TGF-β1 Activates Nasal Fibroblasts through the Induction of Endoplasmic Reticulum Stress.

Jae-Min Shin,Joo-Hoo Park,Hyun-Woo Yang,Il-Ho Park,Ju-Hyung Kang,Heung-Man Lee

doi:10.3390/biom10060942

Abstract

(1) Background: Tissue remodeling and extracellular matrix (ECM) accumulation contribute to the development of chronic inflammatory diseases of the upper airway. Endoplasmic reticulum (ER) stress is considered to be the key signal for triggering tissue remodeling in pathological conditions. The present study aimed to investigate the role of ER-stress in TGF-β1-stimulated nasal fibroblasts and inferior turbinate organ cultures; (2) Methods: Fibroblasts and organ cultures were pretreated with 4-phenylbutyric acid (PBA) and stimulated with TGF-β1 or thapsigargin (TG). Expression of ER-stress markers, myofibroblast marker, and ECM components was measured by Western blotting and real-time PCR. Reactive oxygen species (ROS) were quantified using 2′,7′-dichlorofluorescein diacetate. Cell migration was evaluated using Transwell assays. Contractile activity was measured by collagen contraction assay; (3) Results: 4-PBA inhibited TGF-β1 or TG-induced ER-stress marker expression, phenotypic changes, and ECM. Pre-treatment with ROS scavengers inhibited the expression of TGF-β1-induced ER-stress markers. Migration and collagen contraction of TGF-β1 or TG-stimulated fibroblasts were ameliorated by 4-PBA treatment. These findings were confirmed in ex vivo organ cultures; (4) Conclusions: 4-PBA downregulates TGF-β1-induced ER-stress marker expression, migration, and collagen contraction via ROS in fibroblasts and organ cultures. These results suggest that ER-stress may play an important role in progression of chronic upper airway inflammatory diseases by aiding pathological tissue remodeling.

Highlights

Chronic rhinosinusitis (CRS) is defined as the inflammation of nasal and paranasal sinuses and is characterized by nasal obstruction, rhinorrhea and olfactory dysfunction [1]
We investigated the ability of Transforming growth factor (TGF)-β1 to induce the expression of Endoplasmic reticulum (ER)-stress markers such as GRP78 and XBP-1 via Reactive oxygen species (ROS) production in nasal fibroblasts, and evaluated the potential of ER stress to induce the activation of nasal fibroblasts by assessing extracellular matrix (ECM) production and cell migration
Nasal fibroblasts were stimulated with TGF-β1 (5 ng/mL) for 0–48 h

Summary

Introduction

Chronic rhinosinusitis (CRS) is defined as the inflammation of nasal and paranasal sinuses and is characterized by nasal obstruction, rhinorrhea and olfactory dysfunction [1]. The pathogenesis of CRS is not completely understood; several pieces of evidence indicate an important role of tissue remodeling similar to that in other chronic airway diseases such as chronic obstructive pulmonary disease and asthma [2,3]. Tissue remodeling is considered to be a suitable target during the treatment of CRS for two crucial reasons. Tissue remodeling can induce irreversible structural changes that are known to be responsible for the refractoriness of CRS [4]. Tissue remodeling appears to occur in parallel with, rather than purely subsequent to, inflammation, thereby compromising the normal protective functions of structural cells right from the early stages of the disease [5]

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Discussion

Conclusion