Role of Extracellular Matrix in the Development of Airway Remodeling in Asthma

NCT03388359 | Unknown

• 2 other identifiers: P-MIP-17-115PSUL-010/2014
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

Asthma is a major noncommunicable chronic inflammatory disorder which is characterized by airway inflammation and related to pathological modifications of the bronchial wall structure so called airway remodeling. Airway remodeling seen in asthma is mainly described by epithelial changes, subepithelial fibrosis, increased airway smooth muscle (ASM) mass, decreased distance between ASM and epithelium, mucous gland and goblet cell hyperplasia, vascular changes and edema. Near these well known pathophysiological changes of the airways, the extracellular matrix (ECM) can be distinguished as a new important factor included in development of airway remodeling in asthma.

Conditions

Allergic Asthma; Airway Remodelling; Extracellular Matrix Alteration

Keywords

asthma; eosinophils; Extracellular matrix; airway smooth muscle; airway remodelling; fibroblast

Outcome Measures

Primary Outcomes (1)

• Effect of bronchial challenge with specific allergen on eosinophils activity and impact on pulmonary fibroblasts

  Bronchial challenge is performed with D. pteronyssinus allergen (HEP/ml). Measurements of altered eosinophils ROS production (changes in pct.), viability (changes in pct.), outer-membrane integrins expression (changes in pct.). Altered fibroblasts apoptosis (changes in pct.), proliferation (changes in pct.), migration (changes in pct.) and contractility (changes in pct.) after co-culture with eosinophils from asthmatic or healthy individuals. All mentioned measurements from experimental plan describes one task with final results of increase or decrease in percentage levels.

  First measurements in 24, 48 and 72 h time points after co-culture of eosinophils and pulmonary fibroblasts, summarized data - through study completion, an average of 1 year.

Secondary Outcomes (3)

• Extracellular matrix turnover and deposition

  First measurement in 24 h time points after co-culture of eosinophils and pulmonary fibroblasts, summarized data - through study completion, an average of 1 year.

• Wnt and Smad signaling pathways inhibitors effect

  Through study completion, an average of 1 year.

• Cytokines and growth factors production

  Through study completion, an average of 1 year.

Study Arms (2)

Allergic asthma

EXPERIMENTAL

Bronchial asthma and sensitization to D. pteronyssinus allergen Interventions: Bronchial challenge with allergen (Dermatophagoides pteronyssinus, Dosimeter ProvoX (Ganshorns)); Eosinophil and linear bronchial smooth muscle cell or pulmonary fibroblast co-culture formation (eosinophils, fibrobralst, airway smooth muscle cells); Inhibition of Wnt and Smad signaling pathways; Extracellular matrix turnover and deposition assessment.

Procedure: Bronchial challenge with allergen; Other: Co-culture formation; Other: Inhibition of Wnt and Smad signaling pathways; Other: Extracellular matrix turnover and deposition assessment; Biological: Dermatophagoides pteronyssinus allergen; Device: Dosimeter ProvoX (Ganshorn); Biological: Eosinophils; Biological: Airway smooth muscle cells; Biological: Fibroblasts

Healthy subjects

ACTIVE COMPARATOR

Healthy subjects without allergic and other chronic respiratory diseases (control group). Interventions: Bronchial challenge with allergen (Dermatophagoides pteronyssinus, Dosimeter ProvoX (Ganshorns)); Eosinophil and linear bronchial smooth muscle cell or pulmonary fibroblast co-culture formation (eosinophils, fibrobralst, airway smooth muscle cells); Inhibition of Wnt and Smad signaling pathways; Extracellular matrix turnover and deposition assessment.

Procedure: Bronchial challenge with allergen; Other: Co-culture formation; Other: Inhibition of Wnt and Smad signaling pathways; Other: Extracellular matrix turnover and deposition assessment; Biological: Dermatophagoides pteronyssinus allergen; Device: Dosimeter ProvoX (Ganshorn); Biological: Eosinophils; Biological: Airway smooth muscle cells; Biological: Fibroblasts

Interventions

Bronchial challenge with allergen PROCEDURE

Bronchial challenge is performed with D. pteronyssinus allergen. Measurements of differences in eosinophils activity after allergen challenge.

Allergic asthma; Healthy subjects

Co-culture formation OTHER

Eosinophil and linear bronchial smooth muscle cell or pulmonary fibroblast co-culture formation. Bronchial smooth muscle cell and pulmonary fibroblast proliferation, migration, contractillity, differentiation, eosinophil adhesion to the bronchial smooth muscle cells or pulmonary fibroblast.

Allergic asthma; Healthy subjects

Inhibition of Wnt and Smad signaling pathways OTHER

Wnt and Smad signaling pathways inhibitors effect on development of airway remodelling processes (extracellular matrix production, bronchial smooth muscle cell and pulmonary fibroblast proliferation, contractillity, differentiation, migration).

Allergic asthma; Healthy subjects

Extracellular matrix turnover and deposition assessment OTHER

Eosinophils effect on extracellular matrix proteins (collagen, fibronectin, elastin, versican, decorin, laminin, etc.) and matrix metalloproteinasis (MMP-2,9,12,etc.) production by pulmonary fibroblasts.

Allergic asthma; Healthy subjects

Dermatophagoides pteronyssinus allergen BIOLOGICAL

Dermatophagoides pteronyssinus allergen is required to perform allergen bronchial challenge test.

Allergic asthma; Healthy subjects

Dosimeter ProvoX (Ganshorn) DEVICE

Device for allergen bronchial challenge test.

Allergic asthma; Healthy subjects

Eosinophils BIOLOGICAL

Eosinophils are isolated from peripheral blood

Allergic asthma; Healthy subjects

Airway smooth muscle cells BIOLOGICAL

Airway smooth muscle cells from healthy subjects (support from the University of Groningen)

Allergic asthma; Healthy subjects

Fibroblasts BIOLOGICAL

Normal human fibroblast cell lines (commercial fibroblast lines)

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:
• \. 1. 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; 3. Stable lung function (FEV1≥70 perc.); 4. Postmenopausal women. Premenopausal women if pregnancy test is negative and they agree to use an effective contraceptive measures during the study; 5. Healthy subjects without allergic and other chronic respiratory diseases (control group); 6. Non- smokers; 7. 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 Department

Kaunas, LT-50009, Lithuania

RECRUITING

Related Publications (10)

• Brightling CE, Gupta S, Gonem S, Siddiqui S. Lung damage and airway remodelling in severe asthma. Clin Exp Allergy. 2012 May;42(5):638-49. doi: 10.1111/j.1365-2222.2011.03917.x. Epub 2011 Dec 22.

  PMID: 22192725 BACKGROUND

• 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 BACKGROUND

• Firszt R, Francisco D, Church TD, Thomas JM, Ingram JL, Kraft M. Interleukin-13 induces collagen type-1 expression through matrix metalloproteinase-2 and transforming growth factor-beta1 in airway fibroblasts in asthma. Eur Respir J. 2014 Feb;43(2):464-73. doi: 10.1183/09031936.00068712. Epub 2013 May 16.

  PMID: 23682108 BACKGROUND

• Kendall RT, Feghali-Bostwick CA. Fibroblasts in fibrosis: novel roles and mediators. Front Pharmacol. 2014 May 27;5:123. doi: 10.3389/fphar.2014.00123. eCollection 2014.

  PMID: 24904424 BACKGROUND

• Amara N, Goven D, Prost F, Muloway R, Crestani B, Boczkowski J. NOX4/NADPH oxidase expression is increased in pulmonary fibroblasts from patients with idiopathic pulmonary fibrosis and mediates TGFbeta1-induced fibroblast differentiation into myofibroblasts. Thorax. 2010 Aug;65(8):733-8. doi: 10.1136/thx.2009.113456.

  PMID: 20685750 BACKGROUND

• Bondi CD, Manickam N, Lee DY, Block K, Gorin Y, Abboud HE, Barnes JL. NAD(P)H oxidase mediates TGF-beta1-induced activation of kidney myofibroblasts. J Am Soc Nephrol. 2010 Jan;21(1):93-102. doi: 10.1681/ASN.2009020146. Epub 2009 Nov 19.

  PMID: 19926889 BACKGROUND

• Balestrini JL, Chaudhry S, Sarrazy V, Koehler A, Hinz B. The mechanical memory of lung myofibroblasts. Integr Biol (Camb). 2012 Apr;4(4):410-21. doi: 10.1039/c2ib00149g. Epub 2012 Mar 13.

  PMID: 22410748 BACKGROUND

• Janulaityte I, Januskevicius A, Kalinauskaite-Zukauske V, Palacionyte J, Malakauskas K. Asthmatic Eosinophils Promote Contractility and Migration of Airway Smooth Muscle Cells and Pulmonary Fibroblasts In Vitro. Cells. 2021 Jun 4;10(6):1389. doi: 10.3390/cells10061389.

  PMID: 34199925 DERIVED

• Kalinauskaite-Zukauske V, Januskevicius A, Janulaityte I, Miliauskas S, Malakauskas K. Serum Levels of Epithelial-Derived Cytokines as Interleukin-25 and Thymic Stromal Lymphopoietin after a Single Dose of Mepolizumab in Patients with Severe Non-Allergic Eosinophilic Asthma: A Short Report. Can Respir J. 2019 Dec 1;2019:8607657. doi: 10.1155/2019/8607657. eCollection 2019.

  PMID: 31885750 DERIVED

• Kalinauskaite-Zukauske V, Januskevicius A, Janulaityte I, Miliauskas S, Malakauskas K. Expression of eosinophil beta chain-signaling cytokines receptors, outer-membrane integrins, and type 2 inflammation biomarkers in severe non-allergic eosinophilic asthma. BMC Pulm Med. 2019 Aug 22;19(1):158. doi: 10.1186/s12890-019-0904-9.

  PMID: 31438916 DERIVED

MeSH Terms

Conditions

Airway Remodeling; Asthma

Interventions

Allergens; Antigens, Dermatophagoides

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

• Kęstutis Malakauskas, Prof., Dr.

  Lithuanian University of Health Sciences, Department of Pulmonology

  STUDY CHAIR

Central Study Contacts

Kęstutis Malakauskas, Prof., Dr.

CONTACT

+37037326737; kestutis.malakauskas@lsmuni.lt

Virginija Kalinauskaitė-Žukauskė, Dr.

CONTACT

+37068633551; virgucee@gmail.com

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: Principal Investigator, Clinical Professor, Head of Laboratory

Study Record Dates

• First Submitted: August 23, 2017
• First Posted: January 3, 2018
• Study Start: June 1, 2017
• Primary Completion: November 10, 2020
• Study Completion: December 8, 2020
• Last Updated: September 7, 2020

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will not share

Locations

LI (1)