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The Role of Inflammation in the Pathogenesis of Preterm Birth

Lawson, Matthew J
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511861461945183

Abstract Details

2017, MS, University of Cincinnati, Medicine: Molecular, Cellular and Biochemical Pharmacology.
Preterm birth (PTB) is a worldwide problem and accounts for nearly 1 million infant deaths each year. Preterm birth is a leading cause of neonatal morbidity and mortality. Infants born preterm are at an increased risk for many health complications including respiratory distress syndrome, necrotizing enterocolitis, cerebral palsy as well as developmental delays. Rates of PTB vary across the globe, from as low as 5% in Belarus, to as high as 18% in Malawi. Preterm birth is a problem for developed nations as well, for instance the PTB rate in the United States is reported to be 9.6%. The mechanisms underlying PTB are multifaceted and not well understood. It is known however that factors including maternal age, interpregnancy interval, maternal smoking, maternal weight, and race all are associated with PTB. With the paucity of knowledge on the mechanisms of PTB, it is not surprising that few successful preventative therapies exist yet. Notably, infection has been associated with over 40% of cases of PTB. During influenza pandemics pregnant women are at a significantly increased risk compared to others. Additionally, influenza virus has been linked to cases of PTB, and in fact, flu vaccination is considered to have a protective role in preventing PTB. Bacteria and viruses have both been detected in the reproductive tissues of women with PTB. The mechanisms by which infectious pathogens can induce PTB however, are not well understood. However, the innate immune system, the first line of defense against infection, has been implicated as having a potential role in infection driven PTB. The Toll-like receptors (TLR), pathogen-sensing receptors of the innate immune system, are expressed in the reproductive tissue of pregnant women and in fact play a role in the onset of on-time parturition. Activation of TLRs by infectious pathogens has been associated with induction of uterine inflammation and PTB. However, the mechanisms and regulators of these responses, as well as the contribution of specific pathogens to inducing PTB through these receptors is not well understood. Utilizing mouse and non-human primates models, we investigated 1) the downstream regulators and critical compartments of several TLRs in the pathogenesis of PTB; 2) the competency of various TLR ligands to induce PTB, 3) the identification of the immune mediators driving subclinical infection sensitization to inflammation induced PTB. Collectively, our data demonstrate the following: 1) The type I IFN axis plays a critical role in the inflammatory response of TLR2 and TLR4 as well as the induction of PTB in TLR2 and TLR4; 2) Type I Interferon, and specifically IFN-ß, induction by pathogens can prime for a secondary inflammatory challenge to induce PTB; 3) The magnitude TLR2 induced inflammatory response and subsequent PTB is dependent on the specific ligand detected; 4) Maternal TLR4 expression on hematopoietic cells is required for induction of TLR4 induced PTB. These studies demonstrate that TLR activation by infectious pathogens plays a role in infection-associated preterm birth, warranting future studies to further elucidate the mechanisms behind this and identify therapies for prevention of preterm birth.
Senad Divanovic, Ph.D. (Committee Chair)
Simon Hogan, Ph.D. (Committee Member)
Terry Kirley, Ph.D. (Committee Member)
Ian Lewkowich, Ph.D. (Committee Member)
Robert Rapoport, Ph.D. (Committee Member)
163 p.
Immunology
Preterm Birth; Inflammation; TLR; Infection; Preterm Labor

Recommended Citations

Citations

  • Lawson, M. J. (2017). The Role of Inflammation in the Pathogenesis of Preterm Birth [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511861461945183

    APA Style (7th edition)

  • Lawson, Matthew. The Role of Inflammation in the Pathogenesis of Preterm Birth. 2017. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511861461945183.

    MLA Style (8th edition)

  • Lawson, Matthew. "The Role of Inflammation in the Pathogenesis of Preterm Birth." Master's thesis, University of Cincinnati, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511861461945183

    Chicago Manual of Style (17th edition)

ucin1511861461945183
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© 2017, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.