• Tuberculosis and Respiratory Diseases
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• v.55 no.5
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• pp.478-487
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• 2003

Background : There have been several studies showing that the angiotensin II and angiotensin converting enzyme(ACE) contributes to the apoptosis of alveolar epithelial cells in idiopathic interstitial pneumonia and the activation of fibroblasts during the process of pulmonary fibrosis. These results suggest that the pulmonary fibrosis can be inhibited by the angiotensin II receptor antagonist(AGIIRA). This study was performed to identify the therapeutic effect of AGIIRA in idiopathic pulmonary fibrosis(IPF). Method : Thirteen patients with IPF, who were diagnosed with an open lung biopsy(6 patients) and furfilling the ATS criteria(7 patients) between March 1999 and October 2001 at the Gachon medical center, were enrolled in this study. Of these patients, eight patients were treated with a regimen including AGIIRA(AT group), and five were treated without AGIIRA(NT group). The pulmonary function tests and dyspnea(ATS scale) were measured at diagnosis and 1 year after treatment. All the data was collected to analyze the therapeutic effect of AGIIRA on the patients with IPF. Results : The AT group contained 8 patients(M:F=4:4) and the NT group contained 5 patients(M:F=3:2). There was no significant difference in the serum angiotensin II level between the two groups($202.5{\pm}58.5$ vs $163.7{\pm}47.3pg/ml$, p>0.05). The AT group showed an upward trend in TLC(+3%), FVC(+4%), FEV1(+3%) and DLco(+2%) compared to the NT group(TLC(-14%), FVC(-3%), FEV1(-4%) except for DLco(+5%)). The dyspnea score in the AT group improved significantly but not in the NT group. Conclusion : These results suggest that the angiotensin II receptor antagonist may have an effect on stabilizing IPF.

• Tuberculosis and Respiratory Diseases
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• v.79 no.4
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• pp.257-266
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• 2016

Background: Idiopathic pulmonary fibrosis is a common interstitial lung disease; it is a chronic, progressive, and fatal lung disease of unknown etiology. Over the last two decades, knowledge about the underlying mechanisms of pulmonary fibrosis has improved markedly and facilitated the identification of potential targets for novel therapies. However, despite the large number of antifibrotic drugs being described in experimental pre-clinical studies, the translation of these findings into clinical practices has not been accomplished yet. NADH:quinone oxidoreductase 1 (NQO1) is a homodimeric enzyme that catalyzes the oxidation of NADH to $NAD^+$ by various quinones and thereby elevates the intracellular $NAD^+$ levels. In this study, we examined the effect of increase in cellular $NAD^+$ levels on bleomycin-induced lung fibrosis in mice. Methods: C57BL/6 mice were treated with intratracheal instillation of bleomycin. The mice were orally administered with ${\beta}$-lapachone from 3 days before exposure to bleomycin to 1-3 weeks after exposure to bleomycin. Bronchoalveolar lavage fluid (BALF) was collected for analyzing the infiltration of immune cells. In vitro, A549 cells were treated with transforming growth factor ${\beta}1$ (TGF-${\beta}1$) and ${\beta}$-lapachone to analyze the extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT). Results: ${\beta}$-Lapachone strongly attenuated bleomycin-induced lung inflammation and fibrosis, characterized by histological staining, infiltrated immune cells in BALF, inflammatory cytokines, fibrotic score, and TGF-${\beta}1$, ${\alpha}$-smooth muscle actin accumulation. In addition, ${\beta}$-lapachone showed a protective role in TGF-${\beta}1$-induced ECM expression and EMT in A549 cells. Conclusion: Our results suggest that ${\beta}$-lapachone can protect against bleomycin-induced lung inflammation and fibrosis in mice and TGF-${\beta}1$-induced EMT in vitro, by elevating the $NAD^+$/NADH ratio through NQO1 activation.

• The Korean journal of internal medicine
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• v.39 no.2
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• pp.295-305
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• 2024

Background/Aims: The prognosis of patients with idiopathic pulmonary fibrosis (IPF) and respiratory failure requiring mechanical ventilation is poor. Therefore, mechanical ventilation is not recommended. Recently, outcomes of mechanical ventilation, including those for patients with IPF, have improved. The aim of this study was to investigate changes in the use of mechanical ventilation in patients with IPF and their outcomes over time. Methods: This retrospective, observational cohort study used data from the National Health Insurance Service database. Patients diagnosed with IPF between January 2011 and December 2019 who were placed on mechanical ventilation were included. We analyzed changes in the use of mechanical ventilation in patients with IPF and their mortality using the Cochran-Armitage trend test. Results: Between 2011 and 2019, 1,227 patients with IPF were placed on mechanical ventilation. The annual number of patients with IPF with and without mechanical ventilation increased over time. However, the ratio was relatively stable at approximately 3.5%. The overall hospital mortality rate was 69.4%. There was no improvement in annual hospital mortality rate. The overall 30-day mortality rate was 68.7%, which did not change significantly. The overall 90-day mortality rate was 85.3%. The annual 90-day mortality rate was decreased from 90.9% in 2011 to 83.1% in 2019 (p = 0.028). Conclusions: Despite improvements in intensive care and ventilator management, the prognosis of patients with IPF receiving mechanical ventilation has not improved significantly.

• Tuberculosis and Respiratory Diseases
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• v.50 no.2
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• pp.182-195
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• 2001

Background : Idiopathic pulmonary fibrosis(IPF) is a devastating illness for which there is little effective treatment. The key cytokines currently implicated in the fibrotic process are the transforming growth factor-${\beta}_1$(TGF-${\beta}_1$), tumor necrosis factor-$\alpha$(TNF-$\alpha$), endothelin-1(ET-1) and interferon-$\gamma$(IFN-$\gamma$). The rat model for paraquat-induced pulmonary fibrosis was chosen to investigate the role of ET-1 in this disease. Both ET-1 and TGF-${\beta}_1$ expression in lung lesions were examined using immunohistochemical staining. After $Bosentan^{(R)}$ administration, an orally active ET-$l_A$ and ET-$1_B$ receptor antagonist, the degree of pulmonary fibrosis and ET-1 and TGF-${\beta}_1$ expression were analyzed. Method : Sprague-Dawley rats were divided into three groups, the control group, the fibrosis group, and the fibrosis-$Bosentan^{(R)}$-treated group. The animals were sacrificed periodically at 1, 3, 5, 7, 10, 14 days after administering saline or paraquat. The effects between groups were compared with the results of light microscopy and immunohistochemical staining for ET-1 and TGF-${\beta}_1$. The degree of fibrosis was evaluated by H&E and Masson's trichrome staining, which were graded by a computerized image analyzer. The degree of immunohistochemical staining was categorized by a semi-quantitative analysis method. Results : The lung collagen content had increased in the paraquat instillated animals by day 3, and continued to increase up to day 14. A daily treatment by gavage with $Bosentan^{(R)}$ (100mg/kg) did not prevent the increase in collagen deposition on the lung that was induced by paraquat instillation. There were increased immunohistochemical stains of ET-1 on the exudate, macrophages, vascular endothelial cells and pneumocytes in the paraquat instillated group. Furthermore, TGF-${\beta}_1$ expression was higher on the exudate, macrophages, some inflammatory cells, pneumocytes( type I, and II), vascular endothelium and the respiratory epithelial cells around the fibrotic area. After Bosentan treatment, there were no definite changes in ET-1 and TGF-${\beta}_1$ expression. Conclusion : Fibrosis of the Paraquat instillated group was more advanced when compared with the control group. In addition, there was increased ET-1 and TGF-${\beta}_1$ expression around the fibrotic area. ET-1 is associated with lung fibrosis but there was little effect of the ET-1 receptor blocker($Bosentan^{(R)}$) on antifibrosis.Background : Idiopathic pulmonary fibrosis(IPF) is a devastating illness for which there is little effective treatment. The key cytokines currently implicated in the fibrotic process are the transforming growth factor-${\beta}_1$(TGF-${\beta}_1$), tumor necrosis factor-$\alpha$(TNF-$\alpha$), endothelin-1(ET-1) and interferon-$\gamma$(IFN-$\gamma$). The rat model for paraquat-induced pulmonary fibrosis was chosen to investigate the role of ET-1 in this disease. Both ET-1 and TGF-${\beta}_1$ expression in lung lesions were examined using immunohistochemical staining. After $Bosentan^{(R)}$ administration, an orally active ET-$1_A$ and ET-$1_B$ receptor antagonist, the degree of pulmonary fibrosis and ET-1 and TGF-${\beta}_1$ expression were analyzed. Method : Sprague-Dawley rats were divided into three groups, the control group, the fibrosis group, and the fibrosis-$Bosentan^{(R)}$-treated group. The animals were sacrificed periodically at 1, 3, 5, 7, 10, 14 days after administering saline or paraquat. The effects between groups were compared with the results of light microscopy and immunohistochemical staining for ET-1 and TGF-${\beta}_1$. The degree of fibrosis was evaluated by H&E and Masson's trichrome staining, which were graded by a computerized image analyzer. The degree of immunohistochemical staining was categorized by a semi-quantitative analysis method. Results : The lung collagen content had increased in the paraquat instillated animals by day 3, and continued to increase up to day 14. A daily treatment by gavage with $Bosentan^{(R)}$ (100mg/kg) did not prevent the increase in collagen deposition on the lung that was induced by paraquat instillation. There were increased immunohistochemical stains of ET-1 on the exudate, macrophages, vascular endothelial cells and pneumocytes in the paraquat instillated group. Furthermore, TGF-${\beta}_1$ expression was higher on the exudate, macrophages, some inflammatory cells, pneumocytes( type I, and II), vascular endothelium and the respiratory epithelial cells around the fibrotic area. After Bosentan treatment, there were no definite changes in ET-1 and TGF-${\beta}_1$ expression. Conclusion : Fibrosis of the Paraquat instillated group was more advanced when compared with the control group. In addition, there was increased ET-1 and TGF-${\beta}_1$ expression around the fibrotic area. ET-1 is associated with lung fibrosis but there was little effect of the ET-1 receptor blocker($Bosentan^{(R)}$) on antifibrosis.

• IMMUNE NETWORK
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• v.15 no.3
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• pp.142-149
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• 2015

Lung fibrosis is a life-threatening disease caused by overt or insidious inflammatory responses. However, the mechanism of tissue injury-induced inflammation and subsequent fibrogenesis remains unclear. Recently, we and other groups reported that Th17 responses play a role in amplification of the inflammatory phase in a murine model induced by bleomycin (BLM). Osteopontin (OPN) is a cytokine and extracellular-matrix-associated signaling molecule. However, whether tissue injury causes inflammation and consequent fibrosis through OPN should be determined. In this study, we observed that BLM-induced lung inflammation and subsequent fibrosis was ameliorated in OPNdeficient mice. OPN was expressed ubiquitously in the lung parenchymal and bone-marrow-derived components and OPN from both components contributed to pathogenesis following BLM intratracheal instillation. Th17 differentiation of $CD4^+$ ${\alpha}{\beta}$ T cells and IL-17-producing ${\gamma}{\delta}$ T cells was significantly reduced in OPN-deficient mice compared to WT mice. In addition, Th1 differentiation of $CD4^+$ ${\alpha}{\beta}$ T cells and the percentage of IFN-$\gamma$-producing ${\gamma}{\delta}$ T cells increased. T helper cell differentiation in vitro revealed that OPN was preferentially upregulated in $CD4^+$ T cells under Th17 differentiation conditions. OPN expressed in both parenchymal and bone marrow cell components and contributed to BLM-induced lung inflammation and fibrosis by affecting the ratio of pathogenic IL-17/protective IFN-$\gamma$ T cells.

• Tuberculosis and Respiratory Diseases
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• v.48 no.2
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• pp.260-267
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• 2000

Giant cell interstitial pneumonia. a synonym for hard metal pneumoconiosis, is a unique form of pulmonary fibrosis resulting from an exposure to hard metal dust. A case of biopsy-proved giant cell interstitial pneumonia in the absence of appropriate history of exposure to hard metal dust is reported. The patient presented with clinical features of chronic interstitial lung disease or idiopathic pulmonary fibrosis. He worked in a chemical laboratory at a fertilizer plant, where he had been exposed to various chemicals such as benzene and toluene. He denied having any other hobby in his house or job at work, which may have exposed him hard metal dust. High-resolution CT scan revealed multi-lobar distribution of ground glass opacity with peripheral and basal lung predominance. The retrieved fluid of bronchoalveolar lavage contained asbestos fiber and showed neutrotphil predominance. Surgical lung biopsy was performed for a definite diagnosis. Lung specimen showed alveolar infiltration of numerous multinucleated giant cells with mild interstitial fibrosis. Upon detailed examination of the lung tissue, one asbestos body was found. An analysis for mineral contents in lung tissue was performed. Compared with the control specimen, the amount of cobalt and several hard metal components in the lung tissue of this patient was ten times higher. We speculated that the inconsistency between occupational history and the findings of pathologic and mineralogical analyses could be explained by the difference in individual immunologic reactivity to hard metal dust despite the relatively small amount of unrecognized environmental exposure(ED: It's hard to understand what this phrase is trying to say).

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.175-176
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• 2002

Airway inflammation is a characteristic of many lung disorders including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. All these diseases involve the recruitment of immune and inflammatory cells to the lungs leading to systemic and local chronic inflammation and oxidative stress. (omitted)

• IMMUNE NETWORK
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• v.23 no.6
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• pp.45.1-45.22
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• 2023

Interstitial lung disease (ILD) involves persistent inflammation and fibrosis, leading to respiratory failure and even death. Adult tissue-derived mesenchymal stem cells (MSCs) show potential in ILD therapeutics but obtaining an adequate quantity of cells for drug application is difficult. Daewoong Pharmaceutical's MSCs (DW-MSCs) derived from embryonic stem cells sustain a high proliferative capacity following long-term culture and expansion. The aim of this study was to investigate the therapeutic potential of DW-MSCs in experimental mouse models of ILD. DW-MSCs were expanded up to 12 passages for in vivo application in bleomycin-induced pulmonary fibrosis and collagen-induced connective tissue disease-ILD mouse models. We assessed lung inflammation and fibrosis, lung tissue immune cells, fibrosis-related gene/protein expression, apoptosis and mitochondrial function of alveolar epithelial cells, and mitochondrial transfer ability. Intravenous administration of DWMSCs consistently improved lung fibrosis and reduced inflammatory and fibrotic markers expression in both models across various disease stages. The therapeutic effect of DW-MSCs was comparable to that following daily oral administration of nintedanib or pirfenidone. Mechanistically, DW-MSCs exhibited immunomodulatory effects by reducing the number of B cells during the early phase and increasing the ratio of Tregs to Th17 cells during the late phase of bleomycin-induced pulmonary fibrosis. Furthermore, DW-MSCs exhibited anti-apoptotic effects, increased cell viability, and improved mitochondrial respiration in alveolar epithelial cells by transferring their mitochondria to alveolar epithelial cells. Our findings indicate the strong potential of DW-MSCs in the treatment of ILD owing to their high efficacy and immunomodulatory and anti-apoptotic effects.

• Korean Journal of Radiology
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• v.21 no.11
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• pp.1273-1275
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• 2020

• Tuberculosis and Respiratory Diseases
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• v.52 no.5
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• pp.550-556
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• 2002

Microscopic polyangiitis is a systemic small-vessel vasculitis that is associated primarily with necrotizing glomerulonephritis and pulmonary capillaritis. A recurrent and diffuse alveolar hemorrhage due to pulmonary capillaritis is the main clinical manifestation of lung involvement. Recently, and interstitial lung disease that mimics idiopathic pulmonary fibrosis was reported to be rarely associated with microscopic polyangiitis. Here we report two patients with microscopic polyangiitis who showed a honeycomb lung at the time of the initial diagnosis with a brief review of relevant literature.