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Title: Therapeutic manipulation of inflammation in exacerbated lung disease
Author: Lai, Cheryl Chuk-Ke
ISNI:       0000 0004 7427 6659
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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It is well known that existing and prior inflammatory events in the lung can adversely affect subsequent inflammatory events even though the inciting antigen might be different. For example, viral infections can enhance secondary bacterial infections and also the symptoms of asthma causing increased morbidity and mortality. Understanding changes in the lung micro-environment that lead to altered lung responsiveness is important given the increasing incidence in allergic diseases and the emergence of pandemic influenza strains. Elucidating the molecular mechanisms of these prolonged alterations could lead to new therapeutic strategies. Susceptibility to bacterial super-infections has been attributed to reduced toll-like receptor (TLR) responses in the inflammation-experienced lung. The triggering receptor expressed on myeloid cells (TREM) family of innate immune receptors fine-tune TLR responses, but have yet to be studied in the context of influenza and secondary bacterial infection. Targeting specific immune signalling receptors or signalling kinases involved in the inflammatory process in the lung by use of inhaled drugs could provide specific treatment of inflammatory lung diseases minimising effects in other organs or tissues. The aim of this thesis was to investigate the role of TREMs during influenza and secondary bacterial infection and to determine the effects of inhaled signalling kinase inhibitors in models of viral exacerbations of allergic inflammation. TREM-2 expression was shown to be upregulated during the peak of influenza-induced inflammation. Furthermore, soluble (s)TREM-1 in bronchoalveolar lavage (BAL), lung and serum coincide with heightened susceptibility to bacterial infection post-influenza virus. These novel findings suggest that targeted manipulation of TREM-1 (or prevention of its cleavage into the soluble form) and TREM-2 has the potential to restore the inflammatory tone of the airspaces to prevent subsequent infectious complications. Narrow-spectrum signalling kinase inhibitor TC2 reduced BAL eosinophils and total and allergen-specific serum IgE production in house dust mite (HDM)-induced allergic inflammation. Furthermore, a new model of viral infection during HDM-induced allergic inflammation was developed. Surprisingly, exposure to HDM prior to respiratory syncytial virus (RSV) infection led to reduced RSV-induced weight loss, damage and proinflammatory mediator release, which correlated with increased TREM-2 expression in the early stages of infection. Treatment with the kinase inhibitor TC2 during viral infection in allergen-exposed mice, however, still reduced airway hyperesponsiveness. Thus, whether severe asthma is characterised by additive inflammatory conditions or exacerbation of an underlying problem by infection, kinase inhibitors still hold promise in the clinic.
Supervisor: Dean, Charlotte ; Hussell, Tracy ; Lloyd, Clare Sponsor: Medical Research Council ; Asthma UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral