Increased expression of collagen-binding heat shock protein 47 in murine bleomycin-induced pneumopathy

Ishii, Hiroshi; Mukae, Hiroshi; Kakugawa, Tomoyuki; Iwashita, Tetsuji; Kaida, Hideyuki; Fujii, Takeshi; Hayashi, Tomayoshi; Kadota, Jun‐ichi; Kohno, Shigeru

doi:10.1152/ajplung.00305.2002

Cited by 34 publications

(41 citation statements)

References 17 publications

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“…The present authors previously reported that regenerated type II pneumocytes in UIP start expressing type I procollagen through the induction of HSP47 and play an important role in the development of fibrosis [9]. Recently, the present authors have also shown that type II pneumocytes start expressing HSP47 as fibrosis proceeds, in a rodent BL-induced pulmonary fibrosis model [26]. These findings suggest that increased type II pneumocytes, in addition to myofibroblasts, contribute to the fibrotic process through the production of HSP47-induced type I procollagen and suggest that HSP47-positive type II pneumocytes might represent a suitable target for therapeutic strategies designed for chronic pulmonary fibrosis.…”

Section: Discussionsupporting

confidence: 57%

Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis

Kakugawa¹,

Mukae²,

Hayashi³

et al. 2004

Eur Respir J

148

122

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Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagen. The present study was undertaken to investigate whether treatment with the antifibrotic drug pirfenidone attenuates the bleomycin (BL)-induced overexpression of HSP47 in the lungs.Male ICR mice were intravenously injected with BL or saline (SA). Pirfenidone or control drug (CD) was administered 14 days after commencement of BL or SA, and continued throughout the course of the experiment. The mice were randomly divided into three experimental groups: 1) SA-treated with CD (SA group); 2) BL-treated with CD (BL group); and 3) BL-treated with pirfenidone (pirfenidone group).Lungs of the pirfenidone group showed a marked reduction of fibrotic lesions compared with the corresponding BL group. Immunohistochemical studies showed that BL treatment significantly increased the number of macrophages, myofibroblasts, HSP47-positive type II pneumocytes and HSP47-positive interstitial spindle-shaped cells. Treatment with pirfenidone significantly reduced the number of these cells compared with the corresponding BL group. Furthermore, treatment with pirfenidone significantly suppressed the BL-induced increase of the positive ratio of HSP47 and asmooth muscle actin to interstitial spindle-shaped cells.The present study results showed that pirfenidone inhibited heat shock protein 47-positive cells and myofibroblasts, the principal cells responsible for the accumulation and deposition of extracellular matrix seen in pulmonary fibrosis.

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Section: Discussionsupporting

confidence: 57%

Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis

Kakugawa¹,

Mukae²,

Hayashi³

et al. 2004

Eur Respir J

148

122

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“…Similar to FKBP65, the collagen-specific chaperone, Hsp47, has also been shown to be upregulated in bleomycin-induced pulmonary fibrosis (Razzaque et al 1998a;Ishii et al 2003) and induced in a dose-dependent manner by TGF-␤1 in cultured collagen-producing cells (Yamamura et al 1998;Sasaki et al 2002). Consistent with this experimental data, both pulmonary and dermal fibrotic lesions in humans show an increased production of Hsp47 concomitant with that of collagen (Razzaque et al 1998b;Razzaque and Ahmed 2002).…”

Section: Discussionmentioning

confidence: 78%

Developmental regulation and coordinate reexpression of FKBP65 with extracellular matrix proteins after lung injury suggest a specialized function for this endoplasmic reticulum immunophilin

et al. 2005

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FKBP65 (65-kDa FK506-binding protein) is an endoplasmic reticulum (ER)-localized peptidyl-prolyl cis-trans isomerase predicted to play a role in the folding and trafficking of secretory proteins. In previous studies, we have shown that FKBP65 is developmentally regulated and associates with the extracellular matrix protein, tropoelastin, during its maturation and transport through the ER. In this study, we show that FKBP65 is expressed in the lung with the same developmental pattern as tropoelastin and other matrix proteins. To test the hypothesis that FKBP65 is upregulated at times when extracellular matrix proteins are being actively synthesized and assembled, adult mice were treated with bleomycin to cause reinitiation of matrix protein production during the ensuing development of pulmonary fibrosis. After bleomycin instillation, FKBP65 expression was reactivated in the lung with a pattern similar to that observed for tropoelastin and type I collagen. Using human lung fibroblast cultures, we showed that FKBP65 does not undergo the unfolded protein response, a response associated with an upregulation of resident ER proteins that occurs after increased ER stress. When fibroblasts were treated with transforming growth factor (TGF)-␤1, which is upregulated during the development of pulmonary fibrosis and known to induce matrix production, FKBP65 expression and synthesis was also increased. Similar to type I collagen and tropoelastin, this response was completely inhibited in a dose-dependent manner by GGTI-298, a geranylgeranyl transferase I inhibitor. Treatment of fibroblasts with an inhibitor of ribonucleic acid (RNA) polymerase II after TGF-␤1 treatment showed that the effect of TGF-␤1 was not because of increased stabilization of the FKBP65 messenger RNA. In summary, we have shown that FKBP65 is highly expressed in lung development, downregulated in the adult, and can be reactivated in a coordinated manner with extracellular matrix proteins after lung injury. The expression pattern of FKBP65, which is atypical for general ER foldases, suggests that FKBP65 has a distinct set of developmentally regulated protein ligands. The response to injury, which may be in part a direct response to TGF-␤1, assures the presence of FKBP65 in the ER of cells actively producing components of the extracellular matrix.

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“…We have recently shown in rodent bleomycin-induced pulmonary fibrosis model that type II pneumocytes in addition to myofibroblasts express HSP47 with the progression of fibrosis, while these cells didn't express HSP47 in the control lungs [13,14]. We also previously reported that regenerated type II pneumocytes in usual interstitial pneumonia express HSP47 [17,18].…”

Section: Introductionmentioning

confidence: 91%

“…HSP47 expression was upregulated in experimental animal models of fibrosis, including murine bleomycin-induced pulmonary fibrosis [13,14], rat peritoneal sclerosis [15] and carbon tetrachloride-induced rat liver cirrhosis [16]. In addition, we previously reported that the expression of human HSP47 was increased in the fibrotic lesions of idiopathic pulmonary fibrosis (IPF) [17,18], fibrotic transplanted kidney [19], and peritoneal sclerosis [20].…”

Section: Introductionmentioning

confidence: 99%

Localization of HSP47 mRNA in murine bleomycin-induced pulmonary fibrosis

et al. 2010

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Heat shock protein (HSP) 47 is a collagen-specific molecular chaperone that has been shown to play a major role in the processing and/or secretion of procollagen. However, the knowledge on which cells are actually synthesizing HSP47 in the lung parenchyma in pulmonary fibrosis was only limited. The aim of the present study was to investigate the localization of HSP47 messenger ribonucleic acid (mRNA) in normal lung, and in the lungs of mice in bleomycin-induced pulmonary fibrosis, using in situ hybridization.For the purpose, ICR mice were intravenously injected with 10 mg/kg/day of bleomycin for 5 consecutive days. The lung cells expressing HSP47 mRNA were identified in control (saline alone) and bleomycin-treated mice by in situ hybridization. The signal for HSP47 mRNA was markedly increased in bleomycin-treated lungs compared with that of controls. HSP47 mRNA was localized in -smooth muscle actin-positive myofibroblasts, surfactant protein A-positive type II pneumocytes and F4/80 positive macrophages in the active fibrotic areas. These results suggest that these cells may synthesize procollagen in the fibrotic process of bleomycin-treated lungs through upregulation of HSP47 mRNA and play an important role in fibrogenesis.

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Increased expression of collagen-binding heat shock protein 47 in murine bleomycin-induced pneumopathy

Abstract: Kohno. Increased expression of collagen-binding heat shock protein 47 in murine bleomycin-induced pneumopathy.

Cited by 34 publications

References 17 publications

Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis

Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis

Developmental regulation and coordinate reexpression of FKBP65 with extracellular matrix proteins after lung injury suggest a specialized function for this endoplasmic reticulum immunophilin

Localization of HSP47 mRNA in murine bleomycin-induced pulmonary fibrosis

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