p38 Mitogen-Activated Protein Kinase (MAPK) and Steroid Insensitivity in Asthma
Condition: Asthma
MeSH terms: Asthma
Study type: Observational

Summary: 
      This research aims to find out how the inflammation in patients suffering from severe asthma
      is different from that in non-severe asthma, and how it may prevent corticosteroids from
      working efficiently in severe asthma.

      It will look,in particular, at a protein enzyme called p38 mitogen-activated protein kinase
      (p38 MAPK for short)which controls the activation of several important pathways in the cell.
      We wish to find out whether this enzyme is more active in cells obtained from patients with
      severe asthma compared to those with non-severe asthma. We would like to understand how this
      enzyme can cause the cell to respond less well to the anti-inflammatory effects of
      corticosteroids. We also wish to find out whether any specific inhibitors of p38 MAPK can
      improve severe asthma by improving the effects of corticosteroids on these cells.

      We hypothesise that activation of the intracellular MAPK signalling pathway underlies the
      inflammatory processes of severe asthma, and leads to the diminution of the anti-inflammatory
      actions of CS through histone modification.
    

Detailed description: 
      DESIGN Comparative study to analyse differences in the characteristics of lung macrophages
      and blood monocytes between non-severe and severe asthmatics.

      AIMS

        1. To determine whether there are differences in terms of cell expression and activation
           between lung macrophages and blood monocytes from non-severe and severe asthma

        2. To determine the mechanisms of the lung macrophage and blood monocyte relative
           resistance to the effect of corticosteroids in severe asthma, and particularly focus on
           the role of p38 MAPK

        3. To determine the differences in airway smooth muscle cells between non-severe and severe
           asthma

      OUTCOME MEASURES

        1. Clinically the differences in inflammatory and remodelling markers between non-severe
           and severe asthma

        2. Differences in histone phosphorylation, NF-kB activity and glucocorticoid receptor
           activation and actions in macrophages and monocytes between non- severe and severe
           asthma

        3. Differences in behaviour of airway smooth muscle cells cultured from biopsies obtained
           from non-severe and severe asthma

      Severe and non-severe asthmatic subjects will be classified following ATS criteria. They
      undergo spirometry with reversibility testing, PC20, skin prick tests, exhaled nitric oxide
      measurements and induced sputum. They will have blood taken for PBMCs and undergo fiberoptic
      bronchoscopy for obtention of alveolar macrophages and bronchial biopsies
    

Intervention name(s): Fiberoptic bronchoscopy; blood test
Intervention type(s): Other
Intervention description(s): Fiberoptic bronchoscopy for obtention of alveolar macrophages and bronchial biopsies for histology and culture of airway smooth muscle cells
Observational model: Other
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Asthmatic subjects will be recruited from asthma clinics at the Royal Brompton Hospital and
        from primary care clinics.
      
Biospecimen description: 
      sputum cell pellets and supernatant; BAL supernatant; endobronchial biopsies; smooth muscle
      cell culture from biopsies
    
Keywords: severe asthma; corticosteroid insensitivity