Journal Article

Role of macrophages in bile acid-induced inflammatory response of fetal lung during maternal cholestasis

Lozano, Elisa, De Luca, Daniele, Herraez, Elisa, Keitel, Verena, Williamson, Catherine, Marin, Jose J. G., Macias, Rocio I. R., Poli, Evelyn

2014

Overview

Infant respiratory distress syndrome (iRDS) in babies born from women with intrahepatic cholestasis of pregnancy (ICP) has been associated with intrauterine exposure to high bile acid levels. Here, we have investigated the role of macrophages in hypercholanemia-induced changes in maternal and fetal lung. Obstructive cholestasis in pregnant rats (OCP) was maintained from day 14 of gestation to term. Gene expression was determined by RT-QPCR, Western blot, and immunofluorescence. The maternal-fetal bile acid pool was radiolabelled using [ 3 H]-taurocholate. OCP resulted in increased bile acids in maternal and fetal organs, including lungs. This was accompanied by structural changes in lung tissue, more marked in fetuses (peribronchial edema, collapse of alveolar spaces and deposits of hyaline material in the alveolar lumen), and infiltration of lung tissue by inflammatory cells. The abundance of macrophages and neutrophils in bronchoalveolar lavage fluid (BALF) was also increased in OCP group. Phospholipase A2-IIA (PLA2), the key enzyme in surfactant degradation, was mainly immunodetected in macrophages, which also expressed the bile acid receptor TGR5. The overall expression of PLA2 was markedly enhanced in maternal and fetal lungs of OCP group and in control maternal BALF cells incubated with bile acids. In neonates born from OCP mothers, the enhanced expression of erythropoietin suggested the presence of hypoxia due to iRDS. In conclusion, these results indicate that the accumulation of bile acids due to maternal cholestasis triggers an inflammatory response in the maternal and fetal lungs together with enhanced macrophage-associated PLA2 expression, which may play an important role in iRDS development. Key Messages Maternal cholestasis causes respiratory distress syndrome in rat neonates. Cholestasis in pregnant rats causes bile acid accumulation in the fetal lung. This induces lung macrophages infiltration and inflammatory response. Alveolar macrophages co-express phospholipase A2-IIA and TGR5, but not FXR. Bile acid accumulation stimulates phospholipase A2-IIA, but not TGR5, expression.

• Publisher: Springer Berlin Heidelberg,Springer Nature B.V
• Subject: Animals / Bile Acids and Salts / Biomedical and Life Sciences / Biomedicine / Carrier Proteins - metabolism / Cholestasis, Intrahepatic - immunology / Erythropoietin - genetics / Erythropoietin - metabolism / Female / Fetus - immunology / Fetus - metabolism / Gene Expression / Human Genetics / Humans / Internal Medicine / Liver - metabolism / Lung - immunology / Lung - metabolism / Lung - pathology / Macrophages - immunology / Molecular Medicine / Original Article / Peroxidase - metabolism / Phospholipases A2 - metabolism / Pneumonia - immunology / Pregnancy / Pregnancy Complications - immunology / Rats, Wistar / Receptors, Cytoplasmic and Nuclear - genetics / Receptors, Cytoplasmic and Nuclear - metabolism / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - metabolism / Respiratory Distress Syndrome, Newborn - immunology / Respiratory Distress Syndrome, Newborn - metabolism