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The role of activated protein C and interleukin 37 in bronchopulmonary dysplasia
thesisposted on 27.02.2017, 23:28 by Umapathy, Hemalatha
Bronchopulmonary dysplasia (BPD) is an inflammatory disease that affects premature infants of a low birth weight. It is found to affect 50% of infants with a birth weight between 500-750 grams. BPD is a disease with multiple causes including prenatal infection, postnatal exposure to mechanical ventilation and high levels of oxygen. The disease is characterised by elevated pro-inflammatory cytokines, an increased invasion of inflammatory cells and subsequent fibrosis. Although multiple treatments have been investigated, there is no current treatment for BPD. This thesis examines the use of two anti-inflammatory molecules, activated protein C (aPC) and interleukin 37 (IL-37), as potential therapeutic agents for BPD. We hypothesized that the anti-inflammatory mechanisms of these molecules will reduce the inflammation caused by BPD and thus reduce lung damage. Activated protein C (aPC) modulates the NF-KB pathway and the leukocyte adhesion and trafficking mechanisms to result in anti-inflammatory effects. Recombinant aPC has been used with benefit to treat inflammatory conditions such as sepsis and inflammatory bowel diseases. The thesis investigated aPC and PC in a murine model of BPD by daily subcutaneous injections (aPC - 6mg/kg, PC -1200IU/kg). This model used hyperoxia alone to develop the outcomes of BPD. Both, the cytokine analysis and histological analysis of mice exposed to hyperoxia showed that aPC and PC provided no benefit for lung damage in this study. The absence of an effect of aPC and PC may be due to deficiencies in the model, where only limited inflammation was induced. Interleukin 37 (IL-37) is an anti-inflammatory cytokine that suppresses pro-inflammatory cytokines without affecting the levels of anti-inflammatory cytokines. It works by multiple mechanisms including the modulation of extracellular inflammatory molecules and intracellular modulation of gene transcription. Treatment with IL-37 has resulted in improvements in colitis and IL-37 has been found to act on other inflammatory diseases such as obesity related inflammation and hepatitis. The lung histology of IL-37 transgenic knock-in mice exposed to hyperoxia, showed no improvement to the disease and cytokines assays found that there was no difference in the inflammation states of diseased or control animals. This suggested that using hyperoxia alone did not mimic the inflammatory component of BPD on which the hypothesis of this study was built. These negative results prompted a change in the model to include a pre-natal inflammatory stimulus by means of maternal systemic inflammation (intra-peritoneal LPS injection) and post-natal hyperoxia exposure. Ideally, aPC and IL-37 would have been investigated in this new model. However, due to aPC being no longer available for medical or research use, only IL-37 was investigated. Cytokine analysis early in the experiment showed LPS increased inflammation in the model and that IL-37 production provided anti-inflammatory effects to the IL-37 transgenic mice. Consistently, the analysis of animal growth indicated that IL-37 allowed mice exposed to pre-natal inflammation and hyperoxia to cope better when compared to control mice without IL-37. However, histological analysis showed no improvement in terms of lung development. The use of aPC and PC, while theoretically promising, has shown not improved BPD. IL-37 has resulted in some improvement in an improved murine model of BPD; however, further experiments with a revised model are required to fully understand the potential of IL-37. Furthermore, should IL-37 prove to be effective, greater investigations have to be carried out before this research can be translated to clinical application to aid infants to cope with bronchopulmonary dysplasia.