The Effect of Macrolides on Myofibroblast Differentiation and Collagen Production in Nasal Polyp–Derived Fibroblasts

Park, Hyo Hyun; Park, Il Ho; Cho, Jung Sun; Lee, You Mi; Lee, Heung Man

doi:10.2500/ajra.2010.24.3520

Cited by 32 publications

(16 citation statements)

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“…TGF-β1, which is highly expressed in nasal polyp tissues, is thought to be involved in the structural modifications that characterize nasal polyp formation [6]. In our previous study, we confirmed that TGF-β1 significantly increased the expression of α-SMA, as well as the production of collagen types I and III in NPDFs, and Nox4 and ROS play an important role in phenotypic change and ECM formation of TGF-β1-induced NPDFs [16]. …”

Section: Discussionsupporting

confidence: 62%

Role of Caffeic Acid on Collagen Production in Nasal Polyp-Derived Fibroblasts

Chung

Park

Hong

et al. 2014

Clin Exp Otorhinolaryngol

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ObjectivesCaffeic acids are known to have anti-oxidant, anti-inflammatory, immunomodulatory, and tissue reparative effects. The purposes of this study were to determine the effect of caffeic acid on transforming growth factor (TGF) β1-induced myofibroblast differentiation and collagen production, and to determine whether caffeic acid is involved in the antioxidant effect in nasal polyp-derived fibroblasts (NPDFs).MethodsNPDFs were pretreated with caffeic acid (1-10 µM) for 2 hours and stimulated with TGF-β1 (5 ng/mL) for 24 hours. The expression of α-smooth muscle actin (SMA), collagen types I and III, and Nox4 mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of α-SMA protein was determined by actin ned by immunofluorescence microscopy. The amount of total soluble collagen production was analyzed by the Sircol collagen dye-binding assay. The reactive oxygen species (ROS) generated by NPDFs were determined using 2',7'-dichlorfluorescein-diacetate. siNox4 was used to determine the effect of Nox4.ResultsThe expression of α-SMA and production of collagen were significantly increased following TGF-β1 treatment. In contrast, the level of expression of α-SMA and the level of production of collagen were decreased by pretreatment with caffeic acid. The activation of Nox4 and the subsequent production of ROS were also reduced by pretreatment with caffeic acid. The expression of α-SMA was prevented by inhibition of ROS generation with siNox4.ConclusionCaffeic acid may inhibit TGF-β1-induced differentiation of fibroblasts into myofibroblasts and collagen production by regulating ROS.

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Section: Discussionsupporting

confidence: 62%

Role of Caffeic Acid on Collagen Production in Nasal Polyp-Derived Fibroblasts

Chung

Park

Hong

et al. 2014

Clin Exp Otorhinolaryngol

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“…On the other hand, in naturally occurring allergic rhinitis, there are no significant differences between the rhinitic and nonrhinitic groups in the expression of TGF‐β isoforms or Smad‐3, Smad‐6, and Smad‐7 proteins; however, there is increased gene expression for TGF‐βRI and TGF‐βRII along with CTGF in seasonal allergic rhinitis (Salib, ). Interestingly, there was a report that TGF‐β1 can also stimulate ECM production in CRSwNP‐derived fibroblasts via the MAPK/NF‐κB pathway (Park, Park, Cho, Lee, & Lee, ). In this study, the CTGF induction after TGF‐β1 stimulation mediates collagen synthesis in the CRSsNP nasal mucosa‐derived fibroblasts is strongly suspected.…”

Section: Discussionmentioning

confidence: 99%

TGFβ mediates collagen production in human CRSsNP nasal mucosa‐derived fibroblasts through Smad2/3‐dependent pathway and CTGF induction and secretion

Shieh

Chi

2018

Journal Cellular Physiology

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Chronic rhinosinusitis without nasal polyp (CRSsNP) is characterized by tissue remodeling and fibrosis. Transforming growth factor‐β (TGF‐β) is considered a master switch in the induction of the profibrotic program which can induce fibroblasts to synthesize and contract extracellular matrix (ECM) proteins. A previous study has shown TGF‐β1 signaling and collagen overproduction in the CRSsNP, but the responsible cells and mechanism of action remain unclear. Therefore, this study was aimed to investigate the relationship between TGF‐β1 stimulation and collagen expression and to explore the role of connective tissue growth factor (CTGF) during the remodeling process using human CRSsNP nasal mucosa tissues and mucosa‐derived fibroblasts as main materials. We found that TGF‐β1 and its isoforms could promote collagen protein expression. Concomitantly, TGF‐β1 caused CTGF expression and secretion. An addition of exogenous CTGF to fibroblasts also caused collagen expression. In accordance with these observations, TGF‐β1, CTGF, and collagen were highly expressed in the subepithelial stroma region of CRSsNP nasal mucosa, as determined by immunohistochemistry. The TGF‐β1‐mediated collagen expression could be blocked by actinomycin D and SIS3, suggesting that the induction was through transcriptional regulation and Smad2/3‐dependent pathway. Finally, we demonstrated that CTGF small interfering RNA knockdown led to a substantial decrease in TGF‐β1‐mediated collagen expression. Collectively, our results provide first and further evidence that TGF‐β1 mediates collagen expression–production through a canonical Smad2/3‐dependent pathway and CTGF induction and secretion in human nasal fibroblasts. Moreover, TGF‐β1, CTGF, and collagen are highly expressed in human CRSsNP nasal mucosa specimens, suggesting their roles in tissue remodeling during CRSsNP progression.

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“…Central to the generation of myofibroblasts is the action of TGF-β, released locally from damaged parenchymal cells, and inflammatory cells as well as stimuli provided by matrix components such as fibronectin [48]. Also, TGF-β is a potent stimulus for the production of matrix molecules [52,53], and activation of pSmad 2 [4], a member of the Smad 2 proteins family of transcription factors demonstrated to propagate TGF-β receptor signaling [54]. Our finding of significantly more pSmad2 –positive cells being localized in the stalk part of the polyp indicates increased TGF-β signaling in this part, which can facilitate the transformation from fibroblast to myofibroblast.…”

Section: Discussionmentioning

confidence: 99%

The Development of Nasal Polyp Disease Involves Early Nasal Mucosal Inflammation and Remodelling

et al. 2013

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Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by both a chronic inflammation and tissue remodelling; as indicated by extracellular matrix protein deposition, basement membrane thickening, goblet cell hyperplasia and subepithelial edema, with reduced vessels and glands. Although remodelling is generally considered to be consequence of persistent inflammation, the chronological order and relationship between inflammation and remodelling in polyp development is still not clear. The aim of our study was therefore to investigate the pathological features prevalent in the development of nasal polyps and to elucidate the chronological order and relationship between inflammation and remodelling, by comparing specific markers of inflammation and remodelling in early stage nasal polyps confined to the middle turbinate (refer to as middle turbinate CRSwNP) obtained from 5 CRSwNP patients with bilateral polyposis, mature ethmoidal polyps from 6 CRSwNP patients, and normal nasal mucosal tissue from 6 control subjects. Middle turbinate CRSwNP demonstrated significantly more severe epithelial loss compared to mature ethmoidal polyps and normal nasal mucosa. The epithelial cell junction molecules E-cadherin, ZO-1 and occludin were also expressed in significantly lower amounts in mature ethmoidal polyps compared to healthy mucosa. Middle turbinate CRSwNP were further characterized by significantly increased numbers of subepithelial eosinophils and M2 type macrophages, with a distinct lack of collagen and deposition of fibronectin in polyp part. In contrast, the turbinate area of the middle turbinate CRSwNP was characterized by an increase in TGF-β activated myofibroblasts expressing α-SMA and vimentin, an increase in the number of pSmad2 positive cells, as well as increased deposition of collagen. These findings suggest a complex network of processes in the formation of CRSwNP; including gross epithelial damage and repair reactions, eosinophil and macrophage cell infiltration, and tissue remodelling. Furthermore, remodelling appears to occur in parallel, rather than subsequent to inflammation.

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The Effect of Macrolides on Myofibroblast Differentiation and Collagen Production in Nasal Polyp–Derived Fibroblasts

Abstract: These results suggest the possibility that EM and RXM may play an important role in inhibiting the development of nasal polyps through their antioxidant effect.

Cited by 32 publications

References 20 publications

Role of Caffeic Acid on Collagen Production in Nasal Polyp-Derived Fibroblasts

Role of Caffeic Acid on Collagen Production in Nasal Polyp-Derived Fibroblasts

TGFβ mediates collagen production in human CRSsNP nasal mucosa‐derived fibroblasts through Smad2/3‐dependent pathway and CTGF induction and secretion

The Development of Nasal Polyp Disease Involves Early Nasal Mucosal Inflammation and Remodelling

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