rhKGF stimulates lung surfactant production in neonatal rats in vivo

Abstract

Surfactant deficiency and bronchopulmonary dysplasia (BPD), major obstacles in preterm infants, are addressed with pre- and postnatal glucocorticoids which also evoke harmful catabolic side-effects. Keratinocyte growth factor (KGF) accelerates surfactant production in fetal type II pneumocytes (PN-II), protects epithelia from injury and is deficient in lungs developing BPD, highlighting its potential efficacy in neonates. Neonatal rats were treated with recombinant human (rh)KGF, betamethasone, or their combination for 48 hr prior to sacrifice after which body weight, surfactant, and tissue phosphatidylcholines (PC) were investigated at postnatal d3, d7, d15, and d21. Pneumocyte proliferation, surfactant protein (SP) expression and SP-B/C in lung lavage fluid (LLF) were also determined at d7 and d21 to identify broader surfactant changes occurring at the beginning and end of the initial alveolarization phase. While all treatments increased secreted surfactant PC, BM compromised animal growth whereas rhKGF did not. At d3 rhKGF was more effective in male compared to female rats. Single treatments became less effective towards d21. Neither treatment altered PC composition in LLF. BM inhibited PN-II proliferation and increased surfactant PCs at the expense of tissue PCs. rhKGF however increased surfactant PCs without decreasing other PC species. Whereas SP-B/C gene expression was induced by all treatments, the changes in secreted SP-B/C mirrored those observed for surfactant PC. Our results encourage investigation of the mechanisms by which rhKGF improves surfactant homoeostasis, and detailed examination of its efficacy in neonatal lung injury models with a view to implementing it as a non-catabolic surfactant-increasing therapeutic in neonatal intensive care.

Phosphatidylcholine kinetics in neonatal rat lungs and the effects of rhuKGF and betamethasone

“…5A) but not to docosahexaenoic acid-containing PC (C22:6-D 9 -PC), demonstrating the differential kinetics of individual PC components. Particularly in response to rhuKGF treatment, an increase in C22:6-PC in the lung has already been described, where docosahexaenoic acid is substrate for the production of antiinflammatory resolvins (15,22).…”

“…However, before addressing pulmonary PC metabolism under pathological conditions, it is essential to understand the principles of PC metabolism in healthy immature lungs. We have previously characterized the effects of betamethasone and rhuKGF on lung tissue and surfactant PC in rat lungs from postnatal day (d)3 to d21, demonstrating increased PC pools and a shift from tissue PC toward secreted surfactant (22). However, the underlying mechanisms of such effects have not yet been elucidated.…”

What is the identity of fibroblast-pneumocyte factor?

“…KGF induces surfactant production both in vitro and in vivo (17, 26, 27). Incorporation of [ 3 H]-choline into disaturated surfactant phospholipids in fetal alveolar type II cells is significantly enhanced by KGF.…”

Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre‐clinical models

“…However, controlled administration of palifermin to neonatal and adult animals had a more benign effect, whether given intratracheally (IT) or intravenously (IV): a dose-dependent stimulation of alveolar and bronchial epithelial proliferation [200,201]. Studies show that KGF also regulates lung barrier function including ion and fluid transport in normal and injured tissue [202][203][204][205][206][207][208][209] as well as surfactant homeostasis [37, [210][211][212]. Besides its direct effects on the alveolar epithelium, it may also influence integrity of the pulmonary endothelial barrier via regulation of paracrine factors such as VEGF [213].…”