Allergic AsthmaECMANCT03388359
Role of Extracellular Matrix in the Development of Airway Remodeling in Asthma
A study testing Bronchial challenge with allergen, Co-culture formation and Inhibition of Wnt and Smad signaling pathways in people with Allergic Asthma and Airway Remodelling, run by Lithuanian University of Health Sciences at 1 site in Lithuania.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 50 yearsHealthy volunteers can take part
- Conditions the study is for
- Allergic Asthma, Airway Remodelling, Extracellular Matrix Alteration
- What is being tested?
- Bronchial challenge with allergen, Co-culture formation and Inhibition of Wnt and Smad signaling pathways
- Type of treatment
- Medical device, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 60 participants
- Where
- 1 siteLithuania
- Study dates
- 1 Jun 2017to 8 Dec 2020
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Men and women between the ages of 18-50 years;
- Allergic asthma and sensitization to house dust mites (D. pteronyssinus) allergen, approved with:
- 2. 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.
Who cannot join
- 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;
- Other significant mental and / or internal diseases and conditions, which could be as exclusion criteria due to the opinion of the researcher;
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- Alcohol or narcotic abuse;
- Pregnancy;
- Breast-feeding.
Trial locations and contacts
1 site in 1 country.
Lithuania1 site, 1 recruiting
- Recruiting
Lithuanian University of Health Sciences, Pulmonology Department
Kaunas, LT-50009
Kęstutis Malakauskas, Prof., Dr., +37037326773, kestutis.malakauskas@lsmuni.lt
About this study
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.
Read the detailed description
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.
ECM is a building block between airways and lung parenchyma. It plays a crucial role in the maintenance of pulmonary structure and functions influencing the distribution and adhesion of inflammatory cells, fluid balance, elasticity and can act as a resource of inflammatory mediators. In asthma, predominant eosinophilic airway inflammation can result the dysregulation of ECM, which are identified as altered quantitative and qualitative composition of ECM, activated molecular signaling pathways which are responsible for triggered ECM proteins production. The main sources of ECM proteins in lungs are pulmonary fibroblasts and ASM cells. In asthma, fibroblasts are responsive to many inflammatory cytokines which activate and promote fibroblasts proliferation, contractility and cellular differentiation to myofibroblasts form with up-regulated rate of matrix production. In turn, activated fibroblasts secrete cytokines IL-1β, IL-33, CXC, CC chemokines, various types of matrix metalloproteinases (MMPs) as well as reactive oxygen species. These factors allow fibroblasts to assist in the activation and migration of resident immune cells and endow fibroblast roles in chemical and cell-mediated immunity, acute and chronic inflammation, extravasation of immune cells into connective tissue of the lungs. The ASM cells are also the strong contributor to the ECM protein pool in the lungs - they can produce the variety of ECM proteins contributing to the tissue structure and elasticity which are seen unbalanced in asthma. While fibroblasts and ASM cells determine ECM proteins composition, the ECM in turn can affect the structural cells behavior in lung tissue. The role of cell-matrix interactions represents an area for active investigation on the ability of lung matrix to prime the structural pulmonary cells.
The excess of ECM proteins deposition is associated with activation of profibrotic factor transforming growth factor-beta 1 (TGF-β1) mediated WNT and Smad signaling pathways. Highest levels of TGF-β1 in airways are released by eosinophils - the main inflammatory cells in asthma pathogenesis. During stable asthma and especially allergen provoced acute asthma episodes eosinophils infiltrate into the airways, enhancing local levels of TGF-β1 and other various cytokines, chemokines and growth factors near the connective tissue and ASM bundles. However, how eosinophil-released mediators induce ECM dysregulation leading to development of airway remodeling are not investigated part of asthma pathogenesis.
Asthma still cannot be cured, but appropriate management can control the disease severity. Better understanding in development of asthma is the main objective which must to be pursued. Based on this rationale the investigators aimed to investigate eosinophilic airway inflammation mediated production of ECM proteins and MMPs, activity for their release responsible molecular signaling pathways, and how dysregulated ECM affect fibroblasts and ASM cells proliferation, migration, differentiation and contractility in asthma. Trying to understand and control the development of asthma the investigators will use models of combined cells cultures estimating ECM homeostasis in stable and acute asthma. Blocking with specific inhibitors of WNT and Smad signaling pathways, potentially responsible for ECM proteins and MMPs production, will help to find the controlling mechanisms of ECM dysregulation. Therefore, evaluation of ECM proteins degradation fragments and levels of MMPs will help to estimate an applied value of these circulating biomarkers in asthma patients.
- Being tested
- Bronchial challenge with allergen, Co-culture formation, Inhibition of Wnt and Smad signaling pathways, Extracellular matrix turnover and deposition assessment, Dermatophagoides pteronyssinus allergen
- Keywords
- asthma, eosinophils, Extracellular matrix, airway smooth muscle, airway remodelling, fibroblast
- Medical subject headings
- Airway Remodeling, Asthma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Bronchial challenge with allergenProcedure or surgery
Bronchial challenge is performed with D. pteronyssinus allergen. Measurements of differences in eosinophils activity after allergen challenge.
Co-culture formationOther
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.
Inhibition of Wnt and Smad signaling pathwaysOther
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).
Extracellular matrix turnover and deposition assessmentOther
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.
Dermatophagoides pteronyssinus allergenBiological
Dermatophagoides pteronyssinus allergen is required to perform allergen bronchial challenge test.
Dosimeter ProvoX (Ganshorn)Device
Device for allergen bronchial challenge test.
EosinophilsBiological
Eosinophils are isolated from peripheral blood
Airway smooth muscle cellsBiological
Airway smooth muscle cells from healthy subjects (support from the University of Groningen)
FibroblastsBiological
Normal human fibroblast cell lines (commercial fibroblast lines)
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Eosinophils effect on extracellular matrix proteins (collagen, fibronectin, elastin, versican, decorin, laminin, etc.) and matrix metalloproteinasis (MMP-2,9,12,etc.) altered gene expression in folds over control by pulmonary fibroblasts.
All mentioned measurements from experimental plan describes one task with final results of increase or decrease in folds.
Measured: 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
Wnt and Smad signaling pathways inhibitors effect on development of airway remodelling processes (changes in pct. of extracellular matrix production, bronchial smooth muscle cell and pulmonary fibroblast proliferation, contractillity, differentiation, migration).
All selected measurements from experimental plan describes one task with final results of increase or decrease in percentage levels.
Measured: Through study completion, an average of 1 year.
Cytokines and growth factors production
Proinflammatory cytokines and growth factors production (concentration) of eosinophils, bronchial smooth muscle cell and pulmonary fibroblast.
All selected measurements from experimental plan describes one task with final results of altered concentration (pg/ml; ng/ml).
Measured: Through study completion, an average of 1 year.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Jan 2018
- Study start1 Jun 2017
- Primary completion10 Nov 2020 (estimated)
- Study completion8 Dec 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for Allergic AsthmaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Lithuanian University of Health Sciences
- Sponsor type
- University, hospital or other
- Collaborators
- Research Council of Lithuania, University of Groningen
- Responsible party
- Principal investigator, Kestutis Malakauskas, Lithuanian University of Health Sciences
- Investigators
- Kęstutis Malakauskas, Prof., Dr., Study chair, Lithuanian University of Health Sciences, Department of Pulmonology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03388359
- Sponsor's protocol ID
- P-MIP-17-115
- Other IDs
- PSUL-010/2014
- Acronym
- ECMA
- Status last verified
- Sep 2020
- First submitted
- 23 Aug 2017
- Last updated
- 7 Sep 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 22192725Januskevicius 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.
PubMed 27297409Firszt 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.
PubMed 23682108Kendall 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.
PubMed 24904424Amara 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.
PubMed 20685750Bondi 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.
PubMed 19926889Balestrini 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.
PubMed 22410748Janulaityte 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.
PubMed 34199925Kalinauskaite-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.
PubMed 31885750Kalinauskaite-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.
PubMed 31438916
Study at a glance
From the registry record, last updated by the sponsor on 7 Sep 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Role of Extracellular Matrix in the Development of Airway Remodeling in Asthma
- ClinicalTrials.gov ID
- NCT03388359
- Acronym / sponsor ID
- ECMA / P-MIP-17-115
- Keywords
- asthma, eosinophils, Extracellular matrix, airway smooth muscle, airway remodelling, fibroblast
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- Lithuanian University of Health SciencesUniversity, hospital or other
- Collaborators
- Research Council of Lithuania, University of Groningen
- Study start
- 1 Jun 2017 (actual)
- Primary completion
- 10 Nov 2020 (estimated)
- Study completion
- 8 Dec 2020 (estimated)
- First posted
- 3 Jan 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
ECM is a building block between airways and lung parenchyma. It plays a crucial role in the maintenance of pulmonary structure and functions influencing the distribution and adhesion of inflammatory cells, fluid balance, elasticity and can act as a resource of inflammatory mediators. In asthma, predominant eosinophilic airway inflammation can result the dysregulation of ECM, which are identified as altered quantitative and qualitative composition of ECM, activated molecular signaling pathways which are responsible for triggered ECM proteins production. The main sources of ECM proteins in lungs are pulmonary fibroblasts and ASM cells. In asthma, fibroblasts are responsive to many inflammatory cytokines which activate and promote fibroblasts proliferation, contractility and cellular differentiation to myofibroblasts form with up-regulated rate of matrix production. In turn, activated fibroblasts secrete cytokines IL-1β, IL-33, CXC, CC chemokines, various types of matrix metalloproteinases (MMPs) as well as reactive oxygen species. These factors allow fibroblasts to assist in the activation and migration of resident immune cells and endow fibroblast roles in chemical and cell-mediated immunity, acute and chronic inflammation, extravasation of immune cells into connective tissue of the lungs. The ASM cells are also the strong contributor to the ECM protein pool in the lungs - they can produce the variety of ECM proteins contributing to the tissue structure and elasticity which are seen unbalanced in asthma. While fibroblasts and ASM cells determine ECM proteins composition, the ECM in turn can affect the structural cells behavior in lung tissue. The role of cell-matrix interactions represents an area for active investigation on the ability of lung matrix to prime the structural pulmonary cells.
The excess of ECM proteins deposition is associated with activation of profibrotic factor transforming growth factor-beta 1 (TGF-β1) mediated WNT and Smad signaling pathways. Highest levels of TGF-β1 in airways are released by eosinophils - the main inflammatory cells in asthma pathogenesis. During stable asthma and especially allergen provoced acute asthma episodes eosinophils infiltrate into the airways, enhancing local levels of TGF-β1 and other various cytokines, chemokines and growth factors near the connective tissue and ASM bundles. However, how eosinophil-released mediators induce ECM dysregulation leading to development of airway remodeling are not investigated part of asthma pathogenesis.
Asthma still cannot be cured, but appropriate management can control the disease severity. Better understanding in development of asthma is the main objective which must to be pursued. Based on this rationale the investigators aimed to investigate eosinophilic airway inflammation mediated production of ECM proteins and MMPs, activity for their release responsible molecular signaling pathways, and how dysregulated ECM affect fibroblasts and ASM cells proliferation, migration, differentiation and contractility in asthma. Trying to understand and control the development of asthma the investigators will use models of combined cells cultures estimating ECM homeostasis in stable and acute asthma. Blocking with specific inhibitors of WNT and Smad signaling pathways, potentially responsible for ECM proteins and MMPs production, will help to find the controlling mechanisms of ECM dysregulation. Therefore, evaluation of ECM proteins degradation fragments and levels of MMPs will help to estimate an applied value of these circulating biomarkers in asthma patients.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Allergic asthma | Experimental | 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: FibroblastsBronchial 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. |
| Healthy subjects | Active comparator | 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: FibroblastsHealthy 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. |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- Men and women between the ages of 18-50 years;
- Allergic asthma and sensitization to house dust mites (D. pteronyssinus) allergen, approved with:
- 2. 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.
Key exclusion criteria (9 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Bronchial challenge with allergenBronchial challenge is performed with D. pteronyssinus allergen. Measurements of differences in eosinophils activity after allergen challenge. | Procedure or surgery | Allergic asthma, Healthy subjects |
| Co-culture formationEosinophil 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. | Other | Allergic asthma, Healthy subjects |
| Inhibition of Wnt and Smad signaling pathwaysWnt 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). | Other | Allergic asthma, Healthy subjects |
| Extracellular matrix turnover and deposition assessmentEosinophils effect on extracellular matrix proteins (collagen, fibronectin, elastin, versican, decorin, laminin, etc.) and matrix metalloproteinasis (MMP-2,9,12,etc.) production by pulmonary fibroblasts. | Other | Allergic asthma, Healthy subjects |
| Dermatophagoides pteronyssinus allergenDermatophagoides pteronyssinus allergen is required to perform allergen bronchial challenge test. | Biological | Allergic asthma, Healthy subjects |
| Dosimeter ProvoX (Ganshorn)Device for allergen bronchial challenge test. | Device | Allergic asthma, Healthy subjects |
| EosinophilsEosinophils are isolated from peripheral blood | Biological | Allergic asthma, Healthy subjects |
| Airway smooth muscle cellsAirway smooth muscle cells from healthy subjects (support from the University of Groningen) | Biological | Allergic asthma, Healthy subjects |
| FibroblastsNormal human fibroblast cell lines (commercial fibroblast lines) | Biological | Allergic asthma, Healthy subjects |
Primary outcome
Effect of bronchial challenge with specific allergen on eosinophils activity and impact on pulmonary fibroblasts
Time frame: 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.
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.
3 secondary outcomes
Extracellular matrix turnover and deposition
Time frame: 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
Time frame: Through study completion, an average of 1 year.
Cytokines and growth factors production
Time frame: Through study completion, an average of 1 year.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Sep 2020.
- Background: PubMed 22192725Brightling 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.
- Background: PubMed 27297409Januskevicius 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.
- Background: PubMed 23682108Firszt 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.
- Background: PubMed 24904424Kendall 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.
- Background: PubMed 20685750Amara 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.
- Background: PubMed 19926889Bondi 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.
- Background: PubMed 22410748Balestrini 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.
- Derived from this study: PubMed 34199925Janulaityte 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.
- Derived from this study: PubMed 31885750Kalinauskaite-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.
- Derived from this study: PubMed 31438916Kalinauskaite-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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kęstutis Malakauskas, Prof., Dr. study chair
Lithuanian University of Health Sciences, Department of Pulmonology
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Bronchial challenge with allergen, Co-culture formation and Inhibition of Wnt and Smad signaling pathways in people with Allergic Asthma and Airway Remodelling, run by Lithuanian University of Health Sciences at 1 site in Lithuania.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 7 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Lithuania. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Kęstutis Malakauskas, Prof., Dr. (+37037326737, kestutis.malakauskas@lsmuni.lt), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Effect of bronchial challenge with specific allergen on eosinophils activity and impact on pulmonary fibroblasts (time frame: 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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03388359, which also lists 10 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Sep 2020.