The potential glucocorticoid exposures also are indicated. The lung of the human fetus at 26 weeks gestation is in the saccular stage of lung structural development.
A recent pathologic series demonstrated that 27% of infants with birth weights <1 kg that came to autopsy died from or with severe infection in the lungs acquired antenatally [5]. However, the more commonly low grade, indolent chorioamnionitis that is present but clinically silent over weeks and perhaps months ultimately results in preterm labour between 20 and 30 weeks gestation [1]. Histologic chorioamnionitis and fetal membranes that are culture positive with organisms such as Ureaplasma urealyticum, Mycoplasma and Gardnerella are very frequently associated with preterm deliveries before 30 weeks gestation. Amniotic fluid from women in preterm labour often is culture-positive for the same organisms and that amniotic fluid contains increased numbers of granulocytes and increased levels of pro-inflammatory cytokines such as IL-1, IL-6, IL-8, and TNF [6,7]. Most women at risk of preterm labour are now receiving antenatal glucocorticoids and many will have subclinical chorioamnionitis. Preterms born after chorioamnionitis may have elevated plasma
levels of indicators of pro-inflammatory exposure such as IL-6 [8]. These infants can also have tracheal aspirates positive for Ureaplasma urealyticum, and elevated white blood cells and cytokines in tracheal aspirates but initial blood cultures are rarely positive.
Consequences of fetal exposure to inflammation Severe fetal infection with invasive organisms will cause fetal death or severe pneumonia/sepsis after birth. Preterm infants exposed to elevated proinflammatory cytokines in amniotic fluid or who have a systemic inflammatory response as indicated by elevated IL-6 in cord blood may have more severe RDS and have an increased risk of developing BPD [8,9]. However, the outcomes of many very preterm fetuses exposed to chorioamnionitis is quite different. Infants born at less than 26 weeks
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gestation in the United Kingdom had higher overall survival rates if they were exposed to histologic chorioamnionitis [10]. In selected series, infants born after exposure to chorioamnionitis or who were tracheal aspirate culture positive for Ureaplasma urealyticum were less likely to have RDS but were more likely to develop BPD [11,12]. A number of reports identify a population of infants that have minimal or no RDS after birth but who develop BPD despite minimal mechanical ventilation or supplemental oxygen [13,14]. The explanation for the decreased incidence of RDS may be antenatal exposure to chorioamnionitis while the later progression to BPD may result from progression of the antenatal pro-inflammatory exposure. We have hypothesized that the newborn lung exposed to fetal inflammation may respond with an augmented and prolonged inflammatory response to subsequent newborn care practices such as the use of supplemental oxygen and mechanical ventilation with the result being BPD [15]. The clinical observations that chorioamnionitis may initially be good for the preterm fetus by decreasing RDS are consistent with some experimental results. A decrease in RDS means clinically ‘induced lung maturation’ in very preterm infants. Does the ‘induced lung maturation’ from chorioamnionitis have elements in common with lung maturation induced by antenatal glucocorticoid treatments? Pro-inflammatory stimuli certainly can increase indicators of surfactant and improve lung mechanics. Bry et al. [16] found that intra-amniotic IL-1 increased the mRNAs for the surfactant proteins and improved lung compliance of rabbits delivered preterm. Subsequently Glumoff et al. [17] noted that IL-1 induced surfactant protein mRNAs in lung explants from early gestation rabbits but suppressed the same mRNAs in explants from rabbits close to term. These results demonstrate a direct effect of IL-1 on the fetal lung, which appears to be gestation-dependent. We recently found that recombinant ovine IL-1 or IL-1 when given by intra-amniotic injection at 118 days gestation to fetal sheep induced chorioamnionitis. At delivery 7 days later at 125 days gestation (term=150 days), the lung had increased numbers of white blood cells, indicating inflammation, and improved lung mechanics and increased surfactant lipids and proteins [18]. Therefore, a single pro-inflammatory cytokine can induce fetal-lung maturation, but that maturation was associated with chorioamnionitis.
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Figure 2. Patterns of responses of the fetal sheep to intra-amniotic exposure to endotoxin before preterm delivery at 125 days gestation at the intervals indicated on the horizontal axis. Inflammation indicated by the increased expression of IL-1 mRNA in amnion/chorion and lung tissue increases within 5 hours. The mRNA for SP-A increased by 1 day after endotoxin exposure and remained elevated for 15 days. The amount of SP-A and saturated phosphatidylcholine (Sat PC) were increased significantly by 4 to 7 days. Please note log scales for the inflammation and surfactant measurements. Lung function after preterm delivery also was improved by 4 to 7 days after intra-amniotic endotoxin. Data from [20,21,22].
To model a general pro-inflammatory stimulus, we gave intra-amniotic injections of E. coli endotoxin to sheep in various doses and durations before preterm delivery [19,20]. The endotoxin recruits granulocytes, which express proinflammatory cytokine mRNA, to the amnion/ chorion and amniotic fluid within 5 h (Fig. 2) [21]. The same cytokine expression is highest in the lung at 1 to 2 days. Pro-inflammatory cells also accumulate rapidly in the lungs but are minimally activated within 4 days of the intra-amniotic exposure. The first indication of a maturational stimulus is an increase in the mRNAs for the surfactant proteins within 24 h, although lung mechanics and surfactant proteins and lipids in alveolar washes do
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not increase for 4 to 7 days after the intra-amniotic endotoxin [22]. The mRNAs for the surfactant proteins and other indicators of lung maturation are elevated relative to controls even when the endotoxin was given 15 or 25 days before delivery at 125 days gestation. Fetal cord cortisol values do not increase very much after the inflammation induced by endotoxin or IL-1, indicating that the maturational effect was not dependent on endogenous cortisol [20].
Neonatal inflammation Neonatal exposure to inflammation Once preterm birth has occurred, much of what is standard neonatal care has a pro-inflammatory component. In the mature lung ventilation from tidal volumes below normal functional residual capacity causes injury with the expression of proinflammatory cytokines [23]. Similarly, ventilation of the normal lung to volumes that approach or exceed total lung capacity causes injury and cytokine expression. Ventilation of the injured lung can cause the release of pro-inflammatory mediators, endotoxin and bacteria into the systemic circulation [24]. We evaluated the initiation of mechanical ventilation in preterm lambs and found that recruitment of activated granulocytes and expression of IL-1, IL-6 and IL-8 occurred despite the use of surfactant treatment before the first breath, positive end expiratory pressure, and low tidal volumes to avoid hyperventilation (Fig. 3) [25]. The initiation of ventilation without positive end expiratory pressure resulted in larger proinflammatory responses. Ventilation of preterm lungs that contain endotoxin in the surfactant results in loss of the endotoxin to the systemic circulation [26]. There is no information about how the preterm lung responds to the spontaneous initiation of ventilation using continuous positive airway pressure only. However, our results indicate that any mechanical ventilation can initiate an inflammatory response. If that newborn were exposed to chorioamnionitis, then the lung would already be manifesting an inflammatory response and ventilation could amplify that response and cause pro-inflammatory mediators to spill from the lungs into the systemic circulation. There is an extensive literature based on airway aspirates from ventilated preterm infants demon-
Figure 3. Inflammatory responses of preterm lamb lungs to the initiation of mechanical ventilation. Preterm lambs were treated with surfactant and mechanical ventilation was initiated with tidal volumes of 10 ml/kg using PEEP values of 0, 4, or 7 cmH2O. Neutrophils in alveolar washes and IL-1 mRNA in lung tissues were measured after 2 hours of ventilation. All styles of ventilation resulted in increased expression of IL-1 mRNA and recruitment of neutrophils to the lungs. Data from [25].
strating elevations in white blood cells, proinflammatory cytokines, leukotrienes, and other mediators and indicators of inflammation [27]. In general, infants with elevated indicators of inflammation/injury in airway aspirates progress to BPD. The three factors thought to contribute to this pro-inflammatory response of the preterm lung are ventilation (stretch, barotrauma, volutrauma), supplemental oxygen, and pneumonia/sepsis [28]. In experimental models, each factor can injure the lung and all three commonly occur in the very preterm infant.
Consequences of neonatal exposures to inflammation The pathologic characteristics of the lungs of preterm infants dying of BPD have changed as
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increasingly smaller infants survive, and techniques to ventilate infants have improved. The fibrotic parenchymal and inflammatory airway disease that resulted primarily from barotrauma and oxygen now are less frequent [29]. The pathology more commonly indicates an interference in the ability of the preterm lung to alveolarize and vascularize [30]. Multiple factors can inhibit alveolarization in experimental models. Mice that over-express the pro-inflammatory cytokines TNF, TGF, IL-6 and IL-11 have an arrest in alveolar development [15]. Inflammatory stimuli such as mechanical ventilation, chronic elevated oxygen exposure, and colonization of the lung with low pathogenic organisms have been associated with an arrest in alveolar development in humans and experimental animals [31–33]. Starvation can augment the alveolar arrest as can chronic maternal nicotine exposure in fetal monkeys [34]. Thus there are multiple adverse exposures that have in common the ability to interfere with lung development. Many of these factors that can inhibit lung development are inflammatory.
Fetal and neonatal exposures to glucocorticoids Single- and multiple-dose glucocorticoid effects on the fetal lung in experimental animals Since this article focuses on the very preterm infant, the discussion is limited primarily to glucocorticoid effects on the pre-alveolarized lung. Glucocorticoid exposure of the fetal lung upregulates numerous genes and down-regulates others, and for some genes such as SP-A low doses upregulate and high doses suppress gene expression [35]. In the mid-to-late gestation monkey, maternal glucocorticoid treatments have both acute and chronic effects on the fetal lung. A dose of 0.3 mg/kg betamethasone for 3 days or for 13 days before preterm delivery at 133 days gestation caused mesenchymal thinning and a large increase in maximal lung gas volumes but with minimal effects on surfactant phospholipids (Fig. 4) [36,37]. When fetuses that were exposed to 0.3 mg/kg betamethasone from 120 to 132 days gestation were subsequently delivered at 160 days gestation, the alveolar number, lung surface area and lung gas volumes expressed per kg body weight were
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Figure 4. Effect of maternal betamethasone (Beta) treatments (0.3 mg/kg for 13 days from 120 to 132 days gestation) on fetal lung gas volumes for monkeys that were delivered at 133 or 165 days gestation. At 133 days gestation betamethasone increased lung volumes while by 165 days gestation the early gestational treatment with betamethasone resulted in lower lung volumes. Data from [37].
decreased. These results demonstrate acute increases in lung gas volumes induced by maternal glucocorticoids but an adverse effect on subsequent alveolarization and lung growth. Bunton and Plopper [38] found that 3 days of maternal treatment with high dose triamcinolone acetonide during the pseudoglandular (63–65 days gestation) or canalicular (110–112 days gestation) stages of monkey lung development caused loss of lung interstitial tissue resulting in more mature appearing lungs after preterm delivery. However, when delivery was close to term a severe interference with alveolarization was apparent. These results indicate that the fetal primate lung is sensitive to a ‘lung maturational’ stimulus by mid-gestation. However, high or prolonged fetal exposures cause an inhibition of subsequent lung development. Newborn mice and rats are born with saccular lungs at term, and postnatal glucocorticoid treatments cause a delay in alveolar and vascular development that persists as the animals age [39]. In fetal sheep a single maternal or fetal dose of glucocorticoids at 120 days gestation when the lung is beginning to alveolarize will increase fetal lung gas volumes within 24 hours but with an inhibition in alveolar number [40,41]. If delivery occurs at term, lung gas volumes and lung anatomy are normal [42]. The information from single fetal exposures in sheep suggest no long term adverse
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effects on lung structure. Experimental results in monkeys and sheep demonstrate acute effects of glucocorticoids primarily on lung structure with minimal effects on the surfactant system. There is much less information available about repetitive doses or courses of antenatal glucocorticoids at intervals that are relevant to clinical practice. Although repetitive doses of maternal betamethasone when given to mice cause lung structural maturation and when given to rabbits increase surfactant proteins A and B more than single doses, the short gestations and rapid growth rates complicate the interpretation [43,44]. There is no information on repetitive doses or courses at weekly intervals in primates. In fetal sheep lung structural changes, improvements in lung function after preterm delivery, and increases in mRNA for the surfactant proteins occur within 15 to 24 hours [40]. Surfactant lipid and protein pools in alveolar washes do not increase until 4 to 7 days after fetal glucocorticoid exposure, and the glucocorticoid induced improvements in lung function persist for at least 7 days [45]. The improvements in lung function after a single dose of glucocorticoids result in decreased severity of RDS, and do not prevent the clinical disease in sheep. Therefore we evaluated if a further augmentation of lung function could be achieved with repeated doses of glucocorticoids given at 1 week intervals (Fig. 5). Fetal sheep were given 0.5 mg/kg betamethasone at 7 days intervals prior to preterm delivery and evaluation at 125 days gestation [46]. For all indicators of lung function, surfactant pools in alveolar washes, and antioxidant protection, the lungs seemed to benefit cumulatively from the weekly exposures [47,48]. Alveolar volume increased and alveolar number decreased more after 3 doses than after 1 dose of betamethasone when assessed at 125 days gestation, but lung structure was not altered when delivery was delayed until term [49]. A curious observation was that the lung maturational effects of betamethasone were greater when the betamethasone was given to the ewe rather than when the foetus was treated directly, although fetal plasma betamethasone levels were lower after the maternal treatments [50]. The experimental data demonstrate that lung function after preterm delivery can be improved by repetitive glucocorticoid exposures. The results in monkeys indicate that there may be persistent effects on alveolar development if the glucocorticoids are given before alveolarization has begun or are given in repetitive high doses.
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Antenatal single- and multiple-dose glucocorticoid effects on clinical pulmonary outcomes The multiple clinical trials of antenatal glucocorticoid treatments from the initial trial of Liggins and Howie in 1972 through the 1990s had as the primary outcome a decrease in the incidence of RDS. The Crowley meta-analysis demonstrated definitively that antenatal glucocorticoids decreased the incidence of RDS by about 50% without much impact on the other major respiratory outcome of BPD [51]. This lack of effect of antenatal glucocorticoid treatment on BPD probably results from the increased survival of infants most at risk for BPD. A limitation of the clinical trials is that there is minimal information for infants less than 28 weeks gestation. Garite et al. [52] found no decrease in RDS at earlier gestations, but their results clearly demonstrated benefit because of a decreased severity of RDS and a much lower incidence of severe intraventricular haemorrhage. The results from animal models indicate that the fetal lung should be responsive at gestations as early as 20 weeks [53], although the risks for interfering with subsequent normal development are higher. No adverse long term outcomes after a single course of antenatal glucocorticoids have been reported. Dessens et al. [54] evaluated young adults at an average age of 20 years after randomization to antenatal glucocorticoids and delivery at an average gestation of 32 weeks. There were no differences in growth, blood pressure, cognitive function or educational achievements. Another follow-up report of 14-year-old children with a birth weight average of 1200 g and a gestational age average of 29 weeks found that the children exposed to a single course of glucocorticoids were taller and had better cognitive function than did the comparison group, although the antenatal glucocorticoid exposure was not randomized [55]. There were no differences in lung function at 14 years of age. There is no new information since 1994 to alter the recommendations of the Consensus Conference on Antenatal Steroids that virtually all women at risk of preterm delivery should receive a single course of glucocorticoids. New information does suggest that 2 doses of 12 mg betamethasone given at a 24 h interval are preferable to other dosing schedules or to dexamethasone [56]. A question left unresolved by the Consensus Conference in 1994 was the value of using repetitive courses of antenatal glucocorticoids for
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Figure 5. Effect of repetitive fetal exposures to 0.5 mg/kg betamethasone given at weekly intervals before preterm delivery at 125 days gestation. In comparison to saline-treated controls, lung function as assessed by compliance and lung gas volumes increased with repetitive doses of betamethasone. Surfactant as indicated by saturated phosphatidylcholine (Sat PC) and SP-A in alveolar washes also increased with repetitive doses of betamethasone. The antioxidant enzyme superoxide dismutase increased and, the protein carbonyls as indicators of oxidant injury decreased with increasing doses of betamethasone given at weekly intervals. Data from [46,47,48].
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women at continued risk of preterm delivery but who had not delivered within 7 to 10 days of the initial treatment [57]. A single course of antenatal glucocorticoid decreases the incidence of RDS by only 50%, and the results with fetal sheep demonstrate added benefit to subsequent courses. In explant cultures of human lungs, glucocorticoids induce the surfactant system only when they are present [58]. The stimulation of the mRNAs for the surfactant proteins disappears when glucocorticoids are removed. This same effect occurs in fetal sheep where the increase in mRNAs for the surfactant proteins persists for only a few days after the fetal glucocorticoid exposure [59]. The clinical data suggest a loss of glucocorticoid effects about 7 days after antenatal glucocorticoid treatments [51]. Also, in animal models, larger improvements in lung function after preterm delivery may occur with treatments at later gestational ages [50]. The experimental results clearly support cumulative benefit from repeated doses of antenatal glucocorticoids when given at a 7 days interval. However, the experimental literature also indicates potential risks – with the major risks being decreased fetal growth and concerns about the long term adverse effects on lung and brain development [37,60,61] (see other articles in this issue). Repetitive courses of antenatal glucocorticoids have been rapidly accepted into clinical practice despite a lack of clinical data demonstrating benefit. Numerous abstracts and a few complete papers have been published demonstrating either benefit or no benefit and either risk or no risk using retrospective analyses of data bases that did not randomize for repetitive courses of glucocorticoids. As is common in this situation, the reports with the most adverse outcomes probably are preferentially published. French et al. [62] found that both birth weight and head circumference decreased as number of courses of antenatal glucocorticoids increased without any benefit of less RDS for more than 1 course of treatment. There was a tendency to increased BPD for infants exposed to 3 or more courses of antenatal glucocorticoids. Of more concern, Banks et al. [63] found no decrease in RDS for repetitive courses of glucocorticoids relative to a single course but decreased fetal size and increased death as adverse outcomes. In contrast, Abbasi et al. [64] reported a significant decrease in RDS for infants exposed to 2 or more compared to 1 course of antenatal glucocorticoids. In support of a pulmonary benefit, McEvoy et al. [65] found improved lung mechanics after preterm birth in infants that
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had been exposed to repetitive glucocorticoids relative to infants not exposed or exposed more than 7 days from the time of delivery. This inconsistent information and the potential risks resulted in the Consensus Statement from the Antenatal Corticosteroids Revisited: Repeat Courses Conference in 2000 that repetitive courses should be used only within the context of randomized clinical trials [4]. The option to give a second course only if preterm delivery is imminent (the ‘rescue’ dosing strategy) was also not recommended outside of trials. This latter approach is logical based on what is known about the biology of glucocorticoid effects, although safety or benefit have not been demonstrated.
Effects of glucocorticoids on the newborn lung The postnatal use of glucocorticoids has been primarily to prevent or treat BPD. The rationale for the multiple clinical trials of various treatment, doses, durations, and ages at initiating treatments is that the inflammation and injury associated with ventilation and oxygen exposure can be minimized and thus BPD can be minimized [66]. Based on aspirates from the airways of preterm infants, it is clear that glucocorticoid treatments can suppress a number of indicators of inflammation/injury. The clinical trials demonstrate that glucocorticoid treatments can acutely improve lung function, facilitate extubation and have modest effects on the incidence of BPD defined as oxygen at 36 weeks [67–69]. There is virtually no experimental literature on the effects of glucocorticoids on the injured preterm lung. As noted above, the major effect of glucocorticoids on the pre-alveolarized postnatal rodent lung is to decrease alveolar and vascular development [39].
The combined responses of the developing lung to glucocorticoids and inflammation The experimental models demonstrate that the normal fetal lung responds in predictable and somewhat similar ways to pro-inflammatory stimuli and glucocorticoids. Both induce lung maturation and inhibit alveolar development. However, the clinical situation is much more complex. Women
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Figure 6. Effect of exposure of the fetal sheep to maternal betamethasone (Beta) and/or intra-amniotic endotoxin (Endo) 7 days before preterm delivery at 125 days gestation. Chord blood white blood cells and cells in the alveolar washes were similar for animals exposed to endotoxin or betamethasone plus endotoxin. Lung gas volume increased more with endotoxin plus betamethasone than with betamethasone alone, and all three treatment groups had more saturated phosphatidylcholine (Sat PC) than did the control group, although the amounts tended to be higher in the endotoxin exposed groups (data from Newnham et al. [72].
with fetuses experiencing preterm labour are not normal. As emphasized above, many preterm fetuses destined to be born before 30 weeks are exposed to inflammation from chorioamnionitis, and the process of labour itself has inflammatory characteristics [1]. Gravett et al. [70] recently showed that cortisol levels were elevated in the amniotic fluid of infants exposed to chorioamnionitis, indicating activation of the fetal adrenal axis. Watterberg [71] noted also that cortisol levels were higher for preterm infants delivered after chorioamnionitis and hypothesized that the decreased risks of RDS resulted from the induction of cortisol in the infants exposed to chorioamnionitis. In unstressed ‘normal’ fetal sheep inflammation is associated with lung maturation independently of fetal cortisol [20]. However, the human fetus may have a chronic inflammatory stimulus, elevated cortisol from fetal stress, preterm labour, and other unidentified stimuli. Furthermore, the recommendation that all women at risk of preterm delivery receive glucocorticoids means that many fetuses
exposed to the clinically silent chorioamnionitis before 30 weeks gestation will also be exposed to glucocorticoids, perhaps even repetitive courses of glucocorticoids. In fetal sheep the simultaneous exposure to intra-amniotic endotoxin and maternal betamethasone 7 days before preterm delivery results in an elevation of chord blood white cells similar to the increase caused by endotoxin (Fig. 6) [72]. The addition of the glucocorticoids did not suppress the number of inflammatory cells in peripheral blood, alveolar washes, or change the amount of saturated phosphatidylcholine recovered by alveolar wash. Lung function after preterm delivery tended to be better after the combined fetal exposure to betamethasone and endotoxin than to either stimulus alone. Far more needs to be known about possible interactions, but empirically very preterm infants exposed to chorioamnionitis and antenatal glucocorticoids seem to do better than those exposed to neither factor [10]. We view postnatal glucocorticoids in principle as a continuation of the fetal effects superimposed
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on the lung inflammation/injury sequence resulting from mechanical ventilation and oxygen exposure. The major difference is the much higher dose and longer duration of exposure to glucocorticoids. The concern is that both inflammatory stimuli and glucocorticoid exposures of the fetal or neonatal lung before and during the stage of alveolarization could disrupt subsequent alveolar and vascular development. The combination of both stimuli, especially when present in the developing lung for prolonged periods, has not been evaluated. We speculate that much of the new pathology of an arrest in lung development resulting in the new BPD results from these interactions. Acknowledgements This work was supported and depends on research from the National Institute of Health grants HD-12714 and HL-65397.
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