Understanding chronic inflammatory diseases in the human lung: the cystic fibrosis and idiopathic pulmonary fibrosis paradigms

Liu, Yi-Chia (2014) Understanding chronic inflammatory diseases in the human lung: the cystic fibrosis and idiopathic pulmonary fibrosis paradigms. PhD thesis, University of Nottingham.

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Abstract

The chronic infection of the cystic fibrosis (CF) lung with Pseudomonas aeruginosa strongly correlates with critical outcomes. Pseudomonas alkyl-quinolone signal (PQS) is a diffusible cell-density dependent signal controlling the production of virulence determinants. The PQS amount in the CF lung was proportionate to P. aeruginosa colonisation and PQS molecules have been demonstrated to inhibit pro-inflammatory signalling. However, how PQS influence the recognition of P. aeruginosa by the human lung is unknown. The contribution of PQS to the interaction of P. aeruginosa with human bronchial epithelial cells (HBECs) was characterised using a PQS-deficient mutant ΔpqsA in comparison with its isogenic wild type (WT). Although ΔpqsA appeared attenuated, the pathogenesis of WT and ΔpqsA upon infection of HBEC did not differ in bacterial growth, actin and junctional protein degradation, and pro-inflammatory activation. Despite PQS being highly secreted by a CF isolate LESB58, preliminary data showed that LESB58 was less cytotoxic than the laboratory WT. Our results suggest that PQS does not alter P. aeruginosa pathogenicity on HBECs.

Idiopathic pulmonary fibrosis (IPF) is characterised with heterogeneous pathological patterns caused by scarring leading to irreversible destruction of lung architecture. Emerging evidence suggests that dysregulated immunological events could cause the failure of tissue-healing. Systemic immune responses of patients with IPF and age- and sex-matched healthy donors were determined by quantifying cytokines produced by peripheral blood mononuclear cells (PBMCs) upon an array of stimuli. The results showed that PBMCs in patients with IPF were less likely to produce IL-17A, IL-10 and IL-13 than healthy controls (OR 0.14-0.3, 95% CI 0.003-0.03). Patients with lower levels of cytokines had a four to six-fold increased risk of death (HR 4.31-6.13, 95% CI 0.0052-0.0176).

This study contributes to a better understanding of the role of PQS in P. aeruginosa pathogenesis and identified cytokine production as a novel biomarker in IPF.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Martinez-Pomares, L.
Camara, M.M.
Williams, P.
Keywords: Chronic inflammation, Pseudomonas aeruginosa, Pseudomonas alkyl-quinolone signal, Lung inflammation
Subjects: R Medicine > RC Internal medicine
W Medicine and related subjects (NLM Classification) > WF Respiratory system
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID: 27807
Depositing User: Liu, Yi-chia
Date Deposited: 17 Feb 2015 11:22
Last Modified: 13 Sep 2016 18:10
URI: http://eprints.nottingham.ac.uk/id/eprint/27807

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