Melis, Miranda Jentine;
(2022)
The interplay between stress hormones, mitochondria, and immune cells during sepsis; from adaptation to maladaptation.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Background: Sepsis is a severe dysregulated response of the body to infection, leading to multiple organ dysfunction. This phenomenon, and immunosuppression seen with prolonged sepsis, may relate to insufficient mitochondrial production of ATP. The magnitude of endocrine changes during sepsis has major prognostic implications. These could significantly contribute to decreased mitochondrial activity, and in turn, functional disturbances of immune cells. / Objectives: To study the effects of changes in stress and metabolic hormones during sepsis on mononuclear immune cell mitochondrial and effector function. / Methods: Endocrine, mitochondrial, and inflammatory markers were measured in serum and monocytes taken from septic patients, with subsequent correlations calculated between these markers. Direct effects of a selection of hormones (noradrenaline, adrenaline, and hydrocortisone) on mitochondrial and mononuclear immune cell function were examined in a 6-hour in vitro model of infection. A rat model of faecal peritonitis was then characterised for endocrine, metabolic, and inflammatory parameters for future in vivo studies. / Results: There were no consistent correlations between endocrine levels and various measures of mitochondrial and mononuclear immune cell function in patients with sepsis on admission nor in pre-operative control patients. Mitochondrial dysfunction could not explain changes in immune cell effector function both in patients nor in vitro. In vitro studies indicate that catecholamine- and glucocorticoid-induced effects on mitochondrial and immune function are dose, stimulation, and cell-type specific. / Conclusion: Opposite directions of correlations between endocrine levels and mitochondrial and mononuclear immune cell function suggest a change in regulation of these processes. The variable in vitro effects in terms of dose, stimulation and cell type highlight the importance of stratifying patients to identify who could benefit from manipulation of hormone levels. Further observational, in vitro and in vivo studies are warranted to confirm and elaborate on these observations made, and to study potential interventions to restore mitochondrial and immune cell effector function.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The interplay between stress hormones, mitochondria, and immune cells during sepsis; from adaptation to maladaptation |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10162280 |
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