Ignite Creation Date:
2024-05-06 @ 7:59 AM
Last Modification Date:
2024-10-26 @ 11:55 AM
Study NCT ID:
NCT02648074
Status:
COMPLETED
Last Update Posted:
2020-02-26
First Post:
2015-12-21
Brief Title:
Eosinophil Induced Remodelling in Asthma
Sponsor:
Lithuanian University of Health Sciences
Organization:
Lithuanian University of Health Sciences
Study Overview
Official Title:
Eosinophil Induced Airway Smooth Muscle Remodelling in Asthma
Status:
COMPLETED
Status Verified Date:
2020-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ERA
Brief 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
Winglessintegrase-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
Winglessintegrase-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 3051776-9
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 1876094-107 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
Winglessintegrase-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
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 3051776-9
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 1876094-107 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
Winglessintegrase-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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| PSUL-0102014 | OTHER | Lithuanian University of Health Sciences | None |