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Extracellular matrix turnover and regulation of pulmonary innate immunity

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Title: Extracellular matrix turnover and regulation of pulmonary innate immunity
Authors: Bell, Thomas James
Item Type: Thesis or dissertation
Abstract: Severe respiratory viral infections are often clinically associated with bacterial complications. The regulation of innate immunity has previously been linked to altered susceptibility, e.g. expression of the negative regulator CD200R on alveolar macrophages. Additionally, the ability of alveolar macrophages to respond to pathogenic stimuli is restricted up to 6 months after influenza infection. This restriction and over-regulation of alveolar macrophages occurs after a broad range of both sterile and infectious inflammatory conditions, implying that this is a generic inflammation phenotype. Hyaluronan, an abundant glycosaminoglycan, accumulates in the airway in a number of inflammatory diseases. Small hyaluronan fragments are thought to initiate and perpetuate inflammation through TLR4 and MyD88. Hyaluronan also restricts inflammation by inducing negative regulators of TLR signalling such as A20 and IRAK-M; and an absence of its receptor, CD44, prevents the resolution of inflammation and enhances macrophage TLR responses. This work explores the hypothesis that hyaluronan accumulates during influenza infection, contributing to the blindfolding of alveolar macrophages to bacterial TLR ligands and subsequent susceptibility to secondary bacterial infection. Airway hyaluronan increased >3000-fold following murine influenza, and was associated with upregulated hyaluronan synthase expression in the lung. These changes were persistent, resulting in a long-lived alteration to hyaluronan homeostasis in the airway. Transfer of biotinylated hyaluronan and hyaluronidase enzyme treatment after influenza demonstrated that hyaluronan clearance was not impaired in resolution of infection, suggesting de novo synthesis in the lung is responsible. The inter-alpha-inhibitor and HC·∙HA complexes were also present during influenza infection, suggesting that hyaluronan-protein complexes form in the airways. Abrogating hyaluronan accumulation during influenza infection enhanced the recovery of mice and improved lung function, however excess hyaluronan only had a limited effect on bacterial infection. Determining the contribution of hyaluronan to the severity of viral infection and the effect it has on subsequent bacterial complications using hyaluronan synthase inhibitors and hyaluronidase enzymes will elucidate novel targets to improve outcomes for patients hospitalised with severe influenza.
Content Version: Open Access
Issue Date: Jan-2015
Date Awarded: Jul-2015
URI: http://hdl.handle.net/10044/1/45395
DOI: https://doi.org/10.25560/45395
Supervisor: Hussell, Tracy
Snelgrove, Robert
Lloyd, Clare
Sponsor/Funder: Wellcome Trust (London, England)
Funder's Grant Number: 093612/Z/10/Z
Department: National Heart & Lung Institute
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:National Heart and Lung Institute PhD theses

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