Surfactant metabolism and anti-oxidative capacity in hyperoxic neonatal rat lungs: effects of keratinocyte growth factor on gene expression in vivo

Abstract

Development of preterm infant lungs is frequently impaired resulting in bronchopulmoary dysplasia (BPD). BPD results from interruption of physiologic anabolic intrauterine conditions, the inflammatory basis and therapeutic consequences of premature delivery, including increased oxygen supply for air breathing. The latter requires surfactant, produced by alveolar type II (AT II) cells to lower surface tension at the pulmonary air:liquid interface. Its main components are specific phosphatidylcholine (PC) species including dipalmitoyl-PC, anionic phospholipids and surfactant proteins. Local antioxidative enzymes are essential to cope with the pro-inflammatory side effects of normal alveolar oxygen pressures. However, respiratory insufficiency frequently requires increased oxygen supply. To cope with the injurious effects of hyperoxia to epithelia, recombinant human keratinocyte growth factor (rhKGF) was proposed as a surfactant stimulating, non-catabolic and epithelial-protective therapeutic. The aim of the present study was to examine the qualification of rhKGF to improve expression parameters of lung maturity in newborn rats under hyperoxic conditions (85% O(2) for 7 days). In response to rhKGF proliferating cell nuclear antigen mRNA, as a feature of stimulated proliferation, was elevated. Similarly, the expressions of ATP-binding cassette protein A3 gene, a differentiation marker of AT II cells and of peroxiredoxin 6, thioredoxin and thioredoxin reductase, three genes involved in oxygen radical protection were increased. Furthermore, mRNA levels of acyl-coA:lysophosphatidylcholine acyltransferase 1, catalyzing dipalmitoyl-PC synthesis by acyl remodeling, and adipose triglyceride lipase, considered as responsible for fatty acid supply for surfactant PC synthesis, were elevated. These results, together with a considerable body of other confirmative evidence, suggest that rhKGF should be developed into a therapeutic option to treat preterm infants at risk for impaired lung development.

Targeting the Thioredoxin System as a Strategy for Cancer Therapy

“…A recent report also showed that TrxR may help regulate redox balance, the survival of rheumatoid synoviocytes, and celluar responses to different cytotoxic drugs and protect damaged neurons from oxidative stress . TrxR mRNA expression in AEC II was also associated with exposure to hyperoxia . This finding further indicated that the cytoplasmic Trx system may play a key role in this mechanism.…”

“…90 TrxR mRNA expression in AEC II was also associated with exposure to hyperoxia. 91 This finding further indicated that the cytoplasmic Trx system may play a key role in this mechanism.…”

The Histochem Cell Biol conspectus: the year 2013 in review

“…Since normal alveolar oxygen pressures lead to pro-inflammatory effects, the presence of local antioxidants is necessary to negate such effects. Since the surfactant-stimulating recombinant human keratinocyte growth factor (rhKGF) has been proposed to assist in diminishing the injurious effects of hyperoxia on pulmonary epithelial cells, Koslowski et al (2013) performed experiments to investigate the use of rhKGF in improving expression parameters of lung maturity in newborn rats subjected to hyperoxia. In response to rhKGF treatment, they found the following results: (1) increased PCNA mRNA expression, indicating enhanced cell proliferation; (2) increased expression of three genes involved in oxygen radical protection (ATP-binding cassette protein A3, thioredoxin, and thioredoxin reductase); and (3) increased mRNA levels of acyl-coA:lysophosphatidylcholine acyltransferase I (catalyzes dipalmitoyl-PC synthesis) and adipose triglyceride lipase (supplies fatty acids for surfactant PC synthesis).…”