Regulation of surfactant proteins by LPS and proinflammatory cytokines in fetal and newborn lung

Abstract

Intra-amniotic lipopolysaccharide (LPS) and cytokines may decrease respiratory distress syndrome (RDS) and increase chronic lung disease in the newborn. The aim was to identify the primary inflammatory mediators regulating the expression of surfactant proteins (SP) in explants from immature (22-day-old fetus) and mature (30-day term fetus and 2-day-old newborn) rabbits. In immature lung, interleukin (IL)-1alpha and IL-1beta upregulated the expression of SP-A and SP-B. These effects of IL-1 were diminished, and SP-C mRNA was suppressed additively in the presence of tumor necrosis factor (TNF)-alpha and either LPS or interferon (IFN)-gamma. LPS, TNF-alpha, or IFN-gamma had no effect alone. In explants from the term fetus and the newborn, LPS, IL-1alpha, and TNF-alpha additively suppressed the SPs. LPS acutely induced IL-1alpha in alveolar macrophages in mature lung but not in the immature lung. IFN-gamma that generally has low expression in intrauterine infection decreased the age dependence of the other agonists' effects on SPs. The present study serves to explain the variation of the pulmonary outcome after an inflammatory insult. We propose that IL-1 from extrapulmonary sources induces the SPs in premature lung and is responsible for the decreased risk of RDS in intra-amniotic infection.

Inflammatory and Anti-inflammatory Responsiveness of Surfactant Proteins in Fetal and Neonatal Rabbit Lung

“…In infants born after 31 wk of gestation, the risk of RDS was significantly higher in preterm premature rupture of fetal membranes than in gestational controls without antenatal steroid prophylaxis (22). This finding is consistent with experimental evidence (25,38). After birth, a strong inflammatory reaction is evident in the airways and alveolar spaces in BPD (39) and in acute RDS (40).…”

“…the differentiation takes place spontaneously without added agonists, and it is difficult to relate the dose responsiveness rates of the steroid or cytokine in vitro and in vivo. However, the cytokine-induced expression of SP mRNA has also been shown at the level of SP (25,38). In addition, the documented cytokine and glucocorticoid effects in vitro reveal similarities compared with animal experiments demonstrating a decrease in the severity of RDS.…”

Antenatal inflammation and lung injury: prenatal origin of neonatal disease

“…60 Similar findings have been obtained in lung explants in which the presence of macrophages was mandatory for lung maturation after endotoxin administration. 61 Our current understanding is that fetal lung responds to proinflammatory mediators in amniotic fluid with a recruitment of inflammatory cells, which may be the major source of IL-1b, which in turn initiates maturational signals. Figure 3 Modulation of effects of transforming growth factor-b1 (TGF-b1) in endotoxin-induced chorioamnionitis.…”

Protein kinase C modulates pulmonary endothelial permeability: a paradigm for acute lung injury

“…Throughout the last five decades, investigation into the pathogenesis of the increased endothelial permeability associated with RDS has indicated a role for many mediators, such as cytokines (e.g., IL-1, TNF-␣) (52,93,146), growth factors [e.g., vascular endothelial growth factor (VEGF)] (93), peptides (substance P, bradykinin) (7,150,183), proteases (e.g., elastase) (19), complement activation (e.g., C5a) (125,188), intravascular coagulation (e.g., thrombin) (59,102,103,110,170), reactive oxygen and nitrogen species (e.g., (20,80,89,164,165), and lung sequestration of neutrophils (95) (Fig. 1).…”