Background: Airways diseases comprise mainly of COPD and asthma. There is a need to develop both new models and improve methodologies of existing models these diseases. LPS challenges in smokers would be an excellent model to study the drugs directed against TLR4 mediated inflammation in COPD. In asthma allergen challenges are established models of disease and extensively used in clinical trials. Back to back reproducibility of two bolus dose allergen challenges has not been studied; this would provide intra subject standard deviations which are useful for accurate power calculations for bolus allergen challenge studies. Aims: 1. To investigate Inhaled LPS Challenges in healthy smokers as a model of inflammation in COPD; study systemic and sputum biomarkers for use in such studies and use LPS challenge as a model to study corticosteroid insensitivity 2. Investigate LPS Challenges in HNS as a model to study neutrophil chemotaxis mechanisms 3. Study Reproducibility of bolus dose allergen challengeMethods 1. HNS and HS were recruited and underwent inhaled LPS challenges. Safety, airway and systemic inflammation was studied. 2. Mild atopic asthmatics underwent two bolus allergen challenges, reproducibility of EAR and LAR was studied and intrasubject SD was used for power calculationsResult LPS Challenges were safe in both HNS and HS and led to increase in sputum neutrophil% in both these populations with maximum effect at 6hours post 30µg LPS inhalation. The resulting airway neutrophilic inflammation was reproducible in HS. LPS challenge in HS also leads to increase in systemic biomarkers and upregulation of NFĸB pathways in induced sputum. There was moderate corticosteroid insensitivity in airway inflammation in HS which didnot increase post LPS challenge. In HNS sputum supernatants post LPS challenge increase chemotaxis of blood neutrophils which is related to CXCL8 levels and mediated by both CXCR1 and 2 receptors. Bolus allergen challenges in mild asthmatics show good reproducibility for both EAR and LAR; I have also presented intrasubject SD which maybe used for accurate power calculations for future studies.Conclusions LPS Challenges lead to neutrophilic airway inflammation in HS which is reproducible and mediated by upregulation of TLR4 signalling making this a good model to study anti-inflammatory drugs for COPD in clinical trials. Additionally, LPS challenges in HNS provide a model to study neutrophil chemotaxis mechanisms. Bolus allergen challenges show good reproducibility and accurate power calculations are presented in this thesis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:568634 |
| Date | January 2013 |
| Creators | Aul, Raminder Singh |
| Contributors | Singh, Sukh |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/bronchial-challenges-in-airways-disease(427734bd-d3e2-48be-b6bb-b760da1b333d).html |
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