Motwani, Madhur Parmanand; (2017) Immunomodulatory effect of specialised pro-resolving mediators in humans. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Inflammation is a protective response but if dysregulated it can lead to chronic inflammatory conditions. Currently, these diseases are treated by inhibiting the factors that drive inflammation but such treatments can interfere with the tissue healing processes, e.g. NSAIDs or impair antimicrobial immunity, e.g. corticosteroids and biologics. Resolution is the other end of inflammatory spectrum and has been demonstrated to be an active process mediated by specific cellular events, soluble mediators and their receptors, that provide counter-regulatory signals to switch inflammation off. In this regard, specialised pro-resolving lipid mediators (SPMs), as effector molecules of resolution have shown promise as a novel therapeutic option to treat dysregulated inflammation. However, research supporting beneficial effect of SPMs has been largely conducted in murine models and there is a need to translate it for patient benefit. A human model of resolution of inflammation can facilitate investigation of the pharmacological action of SPM based therapies and their comparison with known anti-inflammatory agents. To attain this objective, I first performed a detailed characterisation of cantharidin skin blister model and learnt that neutrophil clearance, an important sign of resolution, can be affected by stromal scaffold around inflammatory contents. Therefore, I developed a novel model of self-resolving acute inflammation triggered by intradermal injection of UV killed E. coli bacteria (UVkEc), where local inflammatory exudate was acquired into a suction blister raised during onset and resolution phases of inflammatory response. UVkEc triggered self-resolving dermal inflammation model allowed appreciation of quantifiable indices of resolution such as clearance of neutrophils, reduction of inflammatory stimulus, pro-inflammatory cytokines and lipid mediators as well as vascular hyperaemia. In addition, I identified the presence of different classes of SPMs and their receptors at the junction between onset and resolution. Using this model, I showed that local therapeutic supplementation of SPMs, in physiological dose range, reduced neutrophil numbers during resolution but had modest effect on clearance of the inflammatory stimulus, reduction of pro-inflammatory cytokines or switch of macrophages to a pro-resolving phenotype. In another approach, I demonstrated that an oral, SPM inducing small molecule, JBT-101, a CB2 receptor agonist (chemical name: ajulemic acid) inhibited neutrophil numbers at onset coincident with enhanced clearance of inflammatory stimulus and reduction in levels of leukotriene B4, prostanoids and IL-8. It also increased the levels of the SPMs including lipoxin A4, resolvin D1 and resolvin D3 during resolution. However, there was lack of correlation between the rise in SPMs and the effect of JBT-101 on resolution indices and there was no inverse correlation between levels of SPMs and neutrophil numbers during onset or resolution. Using UVkEc triggered self-resolving dermal inflammation model as a tool, this thesis demonstrates that in humans, effect of SPMs, at physiological doses, may be limited only to enhancing neutrophil clearance. It also shows that orally active SPM inducing molecule, JBT-101, at doses currently being employed in phase II clinical trials, has a potent anti-inflammatory effect and uncovers that its main mechanism is possibly via inhibiting the pro-inflammatory mediators than by inducing SPMs. Investigation of effect of pro-resolving therapies on resolution indices in humans can inform their future clinical development.

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