Lipopolysaccharide increases alveolar type II cell number in fetal mouse lungs through Toll-like receptor 4 and NF-{kappa}B

Departments of 1 Pediatrics and 3 Anesthesia, University of Alabama at Birmingham, Birmingham, Alabama 35249; and 2 Central Microscopy Research Facility, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242 Submitted 25 March 2004 ; accepted in final form 7 July 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- B in fetal lung explants. Activation of the TLR4/NF- B 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- B 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- B pathway, leading to increased type II cell maturation. These data implicate an important signaling mechanism in chorioamnionitis and suggest the TLR4/NF- B pathway can influence lung development. surfactant; respiratory distress syndrome; endotoxin; innate immunity Address for reprint requests and other correspondence: L. S. Prince, Dept. of Pediatrics, Div. of Neonatology, Univ. of Alabama at Birmingham, 525 New Hillman Bldg., 619 19th St. So., Birmingham, AL 35249 (E-mail: lprince{at}peds.uab.edu )