Gradual Increase of High Mobility Group Protein B1 in the Lungs after the Onset of Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Ebina, Masahito; Taniguchi, Hiroyuki; Miyasho, Taku; Yamada, Shingo; Shibata, Naoko; Ohta, Hiromitsu; Shu, Hu; Ohkouchi, Shinya; Tamada, Tsutomu; Nishimura, Hidekazu; Ishizaka, Akitoshi; Maruyama, Ikuro; Okada, Yoshinori; Kondo, Takashi; Nukiwa, Toshihiro

doi:10.1155/2011/916486

Cited by 53 publications

(56 citation statements)

References 39 publications

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“…Also, we have shown that cyclosporine suppresses the differentiation of fibroblasts into myofibroblasts in a concentration-dependent manner. These results support the hypothesis that cyclosporine has several potency for fibrotic lung disease by inhibition of collagen deposition but also suppression of the fibroblasts to myofibroblasts differentiation, which are expected to have another mechanisms independent from the activation of lymphocytes (Ebina et al 2011). …”

Section: Discussionsupporting

confidence: 86%

Gene Expression Profiling of Lung Myofibroblasts Reveals the Anti-Fibrotic Effects of Cyclosporine

Hirota

Ito

Miyazaki

et al. 2014

Tohoku J. Exp. Med.

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Cyclosporine, a calcineurin inhibitor, is a potent immunosuppressive agent that acts chiefly through the inactivation of T-lymphocytes. Several clinical studies have demonstrated the effectiveness of cyclosporine for treating fibrotic lung disease, but the underlying mechanism remains elusive. We hypothesized that cyclosporine exerts direct effects against fibrogenesis of lung myofibroblasts, and aimed to elucidate the mechanism of this anti-fibrotic effect through gene-expression profiling using DNA microarray analysis. We found that cyclosporine suppressed the expression of alpha-smooth muscle actin and collagen type I in myofibroblasts that had been differentiated from a fetal human lung fibroblast cell line by induction with transforming growth factor (TGF)-β. Furthermore, microarray analysis revealed that cyclosporine downregulated 57 genes whose expression levels were increased by TGF-β, and up-regulated 73 genes, whose expression was decreased by TGF-β. Classifying these 57 down-regulated and 73 up-regulated genes with the Database for Annotation, Visualization and Integrated Discovery (DAVID) web tool, we have identified the involvement of several functional categories, including innate immunity, cytokine interaction, growth factor, and cancer pathway. Of the identified genes, we selected three fibrosis-related genes, insulin-like growth factor binding protein 2 (IGFBP2), inhibitor of DNA binding 1 (ID1) and peroxisome proliferator-activated receptor gamma (PPARG), and validated their expression patterns by quantitative reverse transcription-polymerase chain reaction. Cyclosporine treatment decreased the expression levels of IGFBP2 and ID1, but increased PPARG expression. These results suggest that cyclosporine is a potent anti-fibrotic agent acting on myofibroblasts. Therefore, cyclosporine shows potential as a novel remedy for fibrotic lung disease.

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Section: Discussionsupporting

confidence: 86%

Gene Expression Profiling of Lung Myofibroblasts Reveals the Anti-Fibrotic Effects of Cyclosporine

Hirota

Ito

Miyazaki

et al. 2014

Tohoku J. Exp. Med.

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“…HMGB-1 may be a late inflammatory mediator, and elevated HMGB-1 concentrations were observed in patients with sepsis [18] and acute lung injury [19]. Ebina et al [14 ]found that HMGB-1 level was elevated in bronchoalveolar lavage fluid from AE-IPF patients. rhTM directly inhibits HMGB-1, leading to an anti-inflammatory effect.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, rhTM directly binds and sequesters high-mobility group box 1 (HMGB-1), leading to suppression of inflammation [11]. Previous studies reported coagulation abnormalities in IPF [12,13] and elevated HMGB-1 levels in the bronchoalveolar lavage fluid from AE-IPF patients [14]; thus, control of the coagulation system and suppression of inflammation by inhibiting HMGB-1 might improve the outcomes of patients with AE-IPF. We examined the clinical effectiveness of rhTM and evaluated whether it had a beneficial effect on the survival of patients with AE-IPF.…”

Section: Introductionmentioning

confidence: 99%

Recombinant Human Soluble Thrombomodulin Treatment for Acute Exacerbation of Idiopathic Pulmonary Fibrosis: A Retrospective Study

et al. 2015

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Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) can be fatal, and abnormalities in the coagulation system of patients with AE-IPF have been reported. Recombinant human soluble thrombomodulin (rhTM) forms a complex with thrombin to inactivate coagulation. It also inhibits high-mobility group box protein 1 (HMGB-1), which results in the suppression of inflammation. Objectives: We aimed to evaluate the effectiveness of rhTM for the treatment of AE-IPF. Methods: We retrospectively reviewed the medical records of 41 patients with AE-IPF who were admitted to our institution during the period 2006-2013. The clinical features and outcomes of 16 patients treated with rhTM (rhTM group) were compared with those of 25 patients treated with conventional therapy (control group). Patients were treated with corticosteroid (CS) pulse therapy for 3 days, followed by maintenance treatment with a tapered dose of CS. Patients in the rhTM group also received rhTM (0.06 mg/kg/day) for 6 days as an initial treatment, in combination with CS. Results: Except for D-dimer level, there were no significant differences in the baseline characteristics of the 2 groups. When compared with the control group, the rhTM group had a significantly higher survival rate at 3 months (40 vs. 69%, p = 0.048). A univariate Cox proportional hazards regression model showed that the predictive factors for survival were lactate dehydrogenase level and rhTM treatment. Regarding adverse events, 1 patient in the rhTM group developed mild bleeding events. Conclusion: rhTM as an add-on to conventional treatment may improve survival in patients with AE-IPF.

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“…Hamada et al (2008), on the other side, reported the following order of decreasing HMGB-1 content: idiopathic pulmonary fibrosis, nonspecific pneumonia, and healthy people. Ebina et al (2001) investigated the level of HMGB-1 in BALF and its expression in tissue specimens from patients with idiopathic pulmonary fibrosis. The authors noted that the level of HMGB-1 was low at the initial active stage of disease, but it was gradually increasing with disease stabilization.…”

Section: Discussionmentioning

confidence: 99%

Clinical Significance of HMGB-1 and TGF-β Level in Serum and BALF of Advanced Non-Small Cell Lung Cancer

Jakubowska

Naumnik

Niklińska

et al. 2015

Advances in Experimental Medicine and Biology

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Lung cancer is associated with poor prognosis. The aim of this study was to evaluate the clinical usefulness of HMGB-1 (high-mobility group protein B1) and TGF-β (transforming growth factor beta) in patients with advanced non-small cell lung cancer (NSCLC). We studied 45 patients with NSCLC prior to chemotherapy, 23 patients with Besnier-Boeck-Schaumann (BBS) disease (sarcoidosis), and 15 healthy volunteers. HMGB-1 and TGF-β levels were measured in serum and BALF samples using ELISA method. A higher serum HMGB-1 and TGF-β levels were in NSCLC patients compared with the other groups. TGF-β concentration in BALF was significantly higher in NSCLC than in healthy controls (p=0.047) but lower than in BBS (p=0.016). Serum HMGB-1 in NSCLC correlated with age and gender while its level in BALF was associated with distant metastasis. A higher levels of HMGB-1 in the serum of NSCLC patients with progressive disease was linked with shorter overall survival and disease-free survival. We found a positive correlation between HMGB-1 and TGF-β in BALF of IIIB NSCLC group and overall survival (p=0.04; p=0.003). Our findings confirmed that the measurement of HMGB-1 and TGF-β levels in serum and BALF of patients with NSCLC prior to treatment may have clinical usefulness and predict poor prognosis.

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Gradual Increase of High Mobility Group Protein B1 in the Lungs after the Onset of Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Cited by 53 publications

References 39 publications

Gene Expression Profiling of Lung Myofibroblasts Reveals the Anti-Fibrotic Effects of Cyclosporine

Gene Expression Profiling of Lung Myofibroblasts Reveals the Anti-Fibrotic Effects of Cyclosporine

Recombinant Human Soluble Thrombomodulin Treatment for Acute Exacerbation of Idiopathic Pulmonary Fibrosis: A Retrospective Study

Clinical Significance of HMGB-1 and TGF-β Level in Serum and BALF of Advanced Non-Small Cell Lung Cancer

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