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The Role of Prostaglandin E2 in Critical Illness-Induced Immune Dysfunction

Fullerton, JN; (2016) The Role of Prostaglandin E2 in Critical Illness-Induced Immune Dysfunction. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Dysregulation of the inflammatory profile in magnitude or duration following severe infectious or sterile insults including sepsis, burn and trauma is associated with a period of immunoparalysis, the acquisition of hospital acquired-infections and an associated increase in mortality. Prostaglandin E2 (PGE2), a cyclooxygenase (COX)-derived eicosanoid classically regarded as pro-inflammatory, regulates multiple aspects of the immune response and has been ascribed a causal role in immunoparalysis during alternate disease states. Systematic review of the clinical literature relating COX-inhibiting non-steroidal anti-inflammatory drugs (NSAIDs) use with either susceptibility to or outcome from acute infection revealed epidemiological evidence of benefit from NSAID administration during severe inflammatory states (sepsis), but not minor infection, providing a rationale for investigation of a mechanistic contribution to critical illness-induced immune dysfunction (CIIID). PGE2, at pathophysiologically relevant concentrations (IC50 317pg/mL, 95% CI 105 – 959pg/mL), suppressed ex vivo whole blood (WB) cytokine secretion: a validated measure of clinically relevant immune dysfunction. EP4 receptor-mediated increase in intracellular cyclic adenosine monophosphate (cAMP) was determined as the principal pathway, antagonism of which afforded an alternate immunorestorative strategy to established immunoadjuvant agents (interferon-γ and granulocyte-macrophage colony stimulating factor). A complementary in vitro bioassay of PGE2-mediated monocyte deactivation employing 1α, 25 dihydroxycholecalciferol differentiated (vitamin D3, 10ng/ml) Mono Mac 6 (MM6), a human cell line, mirrored this response. Pre-clinical evaluation of an association between PGE2 release during the systemic inflammatory response syndrome (SIRS) and subsequent immunoparalysis using the human intravenous endotoxin model (2ng/kg), however neither confirmed this link, nor refuted it, failing to replicate key immunological features of CIIID (sustained reduction in monocyte HLA-DR expression, WB cytokine secretion and absolute lymphocyte count). Mass spectroscopic analysis of plasma revealed significant elevation of COX-derived PGF2α, thromboxane A2 and PGE2, the latter peaking at 3hours, 7.8x higher than baseline values (10pg/mL compared to 1.3pg/mL). These did not suppress MM6 cytokine release. Compelling arguments suggest PGE2 contributes to CIIID. Alternative or adapted techniques will be required to determine the validity of this premise, potentially identifying a novel therapeutic immunorestorative strategy in the critically ill.

Type: Thesis (Doctoral)
Title: The Role of Prostaglandin E2 in Critical Illness-Induced Immune Dysfunction
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: The appendices have not been included in the page count.Third party copyright material has been removed from ethesis.
Keywords: Cyclooxygenase, Inflammation, Monocytes, Non-steroidal anti-inflammatory drugs, Tumour necrosis factor-alpha, Intensive care
UCL classification: 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 > Internal Medicine
URI: http://discovery.ucl.ac.uk/id/eprint/1475750
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