Early gestational intrauterine infection induces postnatal lung inflammation and arrests lung development in a rat model.

OBJECTIVE: In order to investigate the early gestational inflammation effect on the prenatal and postnatal lung development, identification of the proinflammatory cytokines (IL-1ß and TNF-α), genes implicated in angiogenesis (Vascular endothelial growth factor [VEGF], fms-like tyrosine kinase-1 [Flt-1], fetal liver kinase-1 [Flk-1]), and surfactant proteins (SPs) were observed. METHODS: Escherichia coli (E. coli) was inoculated into uterine cervix of pregnant rats at embryonic day 15 (E15) during pseudoglandular period of lung development and the control group was inoculated with normal saline. IL-1ß, TNF-α, VEGF, Flt-1, Flk-1, SP-A, and SP-B mRNA in pup's lung at E17, 19, 21 and postnatal day (P) 1, 3, 7, 14 were quantified by real-time RT-PCR. Western blot or immunohistochemistry analysis was also performed for the evaluation of VEGF, Flk-1, Flt-1, and SP-A expression in pup's lung. RESULTS: Compared with the control group, the fetal lung of the E. coli-treated group was more immature, the postnatal lung development was impaired marked by less alveoli, fewer secondary septa, and thicker alveolar wall. The lung weight and lung/body weight ratio were lower in the E. coli-treated group pups. IL-1ß and TNF-α mRNA were increased significantly in E. coli-treated pup's lung after birth, but no significant difference of IL-1ß and TNF-α mRNA levels in fetal lung were found between the two groups. SP-A expression was depressed at E17, E19, and E21 after intrauterine E. coli treated, accompanied with lower SP-B mRNA level at E19 and E21. Furthermore, intrauterine E. coli treated reduced the VEGF mRNA and protein levels in the fetal lung at E17 and E19, while the expression of Flt-1 and Flk-1 were higher at P7, P14 and P1, P7, P14, respectively, compared to the controls. CONCLUSIONS: These results suggested early gestational intrauterine E. coli infection could induce a postnatal pulmonary inflammation and might arrest the alveolarization in developing lung which was involved with the VEGF signaling. However, intrauterine E. coli infection could not induce the increase of proinflammatory cytokines in fetal lung and might fail to accelerate the maturation of fetal lung.

Intrauterine infection/inflammation and perinatal brain damage: role of glial cells and Toll-like receptor signaling.

The mechanisms or pathophysiology that leads to preterm brain damage including white matter damage during development are complex and not fully understood. Intrauterine infection/inflammation can significantly affect perinatal brain development and result in significant alterations in brain structure and function. Glial cells and Toll-like receptors (TLRs) are vital players in central nervous system immune response; dysregulation of this response plays an important role in brain damage. Intrauterine infection/inflammation has immunomodulatory effects and induces specific alterations in the TLRs response in many tissues. Recent findings indicate that intrauterine infection/inflammation could promote inflammatory processes in brain and in glial cells by up-regulating cytokines and inflammatory mediators, and by activating signaling pathways and transcriptional factors (nuclear factor-kappaB) implicated in inflammatory injury. TLRs may be involved in intrauterine infection-mediated inflammatory signaling, and intrauterine infection/inflammation could interfere with the TLR4 recruitment into the lipid rafts, leading to an effect on the TLR signaling transduction. In summary, current results suggest that TLRs are key mediators of intrauterine infection/inflammation induced preterm brain damage.