Eosinophil Induced Remodelling in Asthma
Condition: Allergic Asthma; Airway Remodelling
MeSH terms: Asthma; Airway Remodeling
Study type: Interventional

Summary: 
      Asthma is a chronic, inflammatory disease of the lung characterized by intermittent airway
      obstruction, airway hyperresponsiveness, presence of activated inflammatory cells,
      inflammatory mediators, and airway structural changes. Airway smooth muscle (ASM) cells
      actively participate in the remodelling and inflammatory processes through proliferation,
      release of proinflammatory cytokines, chemokines, and extracellular matrix (ECM) proteins.
      Eosinophils as essential inflammatory cells may be of importance in ASM remodelling. It is
      known that eosinophil induces ASM cells proliferation via the secretion of cysteinyl
      leukotrienes in asthmatics. However there is a possible direct eosinophil-ASM cells
      functional interaction by adhesion processes. It has been shown that integrins modulate ASM
      proliferation and contractile protein expression demonstrating allergen-induced ASM
      remodelling in an animal model of allergic asthma.

      Wingless/integrase-1 (WNT) signaling regulates not only a wide range of developmental
      processes, but its aberrant activation can lead to disease. Recently, it was confirmed that
      genes polymorphisms in the WNT signaling pathway are associated with impaired lung function
      in childhood asthma. It was also found for the first time a relevant role of noncanonical WNT
      signaling in TGFβ-induced ECM expression by ASM cells and identified WNT-5A is the most
      abundant WNT ligand with increased expression in asthmatics. It demonstrates that WNT-5A
      could contribute to remodelling of the airways. Unfortunately, the effect of eosinophil on
      WNT secretion by ASM cells at present is unknown.

      Despite the widely acknowledged significance of eosinophils in asthma pathogenesis, the
      mechanism of eosinophil induced ASM remodelling is unsolved.
    

Detailed description: 
      Asthma is a chronic, inflammatory disease of the lung characterized by intermittent airway
      obstruction, airway hyperresponsiveness, presence of activated inflammatory cells,
      inflammatory mediators, and remodeling in the airway. Airway remodeling characterizes as the
      cellular and structural changes in the airways, mainly resulting from repair processes in
      response to persistent inflammation. It is generally accepted that airway remodeling is
      closely related to the progression of airway hyperresponsiveness and the severity of asthma.
      The structural changes in the airway include airway smooth muscle (ASM) hypertrophy and
      hyperplasia, collagen deposition to the sub-epithelial basement membrane, hyperplasia of
      goblet cells, thickening of the airway mucosa and an increase in vascularity (Aceves and
      Broide, 2008).

      Airway remodelling mostly is derived from airway inflammation, where eosinophils play a key
      role. The effect of intact eosinophils on ASM cells within a physiological context first time
      was investigated by Halwani with colleagues (2013). They found that prevention contact of
      eosinophils with ASM cells using specific antibodies or blocking cysteinyl leukotrienes was
      associated with inhibition of ASM proliferation in asthmatics. Moreover, Fanat et al. (2009)
      demonstrated that ASM-derived cytokines directly affect the eosinophils differentiation and
      maturation from progenitor cells, which can maintain airway eosinophilic inflammation and
      consequently the tissue remodelling in asthma. Furthermore, eosinophil deficient mice are
      protected from airway remodeling including collagen deposition and smooth muscle thickening
      (Humbles et al Science 2004, 305:1776-9).

      Eosinophils seem to contribute to airway remodelling in several ways, including through
      release of eosinophil-derived mediators such as transforming growth factor (TGF)-β, secretion
      of cationic proteins, and cytokines, as well as through interactions with inflammatory and
      structural cells (Kariyawasam and Robinson, 2007; Aceves and Broide, 2008; Venge, 2010).
      Eosinophil-derived cytokines are in the modulation of Th2 responses that trigger macrophage
      production of TGF-β1, which serves as a stimulus for extracellular matrix (ECM) production
      (Fanta et al., 1999; Holgate, 2001). Masu et al. (2002) confirmed the proliferative effects
      of eosinophils lysates isolated from healthy donors on ASM cells. However, there is a
      possible direct eosinophil-ASM cells functional interaction by adhesion processes.
      Interaction of cells is mediated through integrins, a group of heterodimeric transmembrane
      glycoproteins (Hynes, 2002). Each integrin interacts or potentially interacts with
      counter-receptors on other cells or ligands deposited as part of the ECM (Humphries et al.,
      2006). The communication between eosinophil and ASM cells is not fully understood. Several
      integrins are expressed by eosinophils (α4β1, α6β1, αLβ2, αMβ2, αXβ2, αDβ2, α4β7) and ASM
      cell (α1β1, α2β1, α3β1, α4β1, α5β1, α6β1, α6β4, α7β1, α8β1, α9β1, αvβ1, αvβ3, αvβ5) (Teoh at
      al., 2012; Johansson and Mosher, 2013). It has been shown that integrins modulate ASM
      proliferation and contractile protein expression demonstrating allergen-induced ASM
      remodeling in an animal model of allergic asthma (Bart et al., 2010). Furthermore, several
      ASM derived integrins can function to activate latent TGF-beta into active TGF-beta in
      asthmatic airway smooth muscle (Tatler et al J Immunol 2011, 187:6094-107). Eosinophil
      integrins have the potential to mediate adhesion to endothelium in asthma (Barthel et al.,
      2008). Further studies indicate that integrins mediate trafficking of eosinophils to the lung
      and persistence in the ECM of the bronchi in models of allergen-induced acute and chronic
      asthma (Banerjee et al., 2007, 2009).

      Wingless/integrase-1 (WNT) signalling regulates not only a wide range of developmental
      processes, but its aberrant activation can lead to disease. Up-regulation of several members
      of the WNT signalling pathway in the lungs of patients with idiopathic pulmonary fibrosis and
      other interstitial lung diseases has been demonstrated (Selman et al., 2006; Königshoff et
      al., 2008). More recently, Sharma et al. (2010) have confirmed that genes polymorphisms in
      the WNT signalling pathway are associated with impaired lung function in childhood asthma.
      Kumawat et al. (2013) for the first time reported a relevant role of noncanonical WNT
      signalling in TGFβ-induced extracellular matrix (ECM) expression by ASM cells and identified
      WNT-5A is the most abundant WNT ligand in ASM cells with increased expression in asthmatics.
      This is in line with Choy et al. (2011) who report that airway biopsies from Th2 high asthma
      patients have increased WNT-5A expression. Higher expression of WNT-5A in ASM cells
      demonstrates that WNT-5A could contribute to remodelling of the airways. Despite the reported
      role of WNT in airway remodelling, the regulation of WNT secretion by eosinophils or by
      eosinophil-ASM interactions is at present unknown.

      Despite the widely acknowledged significance of eosinophils in asthma pathogenesis, the
      mechanism for eosinophil mediated airway remodeling is unsolved. At present understanding of
      eosinophils interaction and effect on ASM cells in asthma remains elusive. Therefore the
      nature of the interplay between these two cells types and the consequence of it needs to be
      investigated.

      The aim of the Project: to assess the eosinophil mediated airway remodeling in asthma.
    

Intervention name(s): Bronchial challenge with allergen; Co-culture formation
Intervention type(s): Procedure; Other
Intervention description(s): Bronchial challenge is performed with D. pteronyssinus allergen.; Eosinophil and linear bronchial smooth muscle cell co-culture formation. Airway smooth muscle cell proliferation, eosinophil adhesion to the bronchial smooth muscle cells, the role of eosinophil integrins in the airway remodelling process is assessed in individual formed co-culture
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: asthma; eosinophils; airway smooth muscle; airway remodelling; integrins; cytokines