Fetal Epithelial Expression and Regulation of Antimicrobial Peptides

Boeckel, S. van (Sara) (2014) Fetal Epithelial Expression and Regulation of Antimicrobial Peptides. thesis, Medicine.

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Abstract

Preterm birth (PTB) affects 1 in 10 babies and is associated with severe morbidity and mortality. Inflammation has shown to play a role in initiating term labour and in PTB this inflammatory response is highly pronounced. During pregnancy it has been shown that the maternal and fetal immune systems are delicately balanced in order to keep the pregnancy intact by not causing a potentially harmful early inflammatory response and at the sample time maintaining its ability to produce an adequate inflammatory response in response to infection. The fetal immune system is underdeveloped in utero, where the innate immune system is most developed. Important proteins of the innate immune response are Antimicrobial Peptides and Proteins (AMPs), which have shown to have antibacterial and immunomodulatory functions in epithelial tissues among others. Furthermore AMPs have shown to be expressed in the female reproductive system and have shown to be able to play a role in limiting ascending intra-uterine infections that can cause PTB. However, little is known of the fetal AMP expression and production. Fetal epithelial surfaces can play a decisive role in PTB because of its exposure in utero, its ability to recognize microbes, initiate inflammation and potency to express AMPs. In the present study we assess the fetal epithelial expression of AMPs. Secondly, we developed in-vitro and ex-vivo models in order to examine the fetal AMP regulation in response to stimuli. We show that fetal epithelial tissues express the AMP LL-37, and that additionally, fetal skin expresses the AMPs HBD-1, HBD-2 and HBD-3. Interestingly, contrary to what we expected, both our in-vitro primary keratinocyte model and our ovine ex-vivo lipopolysaccharide (LPS) model show a trend of downregulation of all the AMPs in response to LPS. Previously it was thought that the intra-uterine environment was sterile. However, it is now known that the fetus is exposed to a variety of microbes, making it necessary for the fetus to develop so-called fetal immune tolerance mechanisms in order to protect the fetus from eliciting a potentially damaging inflammatory reaction in response. We hypothesize that our findings suggest that AMPs are also affected by these tolerance mechanisms. Furthermore we show that midgestational fetal skin has an inadequate AMP and inflammatory response, which could explain the finding that preterm neonates have an increased susceptibility to infection and suggest AMPs as a future potential therapy for preterm neonatal infections.

Item Type:	Thesis (Thesis)
Supervisor name:	Zeeman, Prof. Gerda and Horst, Prof. Gert ter
Supervisor name:	Stock, Dr. SJ and Queen’s Medical Research Institute and Edinburgh, United Kingdom
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 11:04
Last Modified:	25 Jun 2020 11:04
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/2399

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