Epigenetic regulation in epithelial and myeloid cells during lung infection and fibrosis

Research output: Doctoral thesisThesis, fully internal

Abstract

Epithelial cells line the surface of the respiratory system and maintain homeostasis under normal conditions and play an eminent role in the initiation of immune responses during lung diseases, including the two pulmonary disorders studied in this thesis: infection and fibrosis. Together with immune cells, epithelial cells orchestrate the early local response to pathogens and non-infectious danger signals, and this complex reaction is regulated at different levels. Epigenetic regulation is one of the mechanisms that control epithelial and myeloid cell responses. DNA methylation is one of the most intensively studied epigenetic modifications. DNA methylation is established and maintained by DNA methyltransferases including Dnmt1, Dnmt3a and Dnmt3b, while methylation is removed by Tet methylcytosine dioxygenase family proteins (Tets). This thesis focused on the role of DNA methylation and the DNA methylation modifiers Dnmt3b and Tet2 in respiratory epithelial cells and myeloid cells during lung infection and fibrosis. We have done so by generating mice with epithelial or myeloid cell specific deficiency of Dnmt3b and Tet2, and by using well-established models of (a) bacterial pneumonia induced by infection with viable Pseudomonas aeruginosa or Klebsiella pneumoniae, important causative pathogens in hospital-acquired pneumonia, via the airways, (b) lung inflammation induced by local instillation of the bacterial components flagellin (expressed by Pseudomonas) or lipopolysaccharide (expressed by both Pseudomonas and Klebsiella), and (c) lung fibrosis induced by local of bleomycin. In one Chapter we in addition utilized a murine model of bacterial peritonitis and sepsis, using intraperitoneal infection with Escherichia coli.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • University of Amsterdam, Netherlands
Supervisors/Advisors
  • van der Poll, Tom, Supervisor
  • Scicluna, Brendon P., Co-supervisor
Award date22 Sep 2021
Print ISBNs9789463327817
Publication statusPublished - 2021

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