Airway Smooth Muscle and Asthma Severity

Completed

Conditions: Asthma

Interventions: Other: bronchoscopy

Registration Number: NCT00779870

Lead Sponsor: Imperial College London

Brief Summary: Our hypothesis is that the severity of asthma is determined by the way in which airway smooth muscle cells grow and release inflammatory mediators. Our main objective is to establish how the properties of the airway smooth muscle cell varies with asthma severity. Environmental agents, such as cigarette smoke, and inflammation can give rise to oxidative stress - this is a process whereby harmful chemicals called free radicals are formed in the body and damage tissues. The damage caused can be limited/prevented by protective, or anti-oxidant mediators. We will also look at molecules involved in oxidative stress which may affect the way in which the airway smooth muscle grows and produces inflammatory mediators.

Detailed Description: Aims and Objectives The objective of this study is to examine whether the severity of asthma is related to (and possibly caused by) ASM dysfunction. Severe asthmatics have been shown to have more ASM in bronchial biopsies than non-severe asthmatics16. Because ASM cells can be obtained from bronchial biopsies obtained via bronchoscopy, we will examine endobronchial biopsies from mild, moderate and severe asthmatics, and healthy non-asthmatic subjects to compare features of remodelling (severe asthmatic subjects will have been assessed through the Difficult Asthma Protocol at the Royal Brompton Hospital24). In particular, we will focus on ASM mass, proliferation and changes in expression of different contractile proteins (α-actin and myosin) and chemokines, and will assess in vitro the response of ASM cells to stimulation by TGF-β and IL-1β. We will also examine the effect of dexamethasone on chemokine release and induced proliferation in vitro. We will also study enzymes and anti-oxidants involved in oxidative stress, such as Nox4, MnSOD and catalase, to look at their role in regulating ASM cell proliferation and chemokine synthesis. We want to see if there is an oxidant-anti oxidant balance in ASM in severe asthma compared to non-severe asthma.

AIM:

1. To establish the difference in ASM phenotype in asthma patients of differing severity of disease in terms of ASM mass, proliferation, migration and chemokine release.

Study design There will be 3 study visits. In the first two visits, the subjects will undergo spirometry with reversibility testing, a methacholine challenge test (to assess degree of bronchial hyper-responsiveness), skin prick tests and IgE levels (to assess atopic status), measurement of exhaled nitric oxide (as a non-invasive marker of inflammation), and the asthmatic subjects will complete an Asthma Control Questionnaire and an Asthma Quality of Life Questionnaire. The third visit will be on the day admission for the bronchoscopy.

Study protocol:

Visit 1 - screening visit

* Explain purpose of study- address any queries/concerns

* History and examination

* Skin prick tests

* Blood test for full blood count, clotting profile and IgE

* Measurement of exhaled nitric oxide (eNO)

* Spirometry pre and post β agonist

* Completion of Asthma Control Questionnaire and

* Completion of Asthma Quality of Life Questionnaire

Visit 2 - Methacholine challenge test

Visit 3 - Day admission for fibreoptic bronchoscopy

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 18

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: OBSERVATIONAL

Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
1	bronchoscopy	healthy volunteers
3	bronchoscopy	moderately-severe asthmatics
2	bronchoscopy	mild asthmatics
4	bronchoscopy	severe asthmatics

Primary Outcome Measures

Name	Time	Method
Difference in ASM Proliferation, Migration and Cytokine Release Between Groups	at time of bronchoscopy, an average of 1 hour
Difference in ASM Mass Between Groups	at time of bronchoscopy, an average of 1 hour
Difference in Intracellular Oxidative Stress Mechanisms From ASM Between Groups	at time of bronchoscopy, an average of 1 hour	Expression of Nrf2 protein

Secondary Outcome Measures