Lipopolysaccharide increases alveolar type II cell number in fetal mouse lungs through Toll-like receptor 4 and NF-κB

Abstract

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.

Toll‐like receptor signaling inhibits structural development of the distal fetal mouse lung

“…We previously determined that the sesquiterpene lactone parthenolide inhibited NF-B activation in fetal lung explants after LPS exposure (Prince et al, 2004). In explants cultured with was injected into the amniotic fluid of embryonic day (E) 15 mice.…”

“…Unlike adaptive immunity, this response is genetically encoded and does not require antigen presentation (Beutler et al, 2003). By using this model, we have shown previously that signaling through TLR4 and NF-B increased alveolar type II cell maturation in both fetal mouse lungs and fetal mouse lung explants (Prince et al, 2004). Whereas these findings might contribute to improved lung function after delivery, they did not explain how chorioamnionitis could lead to bronchopulmonary dysplasia.…”

Hyperoxia and Apoptosis in Developing Mouse Lung Mesenchyme

“…On E16, pregnant females were euthanized and fetal lungs were isolated and dissected free of surrounding tissues. For explant culture, fetal lungs were minced into 0.5-1 mm 3 pieces using sterile technique under a stereomicroscope (11). The explants were then cultured on permeable supports (Transwell, Costar).…”

“…Epithelial-mesenchymal interactions unique to this stage of development may be a potential target of hyperoxia. To study this stage of fetal lung development in mice, we have developed a fetal lung explant model (11). E16 fetal mouse lung explants develop in culture similarly to 23-25 wk human lungs, with branching of terminal saccules and differentiation of alveolar epithelial cells into type I and type II epithelia.…”

Inflammation et dysplasie bronchopulmonaire

“…On retrouve ce double effet de la chorioamniotite chez la souris gestante : l'injection intraamniotique de LPS induit une activation des macrophages alvéolaires qui inhibent le développement pulmonaire foetal [8], mais il existe une accélération de la maturation des pneumocytes de type II [9]. Ainsi, dans ces modèles animaux, une chorioamniotite accélère la maturation des pneumocytes II, favorisant l'adaptation à la vie aérienne, mais a pour conséquences de compromettre l'alvéolisation ultérieure.…”