Prince Lawrence S, Okoh Victor O, Moninger Thomas O, Matalon Sadis
Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama 35249, USA.
Am J Physiol Lung Cell Mol Physiol. 2004 Nov;287(5):L999-1006. doi: 10.1152/ajplung.00111.2004.
Chorioamnionitis is a major cause of preterm delivery. Infants exposed to inflammation in utero and then born preterm may have improved lung function in the immediate postnatal period. We developed a mouse model of chorioamnionitis to study the inflammatory signaling mechanisms that might influence fetal lung maturation. With this in vivo model, we found that Escherichia coli lipopolysaccharide (LPS) increased the number of alveolar type II cells in the fetal mouse lung. LPS also increased type II cell number in cultured fetal lung explants, suggesting that LPS could directly signal the fetal lung in the absence of maternal influences. Using immunostaining, we localized cells within the fetal mouse lung expressing the LPS receptor molecule Toll-like receptor 4 (TLR4). Similar to the signaling pathways in inflammatory cells, LPS activated NF-kappaB in fetal lung explants. Activation of the TLR4/NF-kappaB pathway appeared to be required, as LPS did not increase the number of type II cells in C.C3H-Tlr4(Lps-d) mice, a congenic strain containing a loss of function mutation in tlr4. In addition, the sesquiterpene lactone parthenolide inhibited NF-kappaB activation following LPS exposure and blocked the LPS-induced increase in type II cells. On the basis of these data from our mouse model of chorioamnionitis, it appears that LPS specifically activated the TLR4/NF-kappaB pathway, leading to increased type II cell maturation. These data implicate an important signaling mechanism in chorioamnionitis and suggest the TLR4/NF-kappaB pathway can influence lung development.
绒毛膜羊膜炎是早产的主要原因。在子宫内暴露于炎症然后早产的婴儿在出生后即刻可能具有改善的肺功能。我们建立了绒毛膜羊膜炎小鼠模型来研究可能影响胎儿肺成熟的炎症信号传导机制。利用这个体内模型，我们发现大肠杆菌脂多糖（LPS）增加了胎鼠肺中II型肺泡细胞的数量。LPS还增加了培养的胎肺外植体中II型细胞的数量，这表明LPS在没有母体影响的情况下可以直接向胎儿肺发出信号。通过免疫染色，我们在胎鼠肺中定位了表达LPS受体分子Toll样受体4（TLR4）的细胞。与炎症细胞中的信号通路类似，LPS激活了胎肺外植体中的NF-κB。TLR4/NF-κB通路的激活似乎是必需的，因为LPS没有增加C.C3H-Tlr4（Lps-d）小鼠中II型细胞的数量，C.C3H-Tlr4（Lps-d）小鼠是一种在tlr4中含有功能丧失突变的同源品系。此外，倍半萜内酯小白菊内酯抑制LPS暴露后NF-κB的激活，并阻断LPS诱导的II型细胞增加。基于我们绒毛膜羊膜炎小鼠模型的这些数据，似乎LPS特异性激活了TLR4/NF-κB通路，导致II型细胞成熟增加。这些数据揭示了绒毛膜羊膜炎中的一种重要信号传导机制，并表明TLR4/NF-κB通路可以影响肺发育。
