Abstract

Cigarette smoke exposure has been shown to be associated with chronic rhinosinusitis and tissue remodeling. The present study aimed to investigate the effects of cigarette smoke extract (CSE) on matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) production in nasal fibroblasts and to determine the underlying molecular mechanisms. Primary nasal fibroblasts from six patients were isolated and cultured. After the exposure of fibroblasts to CSE, the expression levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured by real-time PCR, ELISA, and immunofluorescence staining. The enzymatic activities of MMP-2 and MMP-9 were measured by gelatin zymography. Reactive oxygen species (ROS) production was analyzed using dichloro-dihydro-fluorescein diacetate and Amplex Red assays. PI3K/Akt phosphorylation and NF-κB activation were determined by Western blotting and luciferase assay. CSE significantly increased MMP-2 expression and inhibited TIMP-2 expression but did not affect MMP-9 and TIMP-1 expression. Furthermore, CSE significantly induced ROS production. However, treatment with ROS scavengers, specific PI3K/Akt inhibitors, NF-κB inhibitor, and glucocorticosteroids significantly decreased MMP-2 expression and increased TIMP-2 expression. Our results suggest that steroids inhibit CSE-regulated MMP-2 and TIMP-2 production and activation through the ROS/ PI3K, Akt, and NF-κB signaling pathways in nasal fibroblasts. CSE may contribute to the pathogenesis of chronic rhinosinusitis by regulating MMP-2 and TIMP-2 expression.

Highlights

  • Chronic rhinosinusitis (CRS) is a nasal inflammatory disease with symptoms of nasal discharge/postnasal drip, nasal congestion, sinus pain/pressure, and anosmia/hyposmia lasting for at least 12 weeks

  • Activation in cigarette smoke extract (CSE)-stimulated nasal fibroblasts in CSE-stimulated nasal fibroblasts. These results suggested that steroids could (Figure 5F–H). These results suggested that steroids could regulate matrix metalloproteinase (MMP)-2 and tissue inhibitor of metalloproteinase (TIMP)-2 expression by regulate

  • The present study showed that CSE induced MMP-2 expression and decreased TIMP-2 expression but did not affect MMP-9 and TIMP-1 expression in nasal fibroblasts

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Summary

Introduction

Chronic rhinosinusitis (CRS) is a nasal inflammatory disease with symptoms of nasal discharge/postnasal drip, nasal congestion, sinus pain/pressure, and anosmia/hyposmia lasting for at least 12 weeks. Antioxidants 2020, 9, 739 including cigarette smoke, may play a significant role in CRS, which is a characteristic of chronic inflammatory upper airway disease [2]. Tissue remodeling is an energetic process that results in both production and degradation of the extracellular matrix (ECM) and is an important aspect in the pathogenesis of chronic inflammatory diseases in many organs. Like other chronic inflammatory diseases of the airway, tissue remodeling is present in CRS, and obvious remodeling features differentiate the various CRS subgroups [4]. Several factors, such as MMPs, ECM, and TGF-β, are related with remodeling

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