15 research outputs found
Effect of changes in inspired oxygen fraction on oxygen delivery during cardiac surgery: a substudy of the CARROT trial
When hemoglobin (Hb) is fully saturated with oxygen, the additional gain in oxygen delivery (DO2) achieved by increasing the fraction of inspired oxygen (FiO2) is often considered clinically insignificant. In this study, we evaluated the change in DO2, interrogated by mixed venous oxygen saturation (SvO2), in response to a change in FiO2 of 0.5 during cardiac surgery. When patients were hemodynamically stable, FiO2 was alternated between 0.5 and 1.0 in on-pump cardiac surgery patients (pilot study), and between 0.3 and 0.8 in off-pump coronary artery bypass grafting patients (substudy of the CARROT trial). After the patient had stabilized, a blood gas analysis was performed to measure SvO2. The observed change in SvO2 (ฮSvO2) was compared to the expected ฮSvO2 calculated using Fick's equation. A total 106 changes in FiO2 (two changes per patient; total 53 patients; on-pump, n = 36; off-pump, n = 17) were finally analyzed. While Hb saturation remained near 100% (on-pump, 100%; off-pump, mean [SD] = 98.1% [1.5] when FiO2 was 0.3 and 99.9% [0.2] when FiO2 was 0.8), SvO2 changed significantly as FiO2 was changed (the first and second changes in on-pump, 7.7%p [3.8] and 7.6%p [3.5], respectively; off-pump, 7.9%p [4.9] and 6.2%p [3.9]; all P < 0.001). As a total, regardless of the surgery type, the observed ฮSvO2 after the FiO2 change of 0.5 was โฅ 5%p in 82 (77.4%) changes and โฅ 10%p in 31 (29.2%) changes (mean [SD], 7.5%p [3.9]). Hb concentration was not correlated with the observed ฮSvO2 (the first changes, r = - 0.06, P = 0.677; the second changes, r = - 0.21, P = 0.138). The mean (SD) residual ฮSvO2 (observed - expected ฮSvO2) was 0%p (4). Residual ฮSvO2 was more than 5%p in 14 (13.2%) changes and exceeded 10%p in 2 (1.9%) changes. Residual ฮSvO2 was greater in patients with chronic kidney disease than in those without (median [IQR], 5%p [0 to 7] vs. 0%p [- 3 to 2]; P = 0.049). DO2, interrogated by SvO2, may increase to a clinically significant degree as FiO2 is increased during cardiac surgery, and the increase of SvO2 is not related to Hb concentration. SvO2 increases more than expected in patients with chronic kidney disease. Increasing FiO2 can be used to increase DO2 during cardiac surgery.ope
The Effect of Electrical Muscle Stimulation and In-bed Cycling on Muscle Strength and Mass of Mechanically Ventilated Patients: A Pilot Study
Background: Critically ill patients experience muscle weakness, which leads to functional disability. Both functional electrical stimulation (FES) and in-bed cycling can be an alternative measure for intensive care unit (ICU) patients who are not feasible for active exercise. The aim of this study was to examine whether FES and in-bed cycling have a positive effect on muscle mass in ICU patients.
Methods: Critically ill patients who received mechanical ventilation for at least 24 hours were included. After passive range of motion exercise, in-bed cycling was applied for 20 minutes, and FES was applied for 20 minutes on the left leg. The right leg received in-bed cycling and the left leg received both FES and in-bed cycling. Thigh circumferences and rectus femoris cross-sectional area (CSA) were assessed with ultrasonography before and after the intervention. Muscle strength was assessed by Medical Research Council scale.
Results: A total of 10 patients were enrolled in this study as a pilot study. Before and after the intervention, the CSA of right rectus femoris increased from 5.08 ยฑ 1.51 cm2 to 6.01 ยฑ 2.21 cm2 , which was statistically significant (P = 0.003). The thigh circumference was also increased and statistically significant (P = 0.006). There was no difference between left and right in regard to FES application. There is no significant change in muscle strength before and after the intervention (right and left, P = 0.317 and P = 0.368, respectively).
Conclusions: In-bed cycling increased thigh circumferences rectus femoris CSA. Adding FES did not show differences.ope
Combination of Static Echocardiographic Indices for the Prediction of Fluid Responsiveness in Patients Undergoing Coronary Surgery: A Pilot Study
We investigated the role of echocardiographic indices consisting of left ventricular end-diastolic area (LVEDA) in combination with Doppler-derived surrogates of diastolic compliance and filling (E/E', E'/S', E'/A'; early transmitral flow velocity (E), tissue Doppler-derived early (E') diastolic, late (A') diastolic, or peak systolic (S') velocity of the mitral annulus) in predicting fluid responsiveness in off-pump coronary surgery. Hemodynamic and echocardiographic variables were prospectively assessed under general anesthesia before and after a fluid challenge of 6 mL/kg during apnea at atmospheric pressure in 64 patients with LV ejection fraction โฅ40%. Forty patients (63%) were fluid responders (โฅ15% increase in stroke volume index). E/E' and E'/S' could predict fluid responsiveness with area under the receiver operating characteristic curve (AUROC) of 0.71 (95% confidence interval [CI], 0.56-0.85; p = 0.006) and 0.68 (95% CI, 0.54-0.82; p = 0.017), respectively. The combination of LVEDA and E/E' showed incremental predictive ability for fluid responsiveness compared with LVEDA (AUROC, 0.60; p = 0.170) or pulse pressure variation (AUROC, 0.70; p = 0.002), yielding the highest AUROC of 0.78 (95% CI, 0.66-0.90; p < 0.001). The combined index of echocardiographic variables reflecting LV dimension (LVEDA) and diastolic compliance and filling (E/E') is a potentially useful predictor of fluid responsiveness.ope
Associations of creatinine/cystatin C ratio and postoperative pulmonary complications in elderly patients undergoing off-pump coronary artery bypass surgery: a retrospective study
Sarcopenia along with nutritional status are associated with postoperative pulmonary complications in various surgical fields. Recently, the creatinine/cystatin C ratio and CONtrolling NUTritional status score were introduced as biochemical indicators for sarcopenia and malnutrition, respectively. We aimed to investigate the associations among these indicators and postoperative pulmonary complications in elderly patients undergoing off-pump coronary artery bypass surgery. We reviewed the medical records of 605 elderly patients (aged โฅ 65 years) who underwent off-pump coronary artery bypass surgery from January 2010 to December 2019. Postoperative pulmonary complications (pneumonia, prolonged ventilation [> 24 h], and reintubation during post-surgical hospitalisation) occurred in 80 patients. A 10-unit increase of creatinine/cystatin C ratio was associated with a reduced risk of postoperative pulmonary complications (odds ratio: 0.80, 95% confidence interval: 0.69-0.92, P = 0.001); the optimal cut-off values for predicting postoperative pulmonary complications was 89.5. Multivariable logistic regression analysis revealed that age, congestive heart failure, and creatinine/cystatin C ratio < 89.5 (odds ratio 2.36, 95% confidence interval 1.28-4.37) were independently associated with the occurrence of postoperative pulmonary complications, whereas CONtrolling NUTritional status score was not. A low creatinine/cystatin C ratio was associated with an increased risk of developing postoperative pulmonary complications after off-pump coronary artery bypass surgery.ope
Inhalation sedation for postoperative patients in the intensive care unit: initial sevoflurane concentration and comparison of opioid use with propofol sedation
Background: Although the use of volatile sedatives in the intensive care unit (ICU) is increasing in Europe, it remains infrequent in Asia. Therefore, there are no clinical guidelines available. This study investigates the proper initial concentration of sevoflurane, a volatile sedative that induces a Richmond agitation-sedation scale (RASS) score of -2 to -3, in patients who underwent head and neck surgery with tracheostomy. We also compared the amount of postoperative opioid consumption between volatile and intravenous (IV) sedation.
Methods: We planned a prospective study to determine the proper initial sevoflurane concentration and a retrospective analysis to compare postoperative opioid consumption between volatile sedation and propofol sedation. Patients scheduled for head and neck surgery with tracheostomy and subsequent postoperative sedation in the ICU were enrolled.
Results: In this prospective study, the effective dose 50 (ED50) of initial end-tidal sevoflurane concentration was 0.36% (95% confidence interval [CI], 0.20 to 0.60%), while the ED 95 was 0.69% (95% CI, 0.60 to 0.75%) based on isotonic regression methods. In this retrospective study, remifentanil consumption during postoperative sedation was significantly lower in the sevoflurane group (2.52ยฑ1.00 ยตg/kg/hr, P=0.001) than it was in the IV propofol group (3.66ยฑ1.30 ยตg/kg/hr).
Conclusions: We determined the proper initial end-tidal concentration setting of sevoflurane for patients with tracheostomy who underwent head and neck surgery. Postoperative sedation with sevoflurane appears to be a valid and safe alternative to IV sedation with propofol.ope
High Preoperative Serum Syndecan-1, a Marker of Endothelial Glycocalyx Degradation, and Severe Acute Kidney Injury after Valvular Heart Surgery
Degradation of endothelial glycocalyx (EG) is associated with inflammation and endothelial dysfunction, which may contribute to the development of acute kidney injury (AKI). We investigated the association between a marker of EG degradation and AKI after valvular heart surgery. Serum syndecan-1 concentrations were measured at induction of anesthesia and discontinuation of cardiopulmonary bypass in 250 patients. Severe AKI was defined as Kidney Disease: Improving Global Outcomes Criteria Stage 2 or 3. Severe AKI occurred in 13 patients (5%). Receiver operating characteristic analysis of preoperative syndecan-1 to predict severe AKI showed area under curve of 0.714 (95% confidence interval (CI), 0.575-0.853; p = 0.009). The optimal cut-off value was 90 ng/mL, with a sensitivity of 61.5% and specificity of 78.5%. In multivariable analysis, both preoperative syndecan-1 โฅ 90 ng/mL and Cleveland Clinic Foundation score independently predicted severe AKI. Severe tricuspid regurgitation was more frequent (42.4% vs. 17.8%, p < 0.001), and baseline right ventricular systolic pressure (41 (33-51) mmHg vs. 33 (27-43) mmHg, p = 0.001) and TNF-ฮฑ (1.85 (1.37-2.43) pg/mL vs. 1.45 (1.14-1.92) pg/mL, p <0.001) were higher in patients with high preoperative syndecan-1. Patients with high preoperative syndecan-1 had longer hospital stay (16 (12-24) days vs. 13 (11-17) days, p = 0.001). In conclusion, a high preoperative syndecan-1 concentration greater than 90 ng/mL was able to predict severe AKI after valvular heart surgery and was associated with prolonged hospitalization.ope
Risk factors for intensive care unit readmission after lung transplantation: a retrospective cohort study
Background: Lung transplantation (LT) is an accepted therapeutic modality for end-stage lung disease patients. Intensive care unit (ICU) readmission is a risk factor for mortality after LT, for which consistent risk factors have not been elucidated. Thus, we investigated the risk factors for ICU readmission during index hospitalization after LT, particularly regarding the posttransplant condition of LT patients.
Methods: In this retrospective study, we investigated all adult patients undergoing LT between October 2012 and August 2017 at our institution. We collected perioperative data from electronic medical records such as demographics, comorbidities, laboratory findings, ICU readmission, and in-hospital mortality.
Results: We analyzed data for 130 patients. Thirty-two patients (24.6%) were readmitted to the ICU 47 times during index hospitalization. At the initial ICU discharge, the Sequential Organ Failure Assessment (SOFA) score (odds ratio [OR], 1.464; 95% confidence interval [CI], 1.083-1.978; P=0.013) and pH (OR, 0.884; 95% CI, 0.813-0.962; P=0.004; when the pH value increases by 0.01) were related to ICU readmission using multivariable regression analysis and were still significant after adjusting for confounding factors. Thirteen patients (10%) died during the hospitalization period, and the number of ICU readmissions was a significant risk factor for in-hospital mortality. The most common causes of ICU readmission and in-hospital mortality were infection-related.
Conclusions: The SOFA score and pH were associated with increased risk of ICU readmission. Early postoperative management of these factors and thorough posttransplantation infection control can reduce ICU readmission and improve the prognosis of LT patients.ope
Equal Ratio Ventilation Reduces Blood Loss During Posterior Lumbar Interbody Fusion Surgery
Study design: A prospective randomized double-blinded study.
Objective: The aim of this study was to compare the effect of two different ventilator modes (inspiratory to expiratory ratio [I:E ratio] of 1:1 and 1:2) on intraoperative surgical bleeding in patients undergoing posterior lumbar interbody fusion (PLIF) surgery.
Summary of background data: During PLIF surgery, a considerable amount of blood loss is anticipated. In the prone position, engorgement of the vertebral vein increases surgical bleeding. We hypothesized that equal ratio ventilation (ERV) with I:E ratio of 1:1 would lower peak inspiratory pressure (PIP) in the prone position and consequentially decrease surgical bleeding.
Methods: Twenty-eight patients were randomly assigned to receive either ERV (ERV group, n = 14) or conventional ventilation with I:E ratio of 1:2 (control group, n = 14). Hemodynamic and respiratory parameters were measured at 5 minutes after anesthesia induction, at 5 minutes after the prone position, at the time of skin closure, and at 5 minutes after turning to the supine position.
Results: The amount of intraoperative surgical bleeding in the ERV group was significantly less than that in the control group (975.7 ยฑ 349.9 mL vs. 1757.1 ยฑ 1172.7 mL, P = 0.030). Among other hemodynamic and respiratory parameters, PIP and plateau inspiratory pressure (Pplat) were significantly lower and dynamic lung compliance (Cdyn) was significantly higher in the ERV group than those of the control group throughout the study period, respectively (all P < 0.05).
Conclusion: Compared to conventional ratio ventilation, ERV provided lower PIP and reduced intraoperative surgical blood loss in patients undergoing PLIF surgery.Level of Evidence: 2.ope
๋ง์ฑ ์ผ์ฆ์ฑ ๋นํ์์ hepcidin ๋ณํ์ ๊ดํ ์ฐ๊ตฌ: ์ฒ ๋ถ์ ํฌ์ฝ ํ hepcidin ์กฐ์ ๊ธฐ์
๋ง์ฑ ์ผ์ฆ์ฑ ๋นํ(anemia of chronic inflammation, ACI)์ ํ์์ ๋ถ์ ์ ์ํ์ ์ฐ๊ด๋ ๊ฒ์ผ๋ก ์๋ ค์ ธ ์๋ค. Hepcidin์ ์ฒด๋ด์ ์ฒ ํญ์์ฑ์ ์กฐ์ ํ๋ ์ฃผ์ ์กฐ์ ์ธ์๋ก, ์ฃผ๋ก ๊ฐ์์ ์์ฑ๋๋ค. ๋ง์ฑ ์ผ์ฆ ์ํ์์๋ hepcidin์ด ์ฆ๊ฐํ์ฌ ์ฒด๋ด์ ์ฒ ์ด ํ์ฉ ๋ถ๊ฐ๋ฅํ ferritin์ ํํ๋ก ์ธํฌ ๋ด์ ์ ์ฅ๋๋๋ฐ, ์ด๋ก ์ธํด ์ฒด๋ด์ ์ถฉ๋ถํ ์ฒ ์ ์ฅ๋์ด ์์์๋ ๋ถ๊ตฌํ๊ณ ์ฒ ์ ์ด์ฉ์ ์ ํ์ด ๋ฐ์ํ์ฌ ์ ํ๊ตฌ ์์ฑ์ด ์ด๋ ค์์ง๊ณ , ๋นํ์ด ๋ฐ์ํ๊ฒ ๋๋ค. ์์์์๋ ๋ชจ๋ ์ข
๋ฅ์ ๋นํ์ ์ฒ ๋ถ ๋ณด์ถฉ์ผ๋ก ์น๋ฃํ๊ณค ํ๋๋ฐ, ACI์ ๊ทผ๋ณธ์ ์ธ ์์ธ์ ๊ณ ๋ คํ์์ ๋ ์ด๊ฒ์ ์ ์ ํ์ง ๋ชปํ ์น๋ฃ๋ฒ์ผ ๊ฐ๋ฅ์ฑ์ด ์๋ค. ๋ฐ๋ผ์, ๋ณธ ์ฐ๊ตฌ์์๋ ์์๊ณผ ์ ์ฌํ ACI ์ฅ ๋ชจ๋ธ์ ํ๋ฆฝํ๊ณ , ์ ๋งฅ ๋ด ์ฒ ๋ถ์ ํฌ์ฌํ ํ ๋จ๊ธฐ๊ฐ์ ๊ฑธ์ณ ๊ฐ์์ hepcidin ๋ฐ ๊ทธ ์กฐ์ ๊ฒฝ๋ก์ ๋ณํ๋ฅผ ์์๋ณด๋ ๊ฒ์ ์ฃผ์ ์ฐ๊ตฌ ๋ชฉํ๋ก ํ์๋ค. ๋ํ ์ฒ ๋ถ ํฌ์ฌ๋ก ์ธํด ๋ฐ์ ๊ฐ๋ฅํ ์ฐํ ์คํธ๋ ์ค๋ฅผ ํ๊ฐํ๊ณ , ์ ์ฅ์์์ erythropoietin (EPO) ๋ฐํ ๋ฐ erythroferrone (ERFE) ๋ณํ๋ฅผ ํจ๊ป ์ดํด๋ณด๊ณ ์ ํ์๋ค. ๋์์, knockdown HepG2 ์ธํฌ์ ์ฒ ์ ์ฒ๋ฆฌํ๋ ์คํ์ ํตํด hepcidin ์กฐ์ ๊ฒฝ๋ก๋ฅผ ํ์ธํ๊ณ ์ ํ์๋ค. ACI๋ Complete Freundโs Adjuvant (CFA)๋ฅผ 2์ฃผ๊ฐ 3ํ ๋ณต๊ฐ ๋ด ํฌ์ฌํ์ฌ ์ ๋ฐํ์๋ค. ์์ปท Sprague-Dawley ์ฅ (n = 30)๋ ๋ค์์ 3๊ฐ ๊ทธ๋ฃน์ผ๋ก ๋๋์ด ๋ฐฐ์ ๋์๋ค: ๋์กฐ-์์ผ์๊ตฐ (n = 10), CFA-์์ผ์๊ตฐ (n = 10), CFA-์ฒ ๋ถ๊ตฐ (n = 10). CFA ํฌ์ฝ ์์ 2์ฃผ ๋ค, ํ์์ ์์น๊ฐ ๊ธฐ์ ์น์ ๋นํด >2 g/dL ๊ฐ์ํ ๊ฒฝ์ฐ ACI๊ฐ ์ ๋ฐ๋ ๊ฒ์ผ๋ก ๋ณด์๋ค. ACI ์ฅ๋ ์ ๋งฅ์ผ๋ก ์ฒ ๋ถ (iron isomaltoside, 20mg/kg) ๋๋ ๋๋์ ์์ผ์๋ฅผ ํฌ์ฌ ๋ฐ์๋ค. ํฌ์ฝ 3์ผ ํ, ํ์กํ์ ๋ณ์, ์ผ์ฆ ํ์ง์, iron profile๊ณผ ํจ๊ป ๊ฐ์์์ hepcidin ๋ฐ ๊ทธ ์ ์ฌ ์กฐ์ ๊ฒฝ๋ก๋ฅผ ํ์ธํ์๋ค. ACI ์ฅ์์๋ ๋นํ๊ณผ ํจ๊ป ์ผ์ฆ ํ์ง์์ ํ์ฑ ์ฐ์์ ์ฆ๊ฐ๊ฐ ํ์ธ๋์๋ค. ์ ๋งฅ ์ฒ ๋ถ ํฌ์ฌ 3์ผ ๋ค, ํ์์ ์์น์๋ ๋ณํ๊ฐ ์์์ผ๋, ๊ฐ ๋ฐ ํ์ฒญ์์ hepcidin ๋๋๊ฐ ์ฆ๊ฐํ์๊ณ , ๊ฐ์์์ ferritin ์ฆ๊ฐ๋ ํ์ธ๋์๋ค. ์ฒ ๋ถ ํฌ์ฝ์ ๊ฐ์์ ROS-generating NADPH oxidase-2 (NOX-2), NOX-4 ๋ฐ superoxide dismutase (SOD)์ ์ฆ๊ฐ๋ฅผ ์ ๋ฐํ์๋ค. ACI ์ฅ์ ๊ฐ์์ interleukin-6/signal transducer and activator of transcription-3 (IL-6/STAT-3) ๊ฒฝ๋ก์ bone morphogenetic protein/Sma mothers against decapentaplegic (BMP/SMAD) ๊ฒฝ๋ก ํ์ฑํ๊ฐ ํ์ธ๋์์ผ๋ฉฐ, ์ ๋งฅ ์ฒ ๋ถ ํฌ์ฌ๋ IL-6์ ์ฆ๊ฐ ์์ด ACI ์กฐ๊ฑด ํ์์ ํ์ฑํ ๋์ด ์๋ SMAD1/5์ STAT-3๋ฅผ ๋ ํ์ฑํ์์ผฐ๋ค. ์ฒ ์ ์ฒ๋ฆฌํ์ ๋ HepG2 ์ธํฌ์์๋ SMAD1/5์ STAT-3๊ฐ ๋ชจ๋ ํ์ฑํ ๋์์ผ๋ฉฐ, ์๊ฐ์ญ RNAs (short interfering RNAs, siRNAs)๋ฅผ ์ด์ฉํ STAT-3์ SMAD1/5์ knockdown์ ์ํํ์ ๋ ์ฒ ์ฒ๋ฆฌ๋ก ์ธํ hepcidin ์ ์ฌ ์ฆ๊ฐ ์ ๋๊ฐ ์ต์ ๋จ์ ํ์ธํ์๋ค. ์ ๋งฅ ์ฒ ๋ถ ํฌ์ฌ๋ ์ ์ฅ์์ EPO mRNA ๋ฐํ๋์ ๊ฐ์์์ผฐ์ผ๋ฉฐ, ์ด๋ ํ์ฒญ์์์ ERFE ๋๋ ๊ฐ์์ ๋๋ฐ๋์๋ค. ๊ฒฐ๋ก ์ ์ผ๋ก, ACI ์ฅ ๋ชจ๋ธ์์ ์ ๋งฅ ์ฒ ๋ถ์ ํฌ์ฌํ๊ณ 3์ผ ๋ค ํ์์ ์์น๊ฐ ํธ์ ๋์ง ์์๋๋ฐ, ์ด๋ ๋ง์ฑ ์ผ์ฆ ์ํ์์ ์ฆ๊ฐํด ์๋ hepcidin์ด ์ฒ ๋ถ ํฌ์ฝ์ผ๋ก ์ธํด ๋ ์ฆ๊ฐํ ๊ฒ๊ณผ ์ฐ๊ด๋์ด ์์ ์ ์๋ค. ์ค์ ๋ก ์ฒ ๋ถ ํฌ์ฝ ํ ๊ฐ์์ hepcidin ๋ฐ ferritin์ ์ ์ํ ์ฆ๊ฐ๊ฐ ํ์ธ๋์๋ค. ์ฒ ๋ถ ํฌ์ฝ ํ hepcidin์ ๋ฐํ ์ฆ๊ฐ๋ SMAD1/5 ์ธ์ STAT-3 ๊ด๋ จ ๊ฒฝ๋ก์ ํ์ฑํ์๋ ๊ด๋ จ์ด ์์์ ๊ด์ฐฐํ ์ ์์๋๋ฐ, ์ฒ ๋ถ ํฌ์ฌ๋ก ์ฐํ ์คํธ๋ ์ค ์งํ๋ค์ด ์ฆ๊ฐํ ๊ฒ๊ณผ ์ฐ๊ด์ฑ์ด ์์ ๊ฒ์ผ๋ก ์๊ฐ๋๋ค. ์ฒ ๋ถ ํฌ์ฝ ํ ์ ์ฅ EPO ๋ฐํ ๋ฐ ํ์ฒญ ERFE ๋๋๊ฐ ๋์์ ๊ฐ์ํ๋ ๊ฒ์ ACI ์กฐ๊ฑด ํ์์ ์ถฉ๋ถํ ์ฒ ๋ถ ๋ณด์ถฉ์๋ ๋ถ๊ตฌํ๊ณ ํจ๊ณผ์ ์ธ ์กฐํ ์์ฉ์ ๋ฐฉํดํ๋ ์ ํ๊ตฌ ์กฐ์ ์ธ์๋ค์ ๋ณต์กํ ์ํธ์์ฉ์ด ๋ฐ์ํจ์ ๋ณด์ฌ์ค๋ค. ์ด๋ฌํ ๊ฒฐ๊ณผ๋ค์ ๊ณ ๋ คํ ๋ ๋ง์ฑ ์ผ์ฆ ์ํ์์ ์ ๋งฅ ์ฒ ๋ถ์ ํฌ์ฝ์ผ๋ก ๋นํ์ ํจ์จ์ ์ผ๋ก ์น๋ฃํ๊ธฐ ์ํด์๋ hepcidin๊ณผ EPO ์กฐ์ ์ ํจ๊ป ๊ณ ๋ คํ๋ ๊ฒ์ด ๋์์ด ๋ ๊ฒ์ผ๋ก ์๊ฐํ๋ค.
Anemia of chronic inflammation (ACI), also known as anemia of chronic disease, is the second most frequent form of anemia in hospitalized patients and a harbinger of adverse health outcomes. Hepcidin, the master regulator of iron homeostasis, is expressed mainly in the liver and induces the degradation of ferroportin, the sole iron exporter. Chronic inflammatory conditions lead to an increase in the levels of hepcidin, resulting in a sequestration of iron inside cells in the form of ferritin, and this hinders iron utilization for erythropoiesis despite sufficient iron stores in the body. However, anemia is often clinically treated with iron supplementation, regardless of the underlying cause, with varying results in patients with ACI. Changes in hepcidin levels and activity in ACI patients have not been fully elucidated, and understanding them may provide new insights for planning treatment strategies. Thus, the primary aim of this study was to establish an animal model of ACI that resembled clinical ACI and use it to investigate changes in hepcidin and upstream regulatory pathways in the liver after intravenous (IV) iron supplementation. Additionally, we examined whether oxidative stress and concomitant changes in the major erythropoiesis-stimulating pathways involving erythropoietin (EPO) and erythroferrone (ERFE), was induced by iron supplementation. We also aimed to identify the role of signaling pathways upstream of hepcidin in HepG2 cells treated with iron using short interfering RNAs. ACI was induced in rats by intraperitoneal administration of Complete Freundโs Adjuvant (CFA, 0.2 mg in oil, 3 times/2 weeks). Male Sprague Dawley rats (n = 30) were randomly assigned to 3 groups: control-saline (n = 10), CFA-saline (n = 10), and CFA-IV iron (n = 10). Rats showing a decline in hemoglobin (Hb) levels >2 g/dL from baseline at 2 weeks after CFA administration were designated as ACI rats. ACI rats received iron (20 mg/kg of iron isomaltoside, CFA-IV iron) or vehicle (CFA-saline) intravenously. Three days after which changes in hematologic parameters, inflammatory cytokine levels, iron profiles, expression of proteins involved in signaling pathways upstream of hepcidin transcription, and iron metabolism gene expression were evaluated in the liver. ACI rats with anemia showed a concomitant increase in the expression of inflammatory mediators (i.e., interleukin [IL]-1ฮฒ, IL-6, tumor necrosis factor-ฮฑ [TNF-ฮฑ]) and reactive oxygen species (ROS). Three days after IV iron administration, Hb levels in ACI rats did not fully recover to the corresponding baseline values. Hepcidin levels in the liver of ACI rats were upregulated with a concomitant increase in ferritin levels in the liver compared to those in CFA-saline rats. Iron supplementation also induced an increase in ROS-generating NADPH oxidase (NOX)-2, NOX-4, and superoxide dismutase in the liver compared to those in CFA-saline rats. In ACI rats, activity of the IL-6/signal transducer and activator of transcription-3 (IL-6/STAT-3) pathway and the bone morphogenetic protein/Sma mothers against decapentaplegic (BMP/SMAD) pathway were increased in the liver compared to those in vehicle treated rats. IV iron supplementation further increased SMAD1/5 phosphorylation and STAT-3 phosphorylation in CFA-IV iron rats compared to those in CFA-saline rats, while there was no difference in IL-6 expression between both groups. Iron caused phosphorylation of STAT-3 and SMAD1/5 in HepG2 cells, and knockdown of STAT-3 and SMAD1/5 using short interfering RNAs in HepG2 cells was found to be associated with diminished iron-induced upregulation in hepcidin transcription compared to that in the corresponding control cells. IV iron supplementation was also associated with decrease in EPO mRNA expression in the kidney and serum ERFE concentration in CFA-IV iron rats compared to those in control-saline rats. In conclusion, in this rat model of ACI, IV iron administration did not effectively ameliorate anemia within 3 days despite an increase in ferritin levels in the liver, which might be related to an additional increase in hepcidin levels that was already upregulated under chronic inflammatory conditions. Both STAT-3 and SMAD1/5 phosphorylation were found to be associated with hepcidin upregulation after IV iron treatment, and this is potentially linked to iron-induced oxidative stress. Concurrent reductions in renal EPO expression and serum ERFE activity after IV iron supplementation imply a complex interplay between erythroid regulatory molecules that hinders effective erythropoiesis despite sufficient iron supplementation under ACI conditions. These results provide primary evidence regarding the importance of hepcidin regulation and EPO availability in increasing the efficacy of IV iron supplementation for the treatment of anemia under chronic inflammatory conditions.open๋ฐ
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ผ๋ฌธ (์์ฌ)-- ์์ธ๋ํ๊ต ํ๊ฒฝ๋ํ์ : ํ๊ฒฝ๋ํ์ ํ๊ฒฝ๊ณํํ๊ณผ ๋์๋ฐ์ง์ญ๊ณํ ์ ๊ณต, 2016. 2. ๊น๊ด์ค.๋ณธ ์ฐ๊ตฌ๋ ๊ณต๋์ฒด์ ํด์ฒด, ๋์ ๋ฌธ์ ์ ๋ฐ์, ์ ํต์ ๋์ ๊ด๋ฆฌ ๋ฐฉ์์ ๋ณํ ๋ฑ์ ๋์์ผ๋ก ๋ฑ์ฅํ ๋ง์๊ณต๋์ฒด๋ฅผ ๋ค๋ฃฌ๋ค. ๋ง์๊ณต๋์ฒด๋ ๊ทธ ๊ฒ์ด ๊ฐ์ง ๊ธฐ๋ํจ๊ณผ์ ๊ฒฐ๊ณผ์ ์ธ ์ธก๋ฉด์์ ์ฃผ๋ชฉ๋ฐ์์๋ค. ๋ฐ๋ฉด ๋ง์๊ณต๋์ฒด๊ฐ ์ด๋ฃจ์ด์ง๋ ๊ณผ์ ์ ์๋์ ์ผ๋ก ๋ง์ ๊ด์ฌ์ ๋ฐ์ง ๋ชปํด์๋ค. ๊ทธ๋ฌ๋ ๋ง์๊ณต๋์ฒด๋ ๊ทธ ์์ฒด๊ฐ ๊ฒฐ๊ณผ์ด๊ธฐ ๋ณด๋ค๋ ์ด๋ฃจ์ด์ง๋ ๊ณผ์ ์ด ์์ฐ์ค๋ฝ๊ฒ ๊ฒฐ๊ณผ๋ฅผ ์๋ฐํ๋ค. ๋ณธ ์ฐ๊ตฌ๋ ๊ฒฝ๊ธฐ๋ ํ์์์ ์๋๋ฌด๋ง์๊ณต๋์ฒด๋ฅผ ์ฌ๋ก๋ก ๋ง์๊ณต๋์ฒด์ ์๊ฐ๋ณ ์ ๊ฐ๊ณผ์ ๊ณผ ํ์ฌ ํ๋์์ ๋๋ฌ๋๋ ์ฐธ์ฌ์ ํํ์ ํน์ง, ๊ทธ๋ฆฌ๊ณ ๊ตฌ์กฐ์ ๋ํด ๋ค๋ฃจ๊ณ ์ ํ๋ค. ๋ง๋ถ์ฌ ํ์ฌ์ ์๋๋ฌด ๋ง์๊ณต๋์ฒด๊ฐ ์ด๋ ํ ๋์ ๊ณํ์ ํจ์๋ฅผ ์ ์ํ๋ ์ง ๋ฐ๊ฒฌํด๋ณด๋ ค๊ณ ํ๋ค.
๋จผ์ ์๋๋ฌด๋ง์๊ณต๋์ฒด ์ฃผ๋ฏผ ์ง๋จ ๊ตฌ์ฑ์ ๋ณํ๊ฐ ์๊ธฐ์ ๊ด๊ณ์์ด ๋ง์์ ๊ฐ์
ํ๋ ์ ์ฑ
์ ๋ณํ๋ก ์ด์ด์ง์ ๋ฐ๊ฒฌํ์ฌ ์ด๋ฅผ ์ค์ฌ์ผ๋ก ์ ๊ฐ๊ณผ์ ์ ๊ธฐ์ ํ์๋ค. 1๊ธฐ์๋ ํ์ํ์ต์๋ฒ๋ง์ ์ฌ์
์ ์ ์ ํตํด ์ค๊ฐ์ง์๋จ์ฒด๊ฐ ๋ง์๊ณต๋์ฒด๋ฅผ ํ์ฑ์ ์ถ์งํ๋ค. ์ผ๋ถ ๋ง์ ์ฃผ๋ฏผ์ด ๋ฆฌ๋๋ก์ ๋ง์์ง๋์๋ก ์ก์ฑ๋๋ค. 2๊ธฐ๋ ์ฌ์
์ง์์ด ์ข
๋ฃ๋์ด 1๊ธฐ์ ์ฃผ์ถ์ผ๋ก ์ฐธ์ฌํ ์ฃผ๋ฏผ์ด ๋ชจ๋ ํ๋์ ๊ทธ๋ง๋๋ ๋์ ๋ง์ ๊ฐ์ฌ ์ฃผ๋ฏผ ๋ช๋ช์ ์ค์ฌ์ผ๋ก ํ๋์ด ์ด๋ฃจ์ด ์ก๋ค. ์ ์ฑ
์ ์ง์์ ์์๋ค. 3๊ธฐ๋ 2๊ธฐ์ ์ฐธ์ฌํ ์ฃผ๋ฏผ์ ํ๋์ด ์ด๋ ค์์ ๋ด์ฐฉํ์ฌ 1๊ธฐ์ ์ฐธ์ฌํ ๋ง์ ์ง๋์ ์ฃผ๋ฏผ ๊ทธ๋ฃน์ ์ผ๋ถ๊ฐ ๋ณต๊ทํ์๋ค. ์ด๋ค์ ์ ๊ทน์ ์ผ๋ก ๋ง์ ์ฌ์
๊ณต๋ชจ์ ์ง์ํ์ฌ ๋ง์๊ณต๋์ฒด ํ๋์ ์ง์ํ๋ ค๊ณ ํ๋ค. 4๊ธฐ๋ ์ง์ ์ฌ์
์ ํตํด ํ์ฑ๋ ์ฃผ๋ฏผ ์๋ชจ์์ด ๊ธฐ์กด์ ๋ง์๊ณต๋์ฒด ์ฐธ์ฌ ์ง๋จ์ ํฉ๋ฅํ๊ฒ ๋์ด ๋ง์๊ณต๋์ฒด์ ๊ท๋ชจ๊ฐ ํ์ฅ๋ ์๊ธฐ์ด๋ค.
๋ค์์ผ๋ก๋ ๋ง์ํ์์ ์ถ์ , ์๋์ง ์๋ฑํ์ฌ๋ฅผ ๊ด์ฐฐํ๊ณ ๊ธฐ์ ํ์์ผ๋ฉฐ, ๋ง์ ์ฃผ๋ฏผ์ ์ฐธ์ฌ์ ๋ํ ์ธ ๊ฐ์ง ํน์ง์ ๋ถ์ํ์๋ค. ๋จผ์ ๋ง์๊ณต๋์ฒด๋ ๋ง์์์ ์ ์ฑ
์ ์ง์์ผ๋ก ๋ง์ ํ๊ฒฝ ๊ฐ์ ํ๋์ ํ๋ ํน์ ๊ทธ์ ๊ด์ฌ์ด ์๋, ์ผ๋ถ์ ์ฃผ๋ฏผ์ด ์ฐธ์ฌํ๋ ๋ง์ ์์ง๋จ์ด๋ค. ๋ง์๊ณต๋์ฒด๊ฐ ๋ณธ๋ ๋ปํ๋ ๋ฐ์ ๋ฌ๋ฆฌ ๋ง์ ๋ฒ์์ ์ฃผ๋ฏผ ์ ์ฒด๋ฅผ ํฌ๊ดํ์ง ์๋๋ค๊ณ ๋ณด์ธ๋ค. ๊ทธ๋ฌ๋ฏ๋ก ์๋๋ฌด ์ํํธ์ ๊ฑฐ์ฃผ๋ฏผ์ ๋ง์๊ณต๋์ฒด ํ๋์ ํ๋ ๋ง์๊ณต๋์ฒด ๊ตฌ์ฑ์๊ณผ ๊ทธ๋ ์ง ์์ ์ฃผ๋ฏผ์ผ๋ก ๊ตฌ๋ถํด ๋ณผ ์ ์๋ค. ๋ ๋ฒ์งธ ๋ง์๊ณต๋์ฒด ํ๋์ ๊ด์ฐฐํ ๊ฒฐ๊ณผ ํ๋์ ํ์ฌ์์ ๊ตฌ์ฑ์๋ค์ ๊ฐ๋ณ์ ์ผ๋ก ๋ค๋ฅธ ์ญํ ์ ๋งก๊ณ ์์๊ณ , ์ด๋ฌํ ์ญํ ์ ๋ค๋ฅธ ํ์ฌ์์๋ ๋ฐ๋ณต์ ์ผ๋ก ๋ํ๋ฌ๋ค. ํ๋์์ ์ง๋จ ๋ด๋ถ ์ญํ ๋ถ๋ด์ด ์๋ค๊ณ ๋ณด์์ผ๋, ๋ช
์์ ์ผ๋ก ์ ํด์ง ๊ฒ์ ์๋๋ค. ์ด๋ ์ผ์ ์์๋ฅผ ์ํ์ฌ ๊ตฌ์ฑ์ ๊ฐ ์ญํ ์ด ๋ถํ(ๅๅ)๋จ์ ์๋ฏธํ๋ค. ์ธ ๋ฒ์งธ ๋ง์๊ณต๋์ฒด ๊ตฌ์ฑ์์ ๋ง์๊ณต๋์ฒด์์ ํ์์ง๋จ์ ๊ตฌ์ฑํ๊ณ ์๋ค. ๋ณธ ํ์์ง๋จ์ ์ญํ , ํน์ง, ์์ฌ๊ฒฐ์ ์์ ์ํฅ๋ ฅ์ด ๋ชจ๋ ์์ดํ๊ฒ ๋ํ๋ฌ๋ค.
์ด์ ๋๋ถ์ด ์ฐ๊ตฌ์๋ ๋ง์๊ณต๋์ฒด ํ๋์์ ์ฃผ๋ฏผ์ ์ฐธ์ฌ๊ฐ ๊ฐ์ธ๋ง๋ค ๋ค๋ฅด๊ฒ ๋ํ๋จ์ ์ฃผ๋ชฉํ์๋ค. ํ์๊ฐ ๋๋๋ฌ์ง๊ฒ ๊ตฌ๋ถ๋์ด ๋ํ๋ ์ฃผ๋ฏผ์ ๋์์ผ๋ก ์ด๋ค์ ์ฐธ์ฌ๋ฅผ ์ดํดํ๊ณ ์ ์ฌ์ธต ๋ฉด๋ด์ ์งํํ์๋ค. ๊ทธ ๊ฒฐ๊ณผ ํน์ ํ ์ญํ ์ ํ๋ ๊ฐ์ธ์ด ๋ง์๊ณต๋์ฒด ํ๋ ์ฐธ์ฌ์ ๋ถ์ฌํ๋ ์๋ฏธ๋ ๋ชจ๋ ๋ฌ๋๋๋ฐ, ์ด๋ ๋ง์๊ณต๋์ฒด์ ์ฐธ์ฌ์ ๋ ๋ฐ ๋ด๋ถ์ ์ญํ ๊ณผ ๊ด๊ณ๊ฐ ์๋ค๊ณ ๋ณด์๋ค. ๊ทธ๋ผ์๋ ๋ง์๊ณต๋์ฒด์ ๊ตฌ์ฑ์์ ๊ณตํต์ ์ผ๋ก ๋ง์ํ๋์์ ์ฐธ์ฌ๋ฅผ ๋ด์ฌ๋ก์ ์๊ฐํ๊ณ ์์์ ๋ฐ๊ฒฌํ์๋ค.
์์ ๊ฐ์ด ๋ง์ ํ๋๊ณผ ์ฌ์ธต ๋ฉด๋ด์์ ๋์ถ๋ ํน์ง์ ๋ฐํ์ผ๋ก ์ฃผ๋ฏผ์ ์ฐธ์ฌ๋ฅผ ์๋กญ๊ฒ ๊ตฌ์กฐํํ์๋ค. ๋ง์๊ณต๋์ฒด ์ฐธ์ฌํ์์ ๋งก์ ์ญํ ์ ๊ธฐ์ค์ผ๋ก ์ผ์ ์ฃผ๋ฏผ ์ง๋จ์ ๋ํ์, ์ค๋ฌด์, ์นํธ์, ์ด์ฉ์, ๋น์ฐธ์ฌ์์ ๋ค์ฏ ์ธต์๋ก ๊ตฌ๋ถํ๋ค. ๋ํ์๋ ๋ง์ํ๊ต์ฅ, ์๋์ง์ ์ฝ๋ง์์์์ฅ์ผ๋ก ์ด๊ธฐ ๋จ๊ณ ๋ง์ ํ๋์ ์ ์ ๋ฐ ๋ฐ์ํ๋ฉฐ, ์ค์ํ ์์ฌ๊ฒฐ์ ์ ๋ด๋ฆฐ๋ค. ์ค๋ฌด์๋ ์ฝ๋๋ค์ดํฐ์ ๋ถ๊ณผ์ฅ์ผ๋ก ์ ์๋ ์ฌ์
์ ๋ฐํ์ผ๋ก ์ค์ ํ๋์ ๊ธฐํํ๊ณ ์ด์ํ๋ ์ง๋จ์ผ๋ก ์ค๋ฌด๋ฅผ ๋ด๋นํ๋ค. ์นํธ์๋ ๋ด์ฌ์์ ๋ง์๊ฐ์ฌ๋ก ๋ด์ฌํ๋์ ํตํด ๋
ธ๋๋ ฅ์ ์ ๊ณตํ๋ฉฐ, ์ค๋ฌด์ ์ง๋จ์ ํ๋์ ์ง์งํ๋ค. ์ด์ฉ์๋ ์ผํ์ ์ผ๋ก ๋ง์๊ณต๋์ฒด ํ๋์ ์ฐธ๊ฐํ๊ฑฐ๋, ๋ง์๊ณต๋์ฒด์ ์ํด ๊ธฐํ๋ ํ๋์ ์ด์ฉํ๋ ์ํํธ ๊ฑฐ์ฃผ๋ฏผ์ด๋ค. ๊ฐ ์ง๋จ์ ๊ตฌ์ฑ์ ์, ๋ง์๊ณต๋์ฒด์์์ ์ญํ , ์์ฌ๊ฒฐ์ ์ ๋ฏธ์น๋ ์ํฅ๋ ฅ์ ์ ๋, ์ค์ ํ์ ๋ฑ์์ ์ฐจ์ด๋ฅผ ๋ณด์ธ๋ค.
ํํธ ์ ์ฑ
์์ ๋ง์๊ณต๋์ฒด๋ ๋ค์ํ ์๋ฏธ๋ฅผ ํฌ๊ดํ๋ค. ํฌ๊ฒ ๋ณธ๋์ ์๋ฏธ์ธ ๊ตฌ์ฑ์์ ํธํ๊ด๊ณ ์ถ๊ตฌ๋ฟ๋ง ์๋๋ผ ๋ง์ ํ๊ฒฝ ๊ฐ์ ์ ๋ปํ๋ ๋ง์๋ง๋ค๊ธฐ์ ์ํฅ์์ ๋์ ๊ด๋ฆฌ ๋ฐ ์ฃผ๋ฏผ์ฐธ์ฌ ๊ฑฐ๋ฒ๋์ค๋ฅผ ๋ปํ๋ ์๋ฏธ๋ก์๋ ์ฌ์ฉ๋๋ค. ๊ทธ๋ฌ๋ฏ๋ก ํ์ฌ ๋ง์๊ณต๋์ฒด ์ฌ์
์ ์์ฐ ์ง์ ๋์์ด ๋๋ ๋ง์๊ณต๋์ฒด์ ํ์ฑํ๋ฅผ ๋
ผํ๊ธฐ ์ํด์๋ ๊ทธ ๊ฒ์ด ํฌ๊ดํ๋ ์๋ฏธ๋ฅผ ๊ตฌ๋ถํ์ฌ ๊ฐ๊ฐ์ ๋ง๋ ๋ชฉ์ ์ด ๋ฌ์ฑ๋๋ ์ง ํ์ธํจ์ด ํ์ํ๋ค.
๋ง์์์ ๋ง์๊ณต๋์ฒด์ ํ์ฑํ๋ ํธํ๊ด๊ณ ํ์ฑ๊ณผ ๋ง์๋ง๋ค๊ธฐ ๋ฌ์ฑ์ ์ธก๋ฉด์์ ์ธ ๊ฐ์ง๋ก ๊ฐ๋
ํํ์ฌ ์ดํด๋ณด๋ ค๊ณ ํ๋ค. ์ฒซ ๋ฒ์งธ๋ ๊ณต๋์ฒด ๋ด๋ถ์์์ ํ์ฑํ, ๋ ๋ฒ์งธ๋ ๊ณต๋์ฒด ๊ท๋ชจ์ ํ์ฅ์ ํตํ ํ์ฑํ, ์ธ ๋ฒ์งธ๋ ๋น๊ตฌ์ฑ์ ๊ฑฐ์ฃผ๋ฏผ ์ง๋จ์์์ ๋ฌ์ฑ์ ํตํ ํ์ฑํ์ด๋ค.
ํธํ๊ด๊ณ ์ธก๋ฉด์์ ๋ง์๊ณต๋์ฒด๋ ๊ตฌ์ฑ์ ์ฌ์ด์ ํธํ์ฑ์ ํ์ฑํ๋ค. ๊ทธ๋ฌ๋ ๊ท๋ชจ์ ํ์ฅ์ ํตํ ํธํ์ฑ์ ํ์ฑํ๋ ์ ์ด๋ฃจ์ด์ง์ง ์์ผ๋ฉฐ, ๋น๊ตฌ์ฑ์์ ๊ฒฝ์ฐ ์ด๋ฒคํธ์ฑ ์ผํ์ ์ฐธ๊ฐ๋ก ์ฐธ์ฌ๊ฐ ๊ธฐํ๋๋ค๋ ์ ์์ ํธํ๊ด๊ณ ํ์ฑ์ ์ด๋ ค์์ ๊ฒช๋๋ค.
์ด์ ๋ง์ ๋ฌธ์ ํด๊ฒฐ์ ์ธก๋ฉด์์ ๋ณด์. ๋ง์๊ณต๋์ฒด์ ๊ตฌ์ฑ์์ ๋ง์๋ง๋ค๊ธฐ๋ฅผ ํ๋ค. ๊ธฐ์กด์๋ ๋ง์๋ง๋ค๊ธฐ์ ํ์ฑํ์ ๋ํด ๋๊ฐ ๋ง์ ํ๋์์ ๋ฆฌ๋์ ์ค์์ฑ์ ๊ฐ์กฐํด ์๋ค. ๊ทธ๋ฌ๋ ๋ง์์์๋ ๋ฆฌ๋๋ฟ๋ง ์๋๋ผ ๋ฆฌ๋์ ์ง๋๋ฅผ ๋ฐ๋ฅด๋ ์ค๋ฌด์์ ์นํธ์ ์ง๋จ์ ํ๋ก์์ญ์ด ๋ง์๊ณต๋์ฒด ํ๋์ ๋ง์ ๊ธฐ์ฌ๋ฅผ ํ๊ณ ์์๋ค. ํํธ ๋ง์๊ณต๋์ฒด ๊ท๋ชจ์ ํ์ฅ์ ํตํ ๋ง์๋ง๋ค๊ธฐ ํ์ฑํ๋ ์์ ์ฌ๋ก์ฒ๋ผ ์ฝ๊ฒ ๋ฌ์ฑ๋์ง ์๋๋ค. ๋น๊ตฌ์ฑ์์ ๋ณํ๋ฅผ ํตํ ๋ง์๋ง๋ค๊ธฐ ํ์ฑํ ๋ํ ์ผํ์ ์ฐธ๊ฐ์ ๋จธ๋ฌด๋ฅด๋ ๊ฒฝ์ฐ๊ฐ ๋ง์ ๋ฌ์ฑ๋๊ธฐ ์ด๋ ต๋ค๊ณ ๋ณด์ธ๋ค.
๋ง์ง๋ง์ผ๋ก ์ฃผ๋ฏผ ์ฐธ์ฌ๋ฅผ ์ด๋ฃจ๋ ๊ฑฐ๋ฒ๋์ค์ ์ถ์ผ๋ก์ ๋ง์๊ณต๋์ฒด๊ฐ ์ง์ํ๊ณ ์ฑ์ฅํ๋ ์ง ํ์ฌ ์ํฉ์ ๋ฐํ์ผ๋ก ์ดํดํ๋ ค๊ณ ํ๋ค. ๋ง์๊ณต๋์ฒด๊ฐ ์๋ฐ์ ์ผ๋ก ํ๋ํ๋ ์ฃผ๋ฏผ์, ์ฃผ๋ฏผ์ ์๋ฏผ์ฑ ํฅ์์ ์ด๋ฃจ์ด๋ด๋๊ฐ. ๋ง์ ์ฃผ๋ฏผ์ ๋ง์๊ณต๋์ฒดํ๋ ์ฐธ์ฌ๋ฅผ ๋ด์ฌ๋ก์ ์ธ์ํ๋ค. ๋ด์ฌ๋ ๊ทธ ๊ฒ์ ๋์์ด ์กด์ฌํ ๋ ์ด๋ฃจ์ด์ง๋ค. ๊ทธ๋ฌ๋ฏ๋ก ๋ง์ ์ฃผ๋ฏผ์ ๋ง์ ์ฌ์
์ ์๋ฐํ ๋ง์๊ณต๋์ฒด ํ๋์ ๋ง์์ ์ํ ํฌ์, ํ์ ์ ๊ด์ ์์ ์ดํดํ๋ค๊ณ ๋ณด์ธ๋ค. ๋ค์ ๋งํ๋ฉด ๋ด์ฌ์ ๋์์ผ๋ก์ ์์ฐ ์ง์์ด ์ข
๋ฃ๋ ๊ฒฝ์ฐ ์ฃผ๋ฏผ์ ํ๋์ ์์ฐ์ค๋ฝ๊ฒ ๋์ ๋งบ๊ธฐ๋ ํ๋ค. ์๋๋ฌด๋ง์์์๋ ๋ง์ ๋ด ๊ฐ๋ฑ, ์ญ๋์ ๋ถ์กฑ ๋ฑ ๋๋๋ผ์ง๋ ๋ถ๋ช
ํ ๋ฌธ์ ๋ ์กด์ฌํ์ง ์์์ผ๋ฉฐ, ํ๋์ ์ข
๋ฃ๋ ์์ฐ์ค๋ฌ์ด ์์์ผ๋ก ์ดํด๋์๋ค. ๊ทธ๋ผ์๋ ๋ง์๊ณต๋์ฒด ํ๋์ด ์ง์๋๋ ๋์ธ์ ๋ง์๊ณต๋์ฒด ํ๋์ด ์ฐธ์ฌ์์ ๊ฐ์ธ์ ์ฑ์ฅ๊ณผ ์ดํด๊ด๊ณ์ ๋ง์ ์ํฅ์ ์ค ๋๋ผ๊ณ ๋ณด์ธ๋ค.
๋์๊ฐ ๋ณธ ์ฐ๊ตฌ๋ ๋ง์๊ณต๋์ฒด๋ ์๋ฏธ๊ฐ ๋ช
๋ฃํ๊ฒ ๊ตฌ๋ถ๋์ด ์ดํด๋ ํ์๊ฐ ์์ผ๋ฉฐ, ๋ง์๊ณต๋์ฒด ํ๋์์ ์ฃผ๋ฏผ์ ์ง์์ ์ธ ์ฐธ์ฌ๋ฅผ ์ํด์๋ ์ผํ์ ์ฑ๊ฒฉ์ ์ฐธ๊ฐ๋ ํจ๊ณผ๋ฅผ ๊ฑฐ๋๊ธฐ ์ด๋ ต๋ค๋ ์ ์ ๋งํ๋ค. ๋ํ ๋ง์๊ณต๋์ฒด ๋ฆฌ๋ ์ธ ์ค๋ฌด์ยท์นํธ์ ๋ฑ ๋ฆฌ๋๊ฐ ์๋ ์ฃผ๋ฏผ์ ์ญํ ๊ณผ ๊ทธ๋ค์ ์ค์์ฑ์ ์ฃผ๋ชฉํ ํ์๊ฐ ์์์ ๋ฐํ๋ค. ๋๋ถ์ด ์ฃผ๋ฏผ์ ๋ง์๊ณต๋์ฒด ํ๋ ์ค๋จ์ ํน์ ํ ๊ณ๊ธฐ์ ๊ธฐ์ธํ์ง ์๊ณ ์ง์ ์ฌ์
๊ธฐ๊ฐ์ ๋ง์ถ ์์ฐ์ค๋ฌ์ด ํ๋์ด๋ผ๋ ์ ์ ๋ค๋ฃฌ ๋ฐ์ ๋ณธ ์ฐ๊ตฌ์ ์๋ฏธ๊ฐ ์๋ค.โ
. ์๋ก 1
1. ์ฐ๊ตฌ์ ๋ฐฐ๊ฒฝ ๋ฐ ๋ชฉ์ 1
2. ์ฐ๊ตฌ์ ๋์์ง 3
1) ์๋๋ฌด์ํํธ 3
2) ์๋๋ฌด๋ง์๊ณต๋์ฒด 6
3. ์ฐ๊ตฌ์ ๋ฐฉ๋ฒ 10
1) ์ฐธ์ฌ๊ด์ฐฐ 10
2) ์ฌ์ธต๋ฉด๋ด 12
โ
ก. ์ ํ์ฐ๊ตฌ ๊ฒํ 14
1. ๋ง์๊ณต๋์ฒด ๊ฐ๋
์ ํผ๋ 14
1) ๊ณต๋์ฒด๋ ๋ฌด์์ธ๊ฐ 15
2) ๋ง์์ ๋ฌด์์ธ๊ฐ 18
3) ๋ง์๊ณต๋์ฒด์ ์๋ฏธ 19
2. ํ ์ ์ฑ
์์์ ๋ง์๊ณต๋์ฒด 20
1) ํธํ๊ด๊ณ์ ํ์ฑ 20
2) ๋ง์๋ง๋ค๊ธฐ 22
3) ์ฃผ๋ฏผ์ฐธ์ฌ๊ฑฐ๋ฒ๋์ค 24
3. ์ฐธ์ฌ์ ๋ด์ฌ์ ๊ฐ๋
25
1) ์ฐธ์ฌ์ ๊ฐ๋
๊ณผ ๊ตฌ๋ถ 25
2) ๋ด์ฌ์ ๊ฐ๋
27
โ
ข. ์๋๋ฌด ๋ง์๊ณต๋์ฒด์ ์ ๊ฐ๊ณผ์ 29
1. ์๋๋ฌด ๋ง์๊ณต๋์ฒด์ ์ ๊ฐ๊ณผ์ 31
1) 1๊ธฐ : ์ ๋ถ ์ฃผ๋์ ๋ง์๊ณต๋์ฒด ์ก์ฑ๊ณผ ๋ง์์ง๋์ ์ฃผ๋ฏผ 31
2) 2๊ธฐ : ์๋ฐ์ ๋ง์ํ๊ต ์ด์๊ณผ ๋ง์๊ฐ์ฌ ์ฃผ๋ฏผ 38
3) 3๊ธฐ : ๋ง์์ง๋์ ์ฃผ๋ฏผ์ ๋ณต๊ท์ ์ง์์ฌ์
๊ณต๋ชจ 44
4) 4๊ธฐ : ์๋ก์ด ์ฃผ๋ฏผ ์ง๋จ์ ํ์ฑ๊ณผ ์ฐธ์ฌ 49
โ
ฃ. ์๋๋ฌด ๋ง์๊ณต๋์ฒด ์ฃผ๋ฏผ์ ์ฐธ์ฌ ํ์ 58
1-1. ์๋๋ฌด ๋ง์๊ณต๋์ฒด์ ์ฐธ์ฌ 58
1) ๋ง์ ํ์์ ์ฐธ์ฌ 58
2) ๋ง์ ์ถ์ ์ ์ฐธ์ฌ 60
3) ์๋์ง ์๋ฑํ์ฌ์ ์ฐธ์ฌ 65
1-2. ์๋๋ฌด ๋ง์๊ณต๋์ฒด ์ฃผ๋ฏผ์ ์ฐธ์ฌ 68
1) ์๋์ง์ ์ฝ๋ง์์์์ฅ๋ง์ํ๊ต ๊ต์ฅ ์๋ํ 68
2) ๋ง์ํ๊ต ์ฝ๋๋ค์ดํฐ ํ์ฝ๋ 72
3) ์๋์ง์ ์ฝ๋ง์ ์ฝ๋๋ค์ดํฐ ์ ์ ์
77
4) ๋ถ์นดํ ๋ด์ฌ์ ๊น๋์ 81
5) ๋ง์ํ๊ต ํ๋ก๊ทธ๋จ ์๊ฐ์ ๋ฐ์๋ฆผ 86
2. ์๋๋ฌด ๋ง์์์์ ์ฐธ์ฌ๊ตฌ์กฐ 89
1) ์๋๋ฌด ๋ง์๊ณต๋์ฒด ํ๋์ ํน์ง 89
2) ์ฃผ๋ฏผ์ ์ฐธ์ฌ๊ตฌ์กฐ 95
โ
ค. ์๋๋ฌด๋ง์ ์ฃผ๋ฏผ์ ์ฐธ์ฌ ํด์ 99
1. ์ ์ฑ
์์์ ์๋๋ฌด ๋ง์๊ณต๋์ฒด 99
1) ํธํ๊ด๊ณ ํ์ฑ 99
2) ์ปค๋ฎค๋ํฐ ํ๊ฒฝ์ ๊ฐ์ 104
3) ์ฃผ๋ฏผ์ฐธ์ฌ ๊ฑฐ๋ฒ๋์ค 109
โ
ฅ. ๊ฒฐ๋ก 111
1. ์ฐ๊ตฌ์ ์์ฝ ๋ฐ ๊ฒฐ๋ก 111
์ฐธ๊ณ ๋ฌธํ 115
Abstract 119Maste