The RECONSTRUCT Study - Reconstructing Disease Mechanisms in Asthma
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional
Phase: Phase 4

Summary: 
      This study aims to assess the effect of inhaled corticosteroids (ICS) on airway smooth muscle
      (ASM) Na+, K+ pumps in patients with asthma.We wish to investigate differences in Na+, K+
      pump content in healthy versus asthmatic patients, whether a reduction in airway
      hyper-responsiveness observed in asthmatic patients treated with ICS is attributable to an
      increase in Na+, K+ pump content in ASM cells and compare this in patients with
      non-eosinophilic asthma versus eosinophilic asthma.
    

Detailed description: 
      Purpose and background

      Inhaled corticosteroids and asthma phenotypes Inhaled corticosteroid (ICS) is a cornerstone
      in the treatment of asthma. ICS acts locally in the airways through several pathways to limit
      inflammation, primarily through reduction of eosinophilic inflammation.

      In clinical practice however a substantial part of adult patients with asthma have no
      eosinophilic inflammation in the airways despite reduced lung function and increased
      contractility of the smooth muscles in the airways i.e., airway hyperresponsiveness(AHR).
      This group of patients with non-eosinophilic asthma (NEA) represents up to 50 % of adult
      asthmatics with even higher occurrence among patients referred to a specialist.

      The effect of ICS in NEA is debated but despite lack of eosinophilic inflammation, ICS has
      been shown to significantly reduce AHR in patients with NEA, suggesting mechanistic pathways
      different from reduction in eosinophilic inflammation.

      Airway smooth muscle and inhaled corticosteroids Airway smooth muscle (ASM) is the most
      abundant tissue type in the airways. It plays a crucial part in the pathogenesis of asthma
      and serves as an important target for therapy especially with β-adrenergic agents and to some
      extent anti-muscarinic agents, counteracting bronchoconstriction. However also ICS has been
      proposed to have direct action on ASM cells affecting contractility through reduction of
      intracellular Ca2+ or down regulation of membrane bound receptors as well as through limiting
      cellular proliferation and secretory function. The bronchodilating effect of β-adrenergic
      agents has in animal models shown to be potentiated by administration of corticosteroids.

      Inhaled corticosteroids and the Na+, K+ pump Both ICS and systemically administered
      prednisone has been shown to increase Na+, K+ pump activity in leucocytes from patients with
      asthma and in both rats and humans systemically administered corticosteroid increases the
      amount of Na+, K+ pumps in striated muscle by 20-40 % and 30-60 % respectively. We have
      recently demonstrated a similar effect with ICS where a therapeutically relevant daily dose
      of 1600 μg budesonide, administered in the respiratory tract by inhalation, increased the
      amount of Na+, K+ pumps in striated muscle by 17 %.

      1.1.4 The Na+, K+ pump and airway smooth muscle The Na+, K+ pump creates an inward Na+
      current by removing Na+ from the intracellular lumen of cells. This may drive extrusion of
      Ca2+ from the lumen of the ASM cells through the Na+, Ca2+ exchanger lowering intracellular
      Ca2+ concentration. Since Ca2+ plays a central role in smooth muscle contraction, lower
      intracellular concentrations may protect against bronchoconstriction as well as the contrary
      might reinforce AHR.

      In vitro studies have demonstrated disturbances in leucocyte Na+, K+ pump activity and
      increased intracellular Na+ in patients with hyperreactivity and asthma. Likewise in vitro
      studies of human bronchial muscle have shown increased AHR and concentrations of
      intracellular Ca2+ as well as decreased β-adrenergic induced relaxation of human bronchial
      muscle when Na+, K+ pumps are blocked.

      Bronchoconstriction and airway remodeling are universal features of asthma and especially
      bronchoconstriction can to some extent be related to proposed disturbances in Na+, K+ pump
      activity and positive effects of ICS besides being anti-inflammatory is therefore suspected
      to be beneficial independent of cellular patterns. However the non-inflammatory effect might
      be more evident in patients with NEA since it is not blurred by the anti-inflammatory effect
      seen in patients with EA.

      No studies have assessed the effect of ICS on ASM Na+, K+ pumps in patients with asthma. In
      the present study the investigators wish to study differences in Na+, K+ pump content in
      healthy versus asthmatic patients, whether a reduction in AHR observed in asthmatic patients
      treated with ICS is attributable to an increase in Na+, K+ pump content in ASM cells and
      compare this in patients with NEA versus EA.

      This results in a study in two parts:

      I. A comparison of the level of Na+, K+ pumps in ASM in patients with asthma vs healthy
      subjects.

      II. A description of the association between changes in Na+, K+ pump content in ASM and
      change in AHR after ICS in patients with asthma.

      Hypothesis Study part I: The amount of ASM Na+, K+ pumps are lower in adult patients with
      asthma compared to healthy subjects.

      Study part II: The reduction in airway hyperresponsiveness in adult patients with asthma
      after treatment with ICS is related to an increase in the content of Na+, K+ pumps in ASM.

      We further hypothesize that the association between the increase in Na+, K+ pumps in ASM and
      the change in AHR after ICS treatment is strongest in NEA versus EA.

      Aim Study part I: To describe differences in ASM content of Na+, K+ pumps among healthy
      subjects and patients with NEA or EA respectively.

      Study part II: To describe the correlation between increase in ASM content of Na+, K+ pumps
      and reduction in airway hyperresponsiveness to mannitol after six weeks of daily inhalation
      of glucocorticoid, in patients with asthma.

      Perspectives Asthma is common and may be difficult to treat, especially the non-eosinophilic
      phenotype. This study aims to increase our understanding of pathogenic mechanisms in asthma,
      unrelated to inflammatory pathways. This may lead towards a shift from the current paradigm
      of asthma as a purely inflammatory condition, creating novel understanding of the role of ion
      transport regulation in the pathogenesis and treatment of asthma, ultimately revealing
      targets for novel treatments.
    

Intervention name(s): Budesonide
Intervention type(s): Drug
Intervention description(s): 1600 ug inhaled daily for 6 weeks
Other intervention name(s): Pulmicort
Intervention MeSH terms: Budesonide
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Inhaled corticosteroids; Airway hyper-responsiveness; Airway smooth muscle; sodium-potassium pump