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The effects of neuregulin-1β on synthesis and secretion of surfactant phosphatidylcholine by cultured fetal rat type II pneumocytes

King, George (2013) The effects of neuregulin-1β on synthesis and secretion of surfactant phosphatidylcholine by cultured fetal rat type II pneumocytes. PhD thesis, Murdoch University.

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In the latter stages of gestation the fetal lung undergoes biochemical maturation leading to the acquisition of the capacity to synthesize pulmonary surfactant. If insufficient amounts of surfactant are generated neonatal respiratory distress syndrome (NRDS) is likely to occur. The production of surfactant is known to involve a cellular communication between lung fibroblasts and the adjacent type II pneumocytes. Glucocorticoids have been shown to induce the production by lung fibroblasts of a soluble peptide, fibroblast-pneumocyte factor (FPF), which in turn acts on type II pneumocytes to enhance the synthesis of surfactant (Smith, 1978). Although Torday et al. (2002) have proposed that leptin has many of the characteristics of FPF, recent research has revealed that the peptide neuregulin-1β also has many of these characteristics (Dammann et al., 2003). `
Neuregulin was first purified from brain tissue and named glial growth factor (Brockes et al., 1980). Subsequently, it was established that the neuregulins are a family of EGF-like growth factors that have been shown to be present in an increasing number of tissues and organisms. Neuregulin-1β stimulates both cell growth and differentiation in a range of target tissues by binding to ErbB3 and ErbB4 receptors thus stimulating the phosphorylation of tyrosine residues of the ErbB receptors and inducing receptor heterodimerization (Riese et al., 1995; Carraway III et al., 1997; Crovello et al., 1998; Mautino et al., 2004). iv

In this study, a commercially available form of neuregulin-1β (heregulin-1β) has been shown to directly stimulate synthesis of surfactant phospholipids in cultured fetal rat type II pneumocytes. Prior exposure of the type II cells to 20-50 ng.mL-1 heregulin-1β for 21 hours led to a more than 3-fold increase in the rate of phospholipid synthesis (p < 0.05), a result similar to that previously observed in cells exposed to leptin (Torday et al., 2002). In addition to this effect, 50 ng.mL-1 heregulin-1β was also shown to directly increase the rate of secretion of surfactant phospholipids from type II cells by 2.4-fold (p < 0.05). Furthermore, exposure of type II cells to this peptide enhances by approximately 2-fold the β-AR activity and, as a consequence, elevates the rate of (—)-isoproterenol-induced surfactant phospholipid secretion to the same extent. Although heregulin-1β alone has no effect on β-AR gene expression in type II cells, the level of expression of this gene was synergistically enhanced when the cells were exposed to both dexamethasone and this peptide. Thus, overall, these findings not only support but considerably extend the concept promoted by Dammann et al. (2003) that neuregulin-1β plays an essential role in the differentiation and maturation of the lung in the later stages of gestation. Moreover, they suggest that neuregulin-1β is a significant component of FPF.
In summary, this study has shown that in type II cells neuregulin-1β enhances both surfactant phospholipid synthesis and secretion, elevates the level of β-adrenergic receptors and boosts the response of both male- and female- derived cells to β-agonists. It is therefore suggested that the administration of neuregulin-1β, in combination with antenatal glucocorticoid treatment, may provide an improved therapeutic mechanism of preventing respiratory distress syndrome of premature infants.

Publication Type: Thesis (PhD)
Murdoch Affiliation: School of Veterinary and Life Sciences
Supervisor: Cake, Max, Berryman, David and Maker, Garth
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