• Tuberculosis and Respiratory Diseases
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• v.78 no.3
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• pp.239-245
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• 2015

Background: Chronic obstructive pulmonary disease is characterized by emphysema, chronic bronchitis, and small airway remodeling. The alveolar destruction associated with emphysema cannot be repaired by current clinical practices. Stem cell therapy has been successfully used in animal models of cigarette smoke- and elastase-induced emphysema. However, the optimal dose of mesenchymal stem cells (MSCs) for the most effective therapy has not yet been determined. It is vital to determine the optimal dose of MSCs for clinical application in emphysema cases. Methods: In the present study, we evaluated the therapeutic effects of various doses of MSCs on elastase-induced emphysema in mice. When 3 different doses of MSCs were intravenously injected into mice treated with elastase, only $5{\times}10^4$ MSCs showed a significant effect on the emphysematous mouse lung. We also identified action mechanisms of MSCs based on apoptosis, lung regeneration, and protease/antiprotease imbalance. Results: The MSCs were not related with caspase-3/7 dependent apoptosis. But activity of matrix metalloproteinase 9 increased by emphysematous lung was decreased by intravenously injected MSCs. Vascular endothelial growth factor were also increased in lung from MSC injected mice, as compared to un-injected mice. Conclusion: This is the first study on the optimal dose of MSCs as a therapeutic candidate. This data may provide important basic data for determining dosage in clinical application of MSCs in emphysema patients.

• Tuberculosis and Respiratory Diseases
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• v.77 no.3
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• pp.116-123
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• 2014

Background: Mesenchymal stem cells (MSCs) obtained from bone marrow or adipose tissue can successfully repair emphysematous animal lungs, which is a characteristic of chronic obstructive pulmonary disease. Here, we describe the cellular distribution of MSCs that were intravenously injected into mice with elastase-induced emphysema. The distributions were also compared to the distributions in control mice without emphysema. Methods: We used fluorescence optical imaging with quantum dots (QDs) to track intravenously injected MSCs. In addition, we used a human Alu sequence-based real-time polymerase chain reaction method to assess the lungs, liver, kidney, and spleen in mice with elastase-induced emphysema and control mice at 1, 4, 24, 72, and 168 hours after MSCs injection. Results: The injected MSCs were detected with QD fluorescence at 1- and 4-hour postinjection, and the human Alu sequence was detected at 1-, 4- and 24-hour postinjection in control mice (lungs only). Injected MSCs remained more in mice with elastase-induced emphysema at 1, 4, and 24 hours after MSCs injection than the control lungs without emphysema. Conclusion: In conclusion, our results show that injected MSCs were observed at 1 and 4 hours post injection and more MSCs remain in lungs with emphysema.

• Biomolecules & Therapeutics
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• v.28 no.3
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• pp.250-258
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• 2020

Emphysema, a major component of chronic obstructive pulmonary disease (COPD), is a leading cause of human death worldwide. The progressive deterioration of lung function that occurs in the disease is caused by chronic inflammation of the airway and destruction of the lung parenchyma. Despite the main impact of inflammation on the pathogenesis of emphysema, current therapeutic regimens mainly offer symptomatic relief and preservation of lung function with little therapeutic impact. In the present study, we aimed to discover novel therapeutics that suppress the pathogenesis of emphysema. Here, we show that LJ-2698, a novel and highly selective antagonist of the adenosine A₃ receptor, a G protein-coupled receptor involved in various inflammatory diseases, significantly reversed the elastase-induced destructive changes in murine lungs. We found that LJ-2698 significantly prevented elastase-induced airspace enlargement, resulting in restoration of pulmonary function without causing any obvious changes in body weight in mice. LJ-2698 was found to inhibit matrix metalloproteinase activity and pulmonary cell apoptosis in the murine lung. LJ-2698 treatment induced increases in anti-inflammatory cytokines in macrophages at doses that displayed no significant cytotoxicity in normal cell lines derived from various organs. Treatment with LJ-2698 significantly increased the number of anti-inflammatory M2 macrophages in the lungs. These results implicate the adenosine A₃ receptor in the pathogenesis of emphysema. Our findings also demonstrate the potential of LJ-2698 as a novel therapeutic/preventive agent in suppressing disease development with limited toxicity.

• The Korean Journal of Nuclear Medicine
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• v.24 no.2
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• pp.229-236
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• 1990

Perfusion and ventilaion imagings of the lung are well established procedure for diagnosing pulmonary embolism, differentiation it from chronic obstructive lung disease, and making an early detection of chronic obstructive lung disease. To evaluate the usefulness of radioaerosol inhalation imaging (RII) in chronic obstructive lung disease, especially pulmonary emphysema, we analyzed RIIs of five normal adult non-smokers, five asymptomatic smokers (age 25-42 years with the mean 36), and 21 patients with pulmonry emphysema (age 59-78 years with the mean 67). Scintigrams were obtained with radioaerosol produced by a BARC nebulizer with 15 mCi of Tc-99m-phytate. Scanning was performed in the anterior, posterior, and lateral projections after five to 10-minute inhalation of the radioaerosol on sitting position. The scans were analyzed and correlated with the results of pulmonary function studies and chest radiographs. Also lung perfusion scan with $^{99m}Tc-MAA$ was performed in 12 patients. In five patients, we performed follow-up scans for the evaluation of the effects of a bronchodilator. Based on the X-ray findings and clinical symptoms, pulmonary emphysema was classified into four types: centrilobular (3 patients), panlobular (4 patients), intermediate (10 patients), and combined (4 patients). RII findings were patternized according to the type, extent, and intensity of the aerosol deposition in the central bronchial and bronchopulmonary system and lung parenchyma. 10 controls, normal five non-smokers and three asymptomatic smokers revealed homogeneous parenchymal deposition in the entire lung fields without central bronchial deposition. The remaining two of asymptomatic smokers revealed mild central airway deposition. The great majority of the patients showed either central (9/21) or combined type (10/21) of bronchopulmonary deposition and the remaining two patients peripheral bronchopulmonary deposition. Parenchymal aerosol deposition in pulmonary emphysema was diffuse (6/21), discrete(6/21), intermediate (3/21), or combined (6/21). In 12 patients studied also with perfusion scans, perfusion defects matched closely with ventilation defects in location and configuration. But the size of the ventilation defects was generally larger than the perfusion defects. In all four patients treated with bronchodilators, the follow-up study demonstrated decrease in abnormal of radioaerosol deposition in the central airway with improvement of ventilation defects. RII was useful technique for the evaluation of regional ventilatory abnormality and the effects of treatment with bronchodilators in pulmonary emphysema.

• Journal of Chest Surgery
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• v.27 no.10
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• pp.882-884
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• 1994

Congenital lobar emphysema is one of the abnormal development of pulmonary parenchyme which may cause respiratory distress in infant. This disease is an unusual condition barely mentioned before 1949, and only 166 cases were reported till 1967 in English literature. This report describes a 13 months old girl who had a congenital left upper lobar emphysema. The left upper lobectomy was the operation for this case and the postoperative course was not eventful, and have been in good condition upto now.

• Korean Journal of Radiology
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• v.22 no.10
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• pp.1719-1729
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• 2021

Objective: Emphysema and small-airway disease are the two major components of chronic obstructive pulmonary disease (COPD). We propose a novel method of quantitative computed tomography (CT) emphysema air-trapping composite (EAtC) mapping to assess each COPD component. We analyzed the potential use of this method for assessing lung function in patients with COPD. Materials and Methods: A total of 584 patients with COPD underwent inspiration and expiration CTs. Using pairwise analysis of inspiration and expiration CTs with non-rigid registration, EAtC mapping classified lung parenchyma into three areas: Normal, functional air trapping (fAT), and emphysema (Emph). We defined fAT as the area with a density change of less than 60 Hounsfield units (HU) between inspiration and expiration CTs among areas with a density less than -856 HU on inspiration CT. The volume fraction of each area was compared with clinical parameters and pulmonary function tests (PFTs). The results were compared with those of parametric response mapping (PRM) analysis. Results: The relative volumes of the EAtC classes differed according to the Global Initiative for Chronic Obstructive Lung Disease stages (p < 0.001). Each class showed moderate correlations with forced expiratory volume in 1 second (FEV₁) and FEV₁/forced vital capacity (FVC) (r = -0.659-0.674, p < 0.001). Both fAT and Emph were significant predictors of FEV₁ and FEV₁/FVC (R² = 0.352 and 0.488, respectively; p < 0.001). fAT was a significant predictor of mean forced expiratory flow between 25% and 75% and residual volume/total vital capacity (R² = 0.264 and 0.233, respectively; p < 0.001), while Emph and age were significant predictors of carbon monoxide diffusing capacity (R² = 0.303; p < 0.001). fAT showed better correlations with PFTs than with small-airway disease on PRM. Conclusion: The proposed quantitative CT EAtC mapping provides comprehensive lung functional information on each disease component of COPD, which may serve as an imaging biomarker of lung function.

• Tuberculosis and Respiratory Diseases
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• v.80 no.1
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• pp.83-89
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• 2017

Background: Previous studies report that apoptosis and autophagy are involved in the pathogenesis of emphysema, and macroautophagy is one of the processes regulating the apoptosis pathway. However, few studies have evaluated whether chaperone-mediated autophagy (CMA) contributes to the regulation of apoptosis. In this study, we investigated the impact of autophagy, including both macroautophagy and CMA, on the apoptosis in bronchial epithelial cells. Methods: Cigarette smoke extract (CSE) was injected intratracheally into C57BL/6 mice, and emphysema and apoptosis were evaluated in the lungs. After treatment with CSE, apoptosis, macroautophagy, and CMA were measured in BEAS2-B cells, and the impact of autophagy on the apoptosis was evaluated following knockdown of autophagy-related genes by short interfering RNAs (siRNAs). Results: Intratracheal CSE injection resulted in the development of emphysema and an increase in apoptosis in mice. CSE increased the apoptosis in BEAS2-B cells, and also elevated the expression of proteins related to both macroautophagy and CMA in BEAS2-B cells. The knockdown experiment with siRNAs showed that macroautophagy increases apoptosis in BEAS2-B cells, while CMA suppresses apoptosis. Conclusion: The intratracheal injection of CSE induces pulmonary emphysema and an increase in apoptosis in mice. CSE also induces apoptosis, macroautophagy, and CMA of bronchial epithelial cells. Macroautophagy and CMA regulate apoptosis in opposite directions.

• Journal of Chest Surgery
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• v.9 no.1
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• pp.78-82
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• 1976

Bullous emphysema is usually associated with extensive chronic obliterative pulmonary disease. It is the disease of old age but rare in children or infancy. The bulla in this disease is acquired one. In general the symptoms are due to not the mere presence of the bulla but the extent of underlying lung pathology as emphysema or bronchitis. Occassionally giant bulla of great size may cause symptoms and in this occassion it should be differentiated from other diseases. Especially in children or infancy pneumothorax, congenital pulmonary cyst of lobar obstructive-emphysema should be excluded. Recently we experienced 2 cases of bullous emphysema in infancy with severe respiratory symptoms because of bullae of great size. We felt difficulties in differentiating with other conditions. The purpose of this report is to review our cases thoroughly and enhance considerations of this disease.

• Tuberculosis and Respiratory Diseases
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• v.50 no.4
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• pp.415-425
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• 2001

Background : The correlation between the high resolution computed tomography(HRCT) emphysema score and the physiologic parameters including resting and exercise pulmonary function test was investigated in 14 patients($60.6{\pm}10.3$ years) with pulmonary emphysema. Methods : The patients underwent a HRCT, a resting pulmonary function test, and incremental exercise testing(cycle ergometer, 10 W/min). Computed tomography scans were obtained on a GE highlight at 10 mm intervals using 10 mm collimation, from the apex to the base after a full inspiration. The emphysema scores were determined by a CT program 'Density mask' outlining the areas with attenuation values less than -900 HU, indicating the emphysema areas, and providing an overall percentage of lung involvement by emphysema. Results : Among the resting PFT parameters, only the diffusing capacity(r=-0.75) and $PaO_2$ (r=-0.66) correlated with the emphysema score(p<0.05). Among the exercise test parameters, the emphysema score correlated significantly with the maximum power(r=-0.74), maximum oxygen consumption(r=-0.68), anaerobic threshold(V-slope method: r=-0.69), maximal $O_2$-pulse(r=-0.73), and the physiologic dead space ratio at the maximum workload(r=-0.80)(p<0.01). Conclusion: We could find that exercise testing parameters showed a much better correlation with the HRCT emphysema score, which is known to have a good correlation with the pathologic severity than the resting PIT parameters. Therefore it is suggested that exercise testing is superior to resting PIT for estimating in the estimation of the physiologic disturbance in emphysema patients.

• Molecules and Cells
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• v.46 no.9
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• pp.558-572
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• 2023

Chronic obstructive pulmonary disease (COPD) will be the third leading cause of death worldwide by 2030. One of its components, emphysema, has been defined as a lung disease that irreversibly damages the lungs' alveoli. Treatment is currently unavailable for emphysema symptoms and complete cure of the disease. Hyaluronan (HA) and proteoglycan link protein 1 (HAPLN1), an HA-binding protein linking HA in the extracellular matrix to stabilize the proteoglycan structure, forms a bulky hydrogel-like aggregate. Studies on the biological role of the full-length HAPLN1, a simple structure-stabilizing protein, are limited. Here, we demonstrated for the first time that treating human alveolar epithelial type 2 cells with recombinant human HAPLN1 (rhHAPLN1) increased TGF-β receptor 1 (TGF-β RI) protein levels, but not TGF-β RII, in a CD44-dependent manner with concurrent enhancement of the phosphorylated Smad3 (p-Smad3), but not p-Smad2, upon TGF-β1 stimulation. Furthermore, rhHAPLN1 significantly increased sirtuins levels (i.e., SIRT1/2/6) without TGF-β1 and inhibited acetylated p300 levels that were increased by TGF-β1. rhHAPLN1 is crucial in regulating cellular senescence, including p53, p21, and p16, and inflammation markers such as p-NF-κB and Nrf2. Both senile emphysema mouse model induced via intraperitoneal rhHAPLN1 injections and porcine pancreatic elastase (PPE)-induced COPD mouse model generated via rhHAPLN1-containing aerosols inhalations showed a significantly potent efficacy in reducing alveolar spaces enlargement. Preclinical trials are underway to investigate the effects of inhaled rhHAPLN1-containing aerosols on several COPD animal models.