• Childhood Kidney Diseases
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• v.13 no.2
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• pp.99-117
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• 2009

Diabetic nephropathy is a major cause of chronic renal failure in developing countries, and the prevalence rate has markedly increased during the past decade. Diabetic nephropathy shows various specific histological changes not only in the glomeruli but also in the tubulointerstitial region. In the early stage, the effacement of podocyte foot processes and thickened glomerular basement membrane (GBM) is noticed even at the stage of microalbuminuria. Nodular, diffuse, and exudative lesions, so-called diabetic glomerulosclerosis, are well known as glomerular lesions. Interstitial lesions also exhibit fibrosis, edema, and thickened tubular basement membrane. Diabetic nephropathy is considered to be multifactorial in origin with increasing evidence that one of the major pathways involved in the development and progression of diabetic nephropathy as a result of hyperglycemia. Hyperglycemia induces renal damage directly or through hemodynamic alterations, such as, glomerular hyperfiltration, shear stress, and microalbuminuria. Chronic hyperglycemia also induces nonhemodynamic dysregulations, such as, increased production of advanced glycosylation endproducts, oxidative stress, activation of signal pathway, and subsequent various cytokines. Those pathogenic mechanisms resulted in extracellular matrix deposition including mesangial expansion and GBM thickening, glomerular hypertrophy, inflammation, and proteinuria. In this review, recent opinions on the histopathologic changes and pathophysiologic mechanisms leading to initiation and progression of diabetic nephropathy will be introduced.

• Molecules and Cells
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• v.41 no.3
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• pp.224-233
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• 2018

Primary cilia are solitary, non-motile, axonemal microtubule-based antenna-like organelles that project from the plasma membrane of most mammalian cells and are implicated in transducing hedgehog signals during development. It was recently proposed that aberrant SHH signaling may be implicated in the progression of idiopathic pulmonary fibrosis (IPF). However, the distribution and role of primary cilia in IPF remains unclear. Here, we clearly observed the primary cilia in alveolar epithelial cells, fibroblasts, and endothelial cells of human normal lung tissue. Then, we investigated the distribution of primary cilia in human IPF tissue samples using immunofluorescence. Tissues from six IPF cases showed an increase in the number of primary cilia in alveolar cells and fibroblasts. In addition, we observed an increase in ciliogenesis related genes such as IFT20 and IFT88 in IPF. Since major components of the SHH signaling pathway are known to be localized in primary cilia, we quantified the mRNA expression of the SHH signaling components using qRT-PCR in both IPF and control lung. mRNA levels of SHH, the coreceptor SMO, and the transcription factors GLI1 and GLI2 were upregulated in IPF compared with control. Furthermore, the nuclear localization of GLI1 was observed mainly in alveolar epithelia and fibroblasts. In addition, we showed that defective KIF3A-mediated ciliary loss in human type II alveolar epithelial cell lines leads to disruption of SHH signaling. These results indicate that a significant increase in the number of primary cilia in IPF contributes to the upregulation of SHH signals.

• The Journal of Internal Korean Medicine
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• v.44 no.3
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• pp.366-386
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• 2023

Objective: In this study, a questionnaire survey was conducted for doctors and patients to obtain basic data necessary for the development of an integrated medical system for idiopathic pulmonary fibrosis (IPF). Methods: Questionnaires were developed separately for doctors and patients through an expert group meeting. The survey subjects were recruited online and offline, and finally, responses from 231 doctors and 59 patients were used for statistical analysis. Results: The most important parts in the treatment of IPF for both doctors and patients were the "improvement of respiratory symptoms," "improvement of quality of life," and "prevention of disease progression." Antifibrotic agents were prescribed at a high rate, and 100% of the specialists in Western medicine (WM) and 45.8% of patients reported experiencing side effects. As for the additional payment costs that patients considered as affordable for an integrated medical system, "under 50,000 won (about 38$)" was reported the most in both doctor and patient groups. With regard to the reasons for their reluctance to recommend an integrated medical system for IPF, specialists in WM responded highly to "uncertain evidence for treatment effectiveness." Regarding complementary and alternative medicine therapies that can be beneficial in patients with IPF, "lifestyle management," "diet management," "herb," "relaxation therapy," and "psychotherapy" were ranked high in both doctor and patient groups. Conclusions: In this study, a questionnaire survey on IPF was conducted to review actual treatment status, analyze shortcomings, and identify considerations for the development of an integrated medical system for IPF in the future.

• Tuberculosis and Respiratory Diseases
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• v.56 no.1
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• pp.51-66
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• 2004

Objectives : The matrix metalloproteinases (MMPs) that participate in the extracellular matrix metabolism play a important role in the progression of pulmonary fibrosis. The effects of the MMPs are regulated by several factors including Th-1 cytokines, $interferon-{\gamma}$ ($IFN-{\gamma}$). Up to now, $IFN-{\gamma}$ is known to inhibit pulmonary fibrosis, but little is known regarding the exact effect of $IFN-{\gamma}$ on the regulation of the MMPs. This study investigated the effects of $interferon-{\gamma}$ on the pulmonary fibrosis and the expression of the lung MMP-2,-9, TIMP-1,-2, and Th-2 cytokines in aa rat model of bleomycin induced pulmonary fibrosis. Materials and methods : Male, specific pathogen-free Sprague-Dawley rats were subjected to an intratracheal bleomycin instillation. The rats were randomized to a saline control, a bleomycin treated, and a bleomycin+$IFN-{\gamma}$ treated group. The bleomycin+$IFN-{\gamma}$ treated group was subjected to an intramuscular injection of $IFN-{\gamma}$ for 14 days. At 3, 7, 14, and 28 days after the bleomycin instillation, the rats were sacrificed and the lungs were harvested. In order to evaluate the effects of the $IFN-{\gamma}$ on lung fibrosis and inflammation, the lung hydroxyproline content, inflammation and fibrosis score were measured. Western blotting, zymography and reverse zymography were performed at 3, 7, 14, 28 days after bleomycin instillation in order to evaluate the MMP-2,-9, and TIMP-1,-2 expression level. ELISA was performed to determine the IL-4 and IL-13 level in a lung homogenate. Results : 1. 7 days after bleomycin instillation, inflammatory changes were more severe in the bleomycin+$IFN-{\gamma}$ group than the bleomycin group (bleomycin group : bleomycin+$IFN-{\gamma}$ group=$2.08{\pm}0.15:2.74{\pm}0.29$, P<0.05), but 28 days after bleomycin instillation, lung fibrosis was significantly reduced as a result of the $IFN-{\gamma}$ treatment (bleomycin group : bleomycin+$IFN-{\gamma}$ group=$3.94{\pm}0.43:2.64{\pm}0.13$, P<0.05). 2. 28 days after bleomycin instillation, the lung hydroxyproline content was significantly reduced as a result of $IFN-{\gamma}$ treatment (bleomycin group : bleomycin+$IFN-{\gamma}$ group=$294.04{\pm}31.73{\mu}g/g:194.92{\pm}15.51{\mu}g/g$, P<0.05). 3. Western blotting showed that the MMP-2 level was increased as a result of the bleomycin instillation and highest in the 14 days after bleomycin instillation. 4. In zymography, the active forms of MMP-2 were significantly increased as a result of the $IFN-{\gamma}$ treatment 3 days after the bleomycin instillation, bleomycin+$IFN-{\gamma}$ group (bleomycin group : bleomycin+$IFN-{\gamma}$ group=$209.63{\pm}7.60%:407.66{\pm}85.34%$, P<0.05), but 14 days after the bleomycin instillation, the active forms of MMP-2 were significantly reduced as a result of the $IFN-{\gamma}$ treatment (bleomycin group : bleomycin+$IFN-{\gamma}$ group=$159.36{\pm}20.93%:97.23{\pm}12.50%$, P<0.05). 5. The IL-4 levels were lower in the bleomycin and bleomycin+$IFN-{\gamma}$ groups but this was not significant, and the IL-13 levels showed no difference between the experiment groups. Conclusion : The author found that lung inflammation was increased in the early period but the pulmonary fibrosis was inhibited in the late stage as a result of $IFN-{\gamma}$. The inhibition of pulmonary fibrosis by $IFN-{\gamma}$ appeared to be associated with the inhibition of MMP-2 activation by $IFN-{\gamma}$. Further studies on the mechanism of the regulation of MMP-2 activation and the effects of MMP-2 activation on pulmonary fibrosis is warranted in the future.

• Endocrinology and Metabolism
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• v.37 no.1
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• pp.96-111
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• 2022

Background Diabetic nephropathy (DN) is characterized by albuminuria and accumulation of extracellular matrix (ECM) in kidney. Transforming growth factor-β (TGF-β) plays a central role in promoting ECM accumulation. We aimed to examine the effects of EW-7197, an inhibitor of TGF-β type 1 receptor kinase (ALK5), in retarding the progression of DN, both in vivo, using a diabetic mouse model (db/db mice), and in vitro, in podocytes and mesangial cells. Methods In vivo study: 8-week-old db/db mice were orally administered EW-7197 at a dose of 5 or 20 mg/kg/day for 10 weeks. Metabolic parameters and renal function were monitored. Glomerular histomorphology and renal protein expression were evaluated by histochemical staining and Western blot analyses, respectively. In vitro study: DN was induced by high glucose (30 mM) in podocytes and TGF-β (2 ng/mL) in mesangial cells. Cells were treated with EW-7197 (500 nM) for 24 hours and the mechanism associated with the attenuation of DN was investigated. Results Enhanced albuminuria and glomerular morphohistological changes were observed in db/db compared to that of the nondiabetic (db/m) mice. These alterations were associated with the activation of the TGF-β signaling pathway. Treatment with EW-7197 significantly inhibited TGF-β signaling, inflammation, apoptosis, reactive oxygen species, and endoplasmic reticulum stress in diabetic mice and renal cells. Conclusion EW-7197 exhibits renoprotective effect in DN. EW-7197 alleviates renal fibrosis and inflammation in diabetes by inhibiting downstream TGF-β signaling, thereby retarding the progression of DN. Our study supports EW-7197 as a therapeutically beneficial compound to treat DN.

• Journal of Korean Foot and Ankle Society
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• v.10 no.2
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• pp.117-124
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• 2006

Purpose: This study was aimed at elucidating the pathogenesis of talar osteochondral lesion by analyzing the histopathological findings. Materials and Methods: Twenty specimens from 20 patients who underwent surgical treatment for talus osteochondral lesions were studied. Preoperative MRI images including T1, T2, and stir images were taken and cases were classified according to modification of the Anderson's classification. There were 5 cases of MRI group 1, 6 cases of group 2, 7 cases of group 3 and 2 cases of group 4. A full thickness osteochondral plug including the osteochondral lesion of the talus was harvested from each patient and reviewed histopathologic changes of osteochondral fragment using H-E staining. Mean diameter of specimens was 8.5 mm and mean depth was 10.3 mm. Pathologic changes of articular cartilage and subchondral bone were observed. Subchondral bone was divided into superficial, middle and deep zones according to depth. Cartilage formation, trabecular thickening and marrow fibrosis were observed in each zone. Results: There were detachment of the joint cartilage at the tidemark in 16 cases of 20 cases and the separated cartilages were almost necrotic on the histopathologic findings. Cartilage formation within subchondral bone was discovered beneath the tidemark in 12 cases. Trabeculae were increased and thickened in 17 cases. These pathologic changes were similar to fracture healing process and these findings were more conspicuous near the tidemark and showed transition to normal bone marrow tissue with depth. No correlation between the pathological progression and MRI stages was found. A large cyst shown on MRI's was microscopically turned out to be multiple micro-cysts accompanied by fibrovascular structure and newly formed cartilage tissue. Conclusion: The histopathologic findings of osteochondral lesions are detachment of overlying cartilage at the tidemark and subsequent changes of subchondral bone. Subchondral bone changes are summarized as cartilage formation, marrow fibrosis and trabecular thickening that mean healing process following repeated micro fractures of trabecular. These osteochondral lesions should have differed from osteochondral fractures.

• Korean Journal of Veterinary Pathology
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• v.3 no.1
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• pp.15-25
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• 1999

To elucidate the mechanism of age-related development in FGS/NgaKIST mice with spontaneous glomerulosclerotic lesion, we examined expression and localization of various cytokine mRNA in the kidney in the progression of diseases. This mouse model is the first to develop spontanously occuring glomerosclerotic lesion in the kidney. In this study, we detected the up-regulation of local cytokine genes such as IL-1$\beta$, IL-2, IL-6, IL-10, TNF-$\alpha$, TGF-$\beta$, and IFN- $\gamma$ in the kidneys. In RT-PCR and Southern blot analysis, we detected gradual expressions of cytokine mRNA of IL-1$\beta$, IL-2, IL-6, IFN- $\gamma$, and TNF $\alpha$ mRNA during the course of disease. Other cytokines including IL -10 and TGF -$\beta$ were found to be appeared the slightly expressed level at 3 to 12 weeks before onset of inflammatory lesion but they are highly expressed at the end-stage of the disease accompaning high proteinurea and wasting. In situ RT-PCR, each cytokine mRNA were specifically localized in a variety of cells including mesangial, endothelial, parietal epithelial, tubular epithelial, arterial muscle cell, and infiltrated inflammatory cells. In addition, TNF - $\alpha$was detected moderately in the visceral and parietal epithelial cell, but weakly in endothelial and mesangial cells, whereas IL-1 $\beta$ and IL -6 were strong in mesangial regions. IL-6 and TNF- $\alpha$ was highly localized in the damaged proximal and collecting tubules. Especially, TGF -$\beta$ mRNA was highly found in mesangial cells within glomerulus and interstitium during the end-stage of this disease.. These results indicate that pro inflammatory cytokines such as IL-1 $\beta$, IL-2, IL-6, and TNF- $\alpha$ were gradually expressed from the early stage of this disease to the end-stage, and that IL-10 and TGF-$\beta$ may be important in the accumulation of extracellular matrix(ECM) within glomerulus and periglomerular fibrosis in the progression of this disease as well as tissue destruction in end-stage of this disease.

• The Korean Journal of Pain
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• v.13 no.1
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• pp.97-100
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• 2000

Thoracic outlet syndrome (TOS) is a combination of signs and symptoms caused by the compression of the vital neurovascular structure at the thoracic outlet region. It may stem from a number of abnormalities, including degenerative or bony disorders, trauma to cervical spine, fibromuscular bands, vascular abnormalities and spasm of the anterior scalene muscle. CPT (current perception threshold) is defined as the minimum amount of current applied transcutaneously that an individual consciously perceives. It enables quantification of the hyperesthesia that precedes progressive nerve impairment, as well as hypoesthetic conditions. We experienced a case of thoracic outlet syndrome caused by fibrosis of anterior scalene muscle. The patient was a 30 years old woman with a 3 years history of numbness on the ulnar side, progressive weakness and coldness of both hand, tiredness in the left arm, nocturnal pain in the left forearm, and pain in the left elbow, shoulder and neck. Conservative treatment, stellate ganglion block, cervical epidural block, anterior scalene block and previous operation, including both carpal tunnel release, provided no remarkable relief to the patient. A left scalenectomy and first rib resection were performed by transaxillary approach and left cervical root neurolysis was done. After surgery, we measured CPT using neurometer and found conditions worsening in the opposite arm. We performed the same procedure on right side, and followed by CPT measurement. This case suggests that CPT is a useful measurement of recovery and progression of TOS.

• Preventive Nutrition and Food Science
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• v.22 no.3
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• pp.184-190
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• 2017

Matrix metalloproteinases (MMPs) are endopeptidases that take significant roles in extracellular matrix degradation and therefore linked to several complications such as metastasis of cancer progression, oxidative stress, and hepatic fibrosis. Hizikia fusiformis, a brown algae, was reported to possess bioactivities, including but not limited to, antiviral, antimicrobial, and anti-inflammatory partly due to bioactive polysaccharide contents. In this study, the potential of H. fusiformis against cancer cell invasion was evaluated through the MMP inhibitory effect in HT1080 fibrosarcoma cells in vitro. H. fusiformis crude extract was fractionated with organic solvents, $H_2O$, n-BuOH, 85% aqueous MeOH, and n-hexane (n-Hex). The non-toxicity of the fractions was confirmed by MTT assay. All fractions inhibited the enzymatic activities of MMP-2 and MMP-9 according to the gelatin zymography assay. Cell migration was also significantly inhibited by the n-Hex fraction. In addition, both gene and protein expressions of MMP-2 and -9, and tissue inhibitor of MMPs (TIMPs) were evaluated by reverse transcription-polymerase chain reaction and Western blotting, respectively. The fractions suppressed the mRNA and protein levels of MMP-2, MMP-9 while elevating the TIMP-1 and TIMP-2, with the $H_2O$ fraction being the least effective while n-Hex fraction the most. Collectively, the n-Hex fraction from brown algae H. fusiformis could be a potential inhibitor of MMPs, suggesting the presence of various derivatives of polysaccharides in high amounts.

• Journal of Korean Medical Science
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• v.33 no.51
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• pp.324.1-324.6
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• 2018

Oxysterol $7{\alpha}$-hydroxylase deficiency is a very rare liver disease categorized as inborn errors of bile acid synthesis, caused by CYP7B1 mutations. As it may cause rapid progression to end-stage liver disease even in early infancy, a high index of suspicion is required to prevent fatal outcomes. We describe the case of a 3-month-old boy with progressive cholestatic hepatitis and severe hepatic fibrosis. After excluding other etiologies for his early liver failure, we found that he had profuse urinary excretion of $3{\beta}$-monohydroxy-${\Delta}^5$-bile acid derivatives by gas chromatography/mass spectrometry analysis with dried urine spots on filter paper. He was confirmed to have a compound heterozygous mutation (p.Arg388Ter and p.Tyr469IlefsX5) of the CYP7B1 gene. After undergoing liver transplantation (LT) from his mother at 4 months of age, his deteriorated liver function completely normalized, and he had normal growth and development until the current follow-up at 33 months of age. We report the first Korean case of oxysterol $7{\alpha}$-hydroxylase deficiency in the youngest infant reported to undergo successful living donor LT to date.