Airway Smooth Muscle and Asthma Severity
Condition: Asthma
MeSH terms: Asthma
Study type: Observational

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
    

Intervention name(s): bronchoscopy
Intervention type(s): Other
Intervention description(s): bronchoscopy under local anaesthetic and sedation to obtain endobronchial biopsies
Observational model: Cohort
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Mild, moderate and severe asthmatics, with a control group of healthy non-smoking
        volunteers
      
Biospecimen description: 
      endobronchial biopsies and cultured airway smooth muscle cells
    
Keywords: asthma severity; airway smooth muscle; oxidative stress