Influence of in utero inflammation on diaphragm function in preterm lambs

Kanakeswary Karisnan

    Research output: ThesisDoctoral Thesis

    263 Downloads (Pure)

    Abstract

    [Truncated] Despite recent major advances in neonatal care, preterm birth remains the leading cause of postnatal morbidity and mortality. The complications of preterm birth arise from immature organ systems of which the dysfunction of the respiratory system is the most common clinical problem. Infants require developed respiratory system to sustain independent ventilation after birth. Respiratory failure among preterm infant is due to the underdevelopment of the lungs, however respiratory muscle weakness and/or fatigue is also a major contributor. The diaphragm is important for lung development in utero as fetal breathing movements that are mainly driven by diaphragm and intercostal contraction, stimulate lung cellular proliferation and growth. Thus, the respiratory system (including muscle pump – diaphragm, as well as gas exchanger – lungs) is poorly developed in preterm infants. In addition, preterm infants face an increased work of breathing due to lack of surfactant proteins, highly compliant chest wall and noncompliant, structurally immature lungs leading to diaphragm weakness, fatigue and respiratory failure.

    Diaphragm function may be compromised further by adverse in utero fetal exposures such as inflammation. Chorioamnionitis, inflammation of the placental and fetal membranes, is associated with up to 70 % of preterm births at < 28 week gestation, the group that is most likely to develop chronic respiratory illness, such as bronchopulmonary dysplasia (BPD). Notably, little is known on how diaphragm function in the preterm infant is affected by chorioamnionitis. Therefore, the overall aim of this thesis was to investigate the impact of chorioamnionitis induced inflammation on contractile function in the preterm diaphragm and to elucidate the molecular mechanism underlying functional alteration. The specific aims of the first study were to establish the functional changes in the preterm fetal diaphragm after exposure to in utero inflammation and to elucidate the underlying molecular mechanisms. The study hypothesis was that acute 2 d and 7 d intra-amniotic (IA) exposure to lipopolysaccharide (LPS) impairs preterm diaphragm function. The specific aims of the second study were to assess how gestational age at time of exposure to IA LPS determines the extent of functional impairment of the fetal diaphragm and whether weekly inflammatory exposures exacerbate diaphragm dysfunction. The study hypotheses were that diaphragm weakness persists after a long duration of LPS exposure (21 d) and that the effects would be more pronounced after a chronic LPS exposure (weekly LPS injections). The third study aims were to investigate the effect of acute LPS exposure (2 d and 7 d prior to delivery) on preterm and term diaphragm function. This study hypothesis was that the preterm diaphragm was more vulnerable to in utero inflammation induced contractile dysfunction than term diaphragm. The fourth study aim was to investigate the role of IL-1 signalling and oxidative stress on IA LPS induced diaphragm weakness in preterm lambs. This study hypothesis was that blockade of IL-1 signalling will protect the diaphragm from inflammation induced contractile dysfunction.

    Original languageEnglish
    QualificationDoctor of Philosophy
    Supervisors/Advisors
    • Pillow, Jane, Supervisor
    • Bakker, Tony, Supervisor
    • Pinniger, Gavin, Supervisor
    Publication statusUnpublished - Apr 2015

    Fingerprint

    Dive into the research topics of 'Influence of in utero inflammation on diaphragm function in preterm lambs'. Together they form a unique fingerprint.

    Cite this