NCT03388359

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

• Status: Unknown
• Phase: N/A
• Study type: Interventional
• Enrollment: 60 (estimated)
• Sponsor: Lithuanian University of Health Sciences · Academic / Other
• Sex: All
• Age: 18 Years – 50 Years
• Healthy volunteers: Accepted

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.

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.

Conditions

• Allergic Asthma
• Airway Remodelling
• Extracellular Matrix Alteration

Interventions

Type	Name	Description
PROCEDURE	Bronchial challenge with allergen	Bronchial challenge is performed with D. pteronyssinus allergen. Measurements of differences in eosinophils activity after allergen challenge.
OTHER	Co-culture formation	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.
OTHER	Inhibition of Wnt and Smad signaling pathways	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).
OTHER	Extracellular matrix turnover and deposition assessment	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.
BIOLOGICAL	Dermatophagoides pteronyssinus allergen	Dermatophagoides pteronyssinus allergen is required to perform allergen bronchial challenge test.
DEVICE	Dosimeter ProvoX (Ganshorn)	Device for allergen bronchial challenge test.
BIOLOGICAL	Eosinophils	Eosinophils are isolated from peripheral blood
BIOLOGICAL	Airway smooth muscle cells	Airway smooth muscle cells from healthy subjects (support from the University of Groningen)
BIOLOGICAL	Fibroblasts	Normal human fibroblast cell lines (commercial fibroblast lines)

Timeline

• Start date: 2017-06-01
• Primary completion: 2020-11-10
• Completion: 2020-12-08
• First posted: 2018-01-03
• Last updated: 2020-09-07

Locations

1 site across 1 country: Lithuania