Abstract 54

Background: Bacterial products, including endotoxin, induce synthesis of primary proinflammatory cytokines, IL-1α, IL-1β, and TNFα that induce a number of secondary proinflammatory cytokines and other mediators, producing an inflammatory response. In intrauterine infections, endotoxin and cytokines accumulate in the amniotic fluid, promoting premature birth and accelerating the maturation of the fetal lung. It is unknown, whether endotoxin directly accelerates the fetal lung maturity. The aim of the present study was to identify the primary inflammatory mediators that regulate the expression of surfactant proteins.

Methods: Explants from immature (22 fetal days) to mature (newborn, 2 days) rabbit lungs were cultured for 7 to 48 hours in the presence of E. coli endotoxin 055:B5 (10-1000 µg/ml)), IL-1α (57-570 ng/ml), TNF (10-100 ng/ml), or vehicle. Expression of SP-A, SP-B and SP-C mRNA was quantilated on the basis of 28S rRNA.

Results: In explants from immature lung, IL-1α upregulated SP-A and -B mRNAs. TNF had no effect, whereas IL-1+TNF synergistically upregulated SP-A mRNAs. In mature lung, IL-1 and TNF additively suppressed SP-B and -C mRNAs. In immature lung, endotoxin (10-1000 µg/ml) had no effect on SP mRNAs, whereas in mature lung, endotoxin (10-1000 µg/ml) decreased the expression of surfactant proteins within 20 h: SP-A (at 10 µg/ml: 46±2% of vehicle), SP-B (55±17% of vehicle) and SP-C (61±7% of vehicle).

Conclusions. As shown in the present study, IL-1 or combination of IL-1 and TNF induce surfactant proteins in explants from immature lung, whereas endotoxin did not. Earlier data indicate that intra-amniotic IL-1 or endotoxin induce striking maturation of the fetal lung (including upregulation of surfactant proteins), whereas a low dose of intrafetal IL-1 or endotoxin is lethal. According to present evidence, proinflammatory cytokines, derived from amniotic fluid via the airways, accelerate the fetal lung maturity. Response of perinatal lung to endotoxin is strikingly dependent on the degree of lung maturity.