Sound the Tocsin! Beware Adverse Effects of Lung Inflammation Early in Gestation

David Warburton, M.D.

Developmental Biology Program, Childrens Hospital Los Angeles Research Institute, USC Keck School of Medicine and School of Dentistry, Los Angeles, California

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Premature delivery of the human fetus places it at risk of dying from respiratory insufficiency, also known as respiratory distress syndrome or hyaline membrane disease. In relatively large premature infants (more than 30 weeks gestation), classical hyaline membrane disease is associated with alveolar surfactant deficiency, in the presence of relatively mature lung structure. Alveolar surfactant lipid and protein deficiency can now be readily corrected with exogenous natural surfactants. But as increasing numbers of extremely premature infants have survived (less than 30 weeks gestation), pulmonary structural immaturity has become the major problem. In fact, arrest of alveolar development is now seen as the major pathobiologic feature of infantile chronic lung disease, also known as "new" bronchopulmonary dysplasia, which occurs in a high proportion of extremely premature infants (1).

Antenatal corticosteroids are now routinely given to human mothers in premature labor with the objective of acutely improving neonatal lung function. But this treatment has the potential side effect of exacerbating the arrest of alveolar development (2, 3). Hence, a search is on for other therapeutic targets that might enhance neonatal lung function among the extremely premature, without causing subsequent arrest of alveolar development.

Recently, a number of key studies have been done in the catheterized fetal sheep model, showing that inflammatory mediators, such as lipopolysaccharide (LPS) endotoxin, can affect various key aspects of fetal lung maturation (4-9). This could be clinically important because human premature delivery is associated with or caused by chorioamnionitis in a very high proportion of cases. Thus, if a bacterially derived inflammatory mediator such as LPS endotoxin proved to be a powerful accelerator of fetal surfactant and/or structural maturation, this could identify a whole new set of potential therapeutic targets.

Now it seems that the timing of exposure to LPS endotoxin during gestation may be critical in determining whether the fetal lung responds predominantly with chronic inflammation, adaptively with increased maturation and improved lung mechanics, and/or with long-term alveolar hypoplasia. This addresses the controversy of whether early exposure to inflammatory mediators can have beneficial or adverse effects on the developing lung.

In this issue of AJRCCM (pp. 805-811), Moss and coworkers (10) have approached this question by giving intra-amniotic doses of Escherichia coli-LPS endotoxin, beginning during the pseudoglandular period (60 days), at the transition to the canalicular stage (80 days), and during the canalicular stage (100 days) of sheep gestation (term 150 days). They found that lung structure and function and the surfactant system were all significantly affected by endotoxin at all of these stages, but the responses differed depending on the gestational timing. In general, early endotoxin exposure increased tissue pools, but not alveolar pools of surfactant phospholipids and proteins, while inducing some thinning of the interstitial mesenchyme; whereas in more mature fetuses, the effects of endotoxin on accelerating lung functional maturation were comparable to or greater than a single dose of corticosteroids (4). Moreover, giving both endotoxin and corticosteroids appeared to be additive in terms of improvements in lung function but not in alveolar surfactant lipid and protein pools (8).

Whereas in the most immature fetuses initial airway inflammation following intra-amniotic endotoxin tended to subside, endotoxin induced persistent inflammation in those fetuses 80 days and older. Also, importantly, overall lung size and alveolar numbers decreased by as much as 30%. Thus, the authors draw functional parallels between the abnormally persistent lung inflammation found in both premature baboons and humans who experience alveolar hypoplasia as the cardinal feature of their chronic lung disease.

It is perhaps not surprising that the introduction of inflammation during extreme prematurity perturbs lung development. Normal lung development is determined by a finely regulated balance between transcriptional factors, peptide growth factor signaling, matrix components, and physical forces (11). Release of LPS endotoxin by microbes contaminating the amniotic and/or tracheal fluid could activate the recently described Toll-like receptors in the lung and hence perturb this critical balance (12, 13). Alternatively, although this is apparently not the case in sheep (5), in human fetuses it seems that endotoxemia might stimulate the release of cortisol by the fetal pituitary-adrenal axis.

Either way, early fetal exposure to LPS endotoxin does not seem to be particularly beneficial for lung development. Although, after 30 weeks gestation, an endotoxin-mediated increase in alveolar surfactant lipids and proteins with mesenchymal thinning may be useful adaptive responses that could help to prepare the fetal lung to withstand the impending catastrophe of premature delivery.

Perhaps, when the tocsin sounds in the struggle for life, relative hypo-alveolarization later on in life could be viewed as an acceptable trade-off for immediate death due to immaturity of the pulmonary surfactant pool size. But this theoretical selection advantage might only be expected in relatively big premature babies, with relatively mature lung development, having the potential for surviving neonatal respiratory distress syndrome/hyaline membrane disease. Unfortunately, it does not seem likely that LPS endotoxin will prove to be a magic bullet for preventing infantile chronic lung disease/bronchopulmonary dysplasia in the extremely premature without inducing eventual alveolar hypoplasia. Rather, minimizing mechanical trauma to the airway and hence minimizing the induction of airway inflammation would seem more advisable (14).

	References

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