Pirfenidone inhibits the expression of HSP47 in TGF-β1-stimulated human lung fibroblasts

Nakayama, Seiko; Mukae, Hiroshi; Sakamoto, Noriho; Kakugawa, Tomoyuki; Yoshioka, Sumako; Soda, Hiroshi; Oku, Hiromasa; Urata, Yoshie; Kondo, Takahito; Kubota, Hiroshi; Nagata, Kazuhiro; Kohno, Shigeru

doi:10.1016/j.lfs.2007.11.003

Cited by 145 publications

(101 citation statements)

References 28 publications

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“…Oishi et al reported that proinflammatory, profibrotic, and proangiogenic cytokines, including TGF-β were eluted from PMX fibers used for the treatment of AE-IPF and suggested that adsorption of such cytokines onto PMX fibers might be one of the mechanisms of action involved. Because TGF-β has been reported to induce the expression of HSP47 (Hisatomi et al 2012;Nakayama et al 2008), adsorption of cytokines by PMX-DHP could decrease expression of HSP47 and thereby attenuate the progression of inflammation and fibrosis in the DAD lung. The precise effects of PMX-DHP on HSP47 expression should be investigated in a future study.…”

Section: Discussionmentioning

confidence: 99%

Serum heat shock protein 47 levels are elevated in acute exacerbation of idiopathic pulmonary fibrosis

Kakugawa

Yokota

Ishimatsu

et al. 2013

Cell Stress and Chaperones

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Little is known about the pathophysiology of acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF). Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, is essential for biosynthesis and secretion of collagen molecules. Previous studies in experimental animal fibrosis models have shown that downregulation of HSP47 expression reduces collagen production and diminishes fibrosis progression. In this study, serum HSP47 levels were evaluated to elucidate pathogenic differences involving HSP47 between AE-IPF and stable (S)-IPF. -013-0411-5 and lactate dehydrogenase (LDH) were measured. Immunohistochemical analysis of lung HSP47 expression was determined in biopsy and autopsy tissues diagnosed as diffuse alveolar damage (DAD) and usual interstitial pneumonia (UIP). Serum levels of HSP47 were significantly higher in AE-IPF than in S-IPF patients, whereas serum levels of KL-6, SP-A, and SP-D did not differ significantly. Receiver operating characteristic curves revealed that HSP47 was superior for discriminating AE-IPF and S-IPF. The cutoff for HSP47 resulting in the highest diagnostic accuracy was 559.4 pg/mL; sensitivity, specificity, and diagnostic accuracy were 100.0 %, 93.9 %, and 96.2 %, respectively. Immunohistochemical analysis revealed that pulmonary HSP47 expression was greater in DAD than UIP tissues. Serum HSP47 was significantly higher in AE-IPF than in S-IPF patients, suggesting that underlying fibrogenic mechanisms involving HSP47 differ in the two conditions.Cell Stress and Chaperones (2013) 18:581-590 DOI 10.1007/s12192

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Section: Discussionmentioning

confidence: 99%

Serum heat shock protein 47 levels are elevated in acute exacerbation of idiopathic pulmonary fibrosis

Kakugawa

Yokota

Ishimatsu

et al. 2013

Cell Stress and Chaperones

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“…Pirfenidone has an inhibitory effect on the collagen I synthesis in lung fibroblasts mediated by the inhibition of intracellular heat-shock protein 47 and the inhibition of Smad3, p38, and Akt factors in the TGF-β1 pathway involved in lung fibrosis. 11,23) These findings strongly suggest that pirfenidone incorporated into tbFGF-liposomes is efficiently accumulated in WI-38 cells, and then pirfenidone is released from liposomes into the cytoplasm where it inhibits the synthesis of collagen in cell.…”

Section: Resultsmentioning

confidence: 87%

“…7) Pirfenidone has anti-fibrotic, anti-inflammatory, and anti-oxidative actions. [8][9][10][11] In particular, pirfenidone inhibits the collagen synthesis by lung fibroblasts. However, pirfenidone frequently causes systemic adverse effects, such as photosensitivity (51%), anorexia (17%), and nausea (44%), during clinical use.…”

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confidence: 99%

Efficient Delivery to Human Lung Fibroblasts (WI-38) of Pirfenidone Incorporated into Liposomes Modified with Truncated Basic Fibroblast Growth Factor and Its Inhibitory Effect on Collagen Synthesis in Idiopathic Pulmonary Fibrosis

Togami

Miyao

Miyakoshi

et al. 2015

Biological & Pharmaceutical Bulletin

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In the present in vitro study, we assessed the delivery of pirfenidone incorporated into liposomes modified with truncated basic fibroblast growth factor (tbFGF) to lung fibroblasts and investigated the antifibrotic effect of the drug. The tbFGF peptide, KRTGQYKLC, was used to modify the surface of liposomes (tbFGF-liposomes). We used the thin-layer evaporation method, followed by sonication, to prepare tbFGFliposomes containing pirfenidone. The cellular accumulation of tbFGF-liposomes was 1.7-fold greater than that of non-modified liposomes in WI-38 cells used as a model of lung fibroblasts. Confocal laser scanning microscopy showed that tbFGF-liposomes were widely localized in WI-38 cells. The inhibitory effects of pirfenidone incorporated into tbFGF-liposomes on transforming growth factor-β1 (TGF-β1)-induced collagen synthesis in WI-38 cells were evaluated by measuring the level of intracellular hydroxyproline, a major component of the protein collagen. Pirfenidone incorporated into tbFGF-liposomes at concentrations of 10, 30, and 100 µM significantly decreased the TGF-β1-induced hydroxyproline content in WI-38 cells. The antifibrotic effect of pirfenidone incorporated into tbFGF-liposomes was enhanced compared with that of pirfenidone solution. These results indicate that tbFGF-liposomes are a useful drug delivery system of anti-fibrotic drugs to lung fibroblasts for the treatment of idiopathic pulmonary fibrosis.

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“…For this reason, effective preventative therapies will likely have the most impact for ischaemic heart failure. Targeted therapies could include some of the newer anti-fibrotic drugs, such as pirfenidone, that block collagen I synthesis in human lung fibroblasts (Nakayama et al 2008) and can reduce fibrosis in ischaemic heart failure in rats (Nguyen et al 2010). Furthermore, the data in Fig.…”

Section: Future Directionsmentioning

confidence: 99%

Transverse tubule remodelling: a cellular pathology driven by both sides of the plasmalemma?

2017

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Transverse (t)-tubules are invaginations of the plasma membrane that form a complex network of ducts, 200-400 nm in diameter depending on the animal species, that penetrates deep within the cardiac myocyte, where they facilitate a fast and synchronous contraction across the entire cell volume. There is now a large body of evidence in animal models and humans demonstrating that pathological distortion of the t-tubule structure has a causative role in the loss of myocyte contractility that underpins many forms of heart failure. Investigations into the molecular mechanisms of pathological t-tubule remodelling to date have focused on proteins residing in the intracellular aspect of t-tubule membrane that form linkages between the membrane and myocyte cytoskeleton. In this review, we shed light on the mechanisms of ttubule remodelling which are not limited to the intracellular side. Our recent data have demonstrated that collagen is an integral part of the t-tubule network and that it increases within the tubules in heart failure, suggesting that a fibrotic mechanism could drive cardiac junctional remodelling. We examine the evidence that the linkages between the extracellular matrix, t-tubule membrane and cellular cytoskeleton should be considered as a whole when investigating the mechanisms of t-tubule pathology in the failing heart.

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Pirfenidone inhibits the expression of HSP47 in TGF-β1-stimulated human lung fibroblasts

Cited by 145 publications

References 28 publications

Serum heat shock protein 47 levels are elevated in acute exacerbation of idiopathic pulmonary fibrosis

Serum heat shock protein 47 levels are elevated in acute exacerbation of idiopathic pulmonary fibrosis

Efficient Delivery to Human Lung Fibroblasts (WI-38) of Pirfenidone Incorporated into Liposomes Modified with Truncated Basic Fibroblast Growth Factor and Its Inhibitory Effect on Collagen Synthesis in Idiopathic Pulmonary Fibrosis

Transverse tubule remodelling: a cellular pathology driven by both sides of the plasmalemma?

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