Mediators of the fetal pulmonary response to intrauterine inflammation
Creators: name: Westover, Alana Jasmine
Publisher: name: Monash University
Year: 2017
Subjects: Uncategorized

description: INTRAUTERINE inflammation is a major cause of preterm birth, which, in turn, is associated with an increased risk of neonatal morbidity and mortality (Goldenberg et al. 2000; Schelonka and Waites 2007). However, clinical studies correlate intrauterine inflammation with a decreased incidence of respiratory distress syndrome (RDS), and experimental studies indicate that inflammation stimulates surfactant production and improves preterm lung function (Jobe et al. 2000; Moss et al. 2002a; Moss et al. 2002b). The underlying mechanisms whereby inflammation induces preterm lung ‘maturation’ are not known but it has been suggested that these effects may be mediated by activating a fetal stress response, resulting in increased circulating cortisol levels (Watterberg et al. 1997), known to have a critical role in lung maturation (Laatikainen et al. 1988; Ye et al. 2004). This now appears unlikely but it is possible that proinflammatory stimuli may modulate enzymatic regulation of cortisol to influence its tissue availability, or may alter tissue sensitivity to cortisol by altering its receptor levels. Alternatively, the maturational effects within the preterm lung may be mediated by prostaglandins (PGs), fundamental inflammatory mediators with established roles in mediating lung maturation (Bustos et al. 1978; Morsy et al. 2001). Therefore, the general aims of this thesis were two-fold: to investigate how intrauterine inflammation may alter tissue availability of, and sensitivity to, cortisol in the fetal lung; and to examine the role of prostaglandins in the fetal pulmonary response to intrauterine inflammation. Tissue availability of cortisol is modulated by expression of the enzymes 11β hydroxysteroid dehydrogenase (HSD) type-1 and -2. 11β-HSD-1 converts inactive cortisone to cortisol, increasing local levels and availability of cortisol for glucocorticoid signalling, whereas 11β-HSD-2 catalyzes the reverse reaction (Chapman et al. 2006). The effects of intrauterine inflammation on the 11β-HSD enzymes and the glucocorticoid receptor (GR), which mediates the majority of glucocorticoid actions (Rupprecht et al. 1993; Schaaf and Cidlowski 2003), had not been investigated in the fetal lung in vivo prior to the studies presented in this thesis. The experiments in Chapter 3 demonstrated that fetal sheep lung GR mRNA levels are not altered in response to intra-amniotic (IA) lipopolysaccharide (LPS), indicating that inflammation-induced changes in fetal lung development are not likely to be mediated by increases in tissue sensitivity to cortisol. However, IA LPS induced a time-specific increase in 11β-HSD-1 and decrease in 11β-HSD-2 mRNA levels in the fetal lung that accompanied increases in surfactant protein mRNA levels and improvements in lung compliance. These data indicate that IA LPS may increase local tissue availability of glucocorticoids, and suggest that locally-produced glucocorticoids may mediate, at least in part, the fetal lung’s response to intra-uterine inflammation. Although inflammation alters 11β-HSD enzyme expression in the lungs, it appears that inflammation-induced lung maturation occurs via an additional mechanism to glucocorticoid signaling given that the characteristics of the fetal lung response to inflammation are different to those of glucocorticoid-induced lung maturation in preterm lambs (Sweet et al. 2008; Moss et al. 2009). Prostaglandins may represent an alternative mechanism for inflammation-induced lung maturation given that some, such as PGE2, are known to increase surfactant production by the preterm fetal lung (Acarregui et al. 1990; Morsy et al. 2001). This is supported by the data in Chapter 4, which demonstrate that IA LPS induces increases in amniotic fluid PGE2 and lung mRNA levels of PGH synthase-2, PGE synthase, and one of the PGE2 receptors, EP4 in response to intrauterine inflammation. Assessment of responses 2 and 7 days after IA LPS administration, enabled us to distinguish when these changes in gene expression occur relative to the changes in lung maturation. Thus, these findings suggest that increased PGE2 synthesis and activity play a role in mediating inflammation-induced alterations in fetal lung development. In Chapter 5, the aim was to further elucidate the role of prostaglandins in the fetal pulmonary response to intra-uterine inflammation. We used a maternal nimesulide infusion to preferentially inhibit inducible prostaglandin production and to assess the effects on the fetal lung’s response to a proinflammatory stimulus in vivo. Nimesulide inhibited LPS-induced increases in PGE2 concentrations, reduced fetal lung inflammation and altered mRNA levels of surfactant proteins, EP receptors, and prostaglandin synthetic enzymes in the fetal lung. The data in Chapter 5 show that inducible prostaglandin inhibition modulates the inflammatory response in the fetal lung and alters surfactant protein mRNA levels, thereby providing some of the strongest evidence to date that inducible prostaglandins have a critical role in mediating the fetal lung’s response to intrauterine inflammation. In conclusion, these studies increase our understanding of the likely mediators involved in inflammation-induced fetal lung maturation and support the theory that these changes are not mediated by increases in circulating cortisol. IA LPS may regulate pulmonary expression of 11β-HSD-1 and -2 to increase local availability of cortisol in the fetal lung, although further investigation is required to confirm the precise roles of these enzymes in the fetal lung’s response to inflammation. Defining these roles may be particularly complex since the response in the lungs may not be directly mediated by an increase in tissue availability of cortisol, but by cortisol activation of different pathways, such as that of prostaglandins. Indeed, we showed that prostaglandins have a regulatory role in the development of an inflammatory response to IA LPS and gene expression of the surfactant proteins in vivo. This suggests that inducible prostaglandins are likely to be involved in mediating fetal lung maturation in response to intrauterine inflammation. Understanding the effects and mechanisms of inflammation-induced changes in lung development will ultimately enable the development of alternative therapies that prevent the adverse respiratory consequences of preterm birth.