Eosinophil Induced Remodelling in Asthma

NCT02648074 | Completed

• 2 other identifiers: MIP-010/2014PSUL-010/2014
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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. 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.

Conditions

Allergic Asthma; Airway Remodelling

Keywords

asthma; eosinophils; airway smooth muscle; airway remodelling; integrins; cytokines

Outcome Measures

Primary Outcomes (2)

• Eosinophils and bronchial smooth muscle cell adhesion change assessment

  There are used the individual eosinophil and airway smooth muscle cell co-culture. It is compared the strength of eosinophil adhesion to the bronchial smooth muscle cells in patients with asthma and healthy.

  In 30, 45, 60, 120, 240 minutes time points after eosinophils and bronchial smooth muscle cell interactions start

• Bronchial smooth muscle cell proliferation change assessment by cell viability

  Bronchial smooth muscle cell proliferation is assessed by cell viability

  In 48 and 72 hrs time points after eosinophils and linear bronchial smooth muscle co-culture formation

Secondary Outcomes (2)

• The change of capacity of eosinophils' integrins to inhibit the bronchial smooth muscle cell proliferation in patients with asthma

  In 48 and 72 hrs time points after eosinophils and linear bronchial smooth muscle co-culture formation

• The change of eosinophils' integrins interaction with bronchial smooth muscle cells and Wnt-5A protein production after allergen challenge

  Up to 72 hrs time points after eosinophils (collected from blood of patients before and after bronchial provocation with an allergen) and linear bronchial smooth muscle co-culture formation

Study Arms (2)

Allergic asthma

EXPERIMENTAL

Bronchial asthma and sensitization to D. pteronyssinus allergen Interventions: Bronchial challenge with allergen; Eosinophil and linear bronchial smooth muscle cell co-culture formation.

Procedure: Bronchial challenge with allergen; Other: Co-culture formation

Healthy subjects

ACTIVE COMPARATOR

Healthy subjects without allergic and other chronic respiratory diseases (control group). Interventions: Bronchial challenge with allergen; Eosinophil and linear bronchial smooth muscle cell co-culture formation.

Procedure: Bronchial challenge with allergen; Other: Co-culture formation

Interventions

Bronchial challenge with allergen PROCEDURE

Bronchial challenge is performed with D. pteronyssinus allergen.

Allergic asthma; Healthy subjects

Co-culture formation OTHER

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

Allergic asthma; Healthy subjects

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Men and women between the ages of 18-50 years;
• Allergic asthma and sensitization to house dust mites (D. pteronyssinus) allergen, approved with:
• Medical history and symptoms more than one year and 2.2. skin prick test positive for D. pteronyssinus (positive wheals are those exceeding 3mm in diameter greater than the negative control) and 2.3. Positive bronchial challenge with methacholine or documented completely reversible bronchial obstruction;
• Stable lung function (FEV1≥70 perc.);
• Postmenopausal women. Premenopausal women if pregnancy test is negative and they agree to use an effective contraceptive measures during the study;
• Healthy subjects without allergic and other chronic respiratory diseases (control group);
• Non- smokers;
• Participants who gave his/her informed written consent.

You may not qualify if:

• Asthma exacerbation 1 month prior to study
• Clinically significant permanent allergy symptoms (ex. cat or dog dander induced allergy)
• Contraindications to perform an allergy skin test and/or bronchial provocation test 3.1. Active airway infection 1 month prior the study; 3.2. Used medicaments: 3.2.1. Inhaled glucocorticoids intake 1 month prior the study; 3.2.2. Antihistamines intake 7 days prior the study; 3.2.3. Short acting β2 agonists 12 hours prior the study; 3.2.4. Long acting β2 agonists 2 days prior the study; 3.2.5. Leukotriene receptor antagonists prior 14 days;
• If the histamine mean wheal diameter is \<= 3 mm or control mean wheal diameter is \>= 3 mm;
• Contraindications for epinephrine;
• Alcohol or narcotic abuse;
• Pregnancy;
• Breast-feeding.

Sponsors & Collaborators

• Lithuanian University of Health Sciences: lead
• Research Council of Lithuania: collaborator
• University of Groningen: collaborator

Study Sites (1)

Lithuanian University of Health Sciences, Pulmonology and Immunology Department

Kaunas, LT-50009, Lithuania

Location

Related Publications (2)

• Januskevicius A, Gosens R, Sakalauskas R, Vaitkiene S, Janulaityte I, Halayko AJ, Hoppenot D, Malakauskas K. Suppression of Eosinophil Integrins Prevents Remodeling of Airway Smooth Muscle in Asthma. Front Physiol. 2017 Jan 9;7:680. doi: 10.3389/fphys.2016.00680. eCollection 2016.

  PMID: 28119625 DERIVED

• Januskevicius A, Vaitkiene S, Gosens R, Janulaityte I, Hoppenot D, Sakalauskas R, Malakauskas K. Eosinophils enhance WNT-5a and TGF-beta1 genes expression in airway smooth muscle cells and promote their proliferation by increased extracellular matrix proteins production in asthma. BMC Pulm Med. 2016 Jun 13;16(1):94. doi: 10.1186/s12890-016-0254-9.

  PMID: 27297409 DERIVED

MeSH Terms

Conditions

Airway Remodeling; Asthma

Interventions

Allergens

Condition Hierarchy (Ancestors)

Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antigens; Biological Factors

Study Officials

• Kestutis Malakauskas, Prof., dr.

  Lithuanian University of Health Sciences, Pulmonology and Immunology Department

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. dr.

Study Record Dates

• First Submitted: December 21, 2015
• First Posted: January 6, 2016
• Study Start: March 1, 2014
• Primary Completion: October 1, 2016
• Study Completion: January 1, 2017
• Last Updated: February 26, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

LI (1)