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

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Abstract

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 [3H]-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.

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Abbreviations

BA:

Bile acid

BALF:

Bronchoalveolar lavage fluid

EPO:

Erythropoietin

ICP:

Intrahepatic cholestasis of pregnancy

MPO:

Myeloperoxidase

OCP:

Obstructive cholestasis during pregnancy

PLA2:

Phospholipase A2

iRDS:

Infant respiratory distress syndrome

TCA:

Taurocholic acid

TLCA:

Taurolithocholic acid

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Acknowledgments

The authors thank N. Skinner for revision of the English text in the manuscript. This study was supported by the Spanish “Instituto de Salud Carlos III” (Grant FIS PI11/00337), “Ministerio de Ciencia e Innovación” (Grant SAF2010-15517), “Junta de Castilla y León” (Grants SAN673SA07/08, SA070A11-2, SA023A11-2, BIO/03/SA23/11, BIO/SA64/13, BIO/SA65/13 and SA015U13), and “Fundación Investigación Mutua Madrileña” (Call 2009). The group belongs to the Spanish Network for Cooperative Research on membrane Transport Proteins (REIT) and CIBERehd. E.L. was supported by a PhD grant from the “Fondo Social Europeo/Junta de Castilla y León”.

Disclosure Statement

The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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Authors and Affiliations

  1. Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain

    Elisa Herraez, Elisa Lozano, Evelyn Poli, Jose J. G. Marin & Rocio I. R. Macias

  2. Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University, Düsseldorf, Germany

    Verena Keitel

  3. Division of Pediatrics and Neonatal Critical Care, CHU Antoine-Beclere, Paris South University, Paris, France

    Daniele De Luca

  4. Institute for Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, UK

    Catherine Williamson

  5. Carlos III National Institute of Health, Centre for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Madrid, Spain

    Jose J. G. Marin & Rocio I. R. Macias

  6. Department of Physiology and Pharmacology, Campus Miguel de Unamuno, E.I.D., S-09, 37007, Salamanca, Spain

    Jose J. G. Marin & Rocio I. R. Macias

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  1. Elisa Herraez
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  2. Elisa Lozano
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  3. Evelyn Poli
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  4. Verena Keitel
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  5. Daniele De Luca
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  6. Catherine Williamson
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  7. Jose J. G. Marin
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  8. Rocio I. R. Macias
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Corresponding authors

Correspondence to Jose J. G. Marin or Rocio I. R. Macias.

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Herraez, E., Lozano, E., Poli, E. et al. Role of macrophages in bile acid-induced inflammatory response of fetal lung during maternal cholestasis. J Mol Med 92, 359–372 (2014). https://doi.org/10.1007/s00109-013-1106-1

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  • DOI: https://doi.org/10.1007/s00109-013-1106-1

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