Synthesis of tenascin and laminin beta2 chain in human bronchial epithelial cells is enhanced by cysteinyl leukotrienes via CysLT1 receptor

Siiri Altraja,Martin Kadai,Alan Altraja,Erki Rekker

doi:10.1186/1465-9921-9-44

Siiri Altraja, Martin Kadai + Show 2 more

Open Access

https://doi.org/10.1186/1465-9921-9-44

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Journal: Respiratory research	Publication Date: May 26, 2008
Citations: 46	License type: cc-by

Affiliation: University of Tartu, Estonian Biocentre

Abstract

BackgroundCysteinyl leukotrienes (CysLTs) are key mediators of asthma, but their role in the genesis of airway remodeling is insufficiently understood. Recent evidence suggests that increased expression of tenascin (Tn) and laminin (Ln) β2 chain is indicative of the remodeling activity in asthma, but represents also an example of deposition of extracellular matrix, which affects the airway wall compliance. We tested the hypothesis that CysLTs affect production of Tn and Ln β2 chain by human bronchial epithelial cells and elucidated, which of the CysLT receptors, CysLT1 or CysLT2, mediate this effect.MethodsCultured BEAS-2B human bronchial epithelial cells were stimulated with leukotriene D4 (LTD4) and E4 (LTE4) and evaluated by immunocytochemistry, Western blotting, flow cytometry, and RT-PCR. CysLT receptors were differentially blocked with use of montelukast or BAY u9773.ResultsLTD4 and LTE4 significantly augmented the expression of Tn, whereas LTD4, distinctly from LTE4, was able to increase also the Ln β2 chain. Although the expression of CysLT2 prevailed over that of CysLT1, the up-regulation of Tn and Ln β2 chain by CysLTs was completely blocked by the CysLT1-selective antagonist montelukast with no difference between montelukast and the dual antagonist BAY u9773 for the inhibitory capacity.ConclusionThese findings suggest that the CysLT-induced up-regulation of Tn and Ln β2 chain, an important epithelium-linked aspect of airway remodeling, is mediated predominantly by the CysLT1 receptor. The results provide a novel aspect to support the use of CysLT1 receptor antagonists in the anti-remodeling treatment of asthma.

Highlights

Cysteinyl leukotrienes (CysLTs) are key mediators of asthma, but their role in the genesis of airway remodeling is insufficiently understood
In bronchial epithelial cells in vitro, Tn can be up-regulated by cytokines like transforming growth factor-β (TGF-β) [8] and tumor necrosis factor-α (TNF-α) [9], which are operative in asthma
Tn-specific reactivity localized intracellularly in the BEAS-2B cells (Figure 1C) and, like that detected with immunoblot, it increased in response to both leukotriene D4 (LTD4) and LTE4

Summary

Introduction

Cysteinyl leukotrienes (CysLTs) are key mediators of asthma, but their role in the genesis of airway remodeling is insufficiently understood. Recent evidence suggests that increased expression of tenascin (Tn) and laminin (Ln) β2 chain is indicative of the remodeling activity in asthma, but represents an example of deposition of extracellular matrix, which affects the airway wall compliance. Airway remodeling is a fundamental abnormality in the pathobiology of inflammatory airway diseases like bronchial asthma and chronic obstructive pulmonary disease (COPD) [1,2]. This remodeling is irreversible in its many aspects including airway fibrosis and deposition of new extracellular matrix (ECM) components into the airway wall [2]. In addition to serving as a marker of ongoing inflammation, the deposition of Tn can contribute to increased airway narrowing and decreased airway wall compliance, as does the deposition of other ECM components

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