• Journal of Yeungnam Medical Science
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• v.16 no.2
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• pp.181-192
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• 1999

Background: Nitric oxide, a vasodilator synthesized from L-arginine by vascular endothelial cells, accounts for the biological activity of endothelium derived relaxing factor. Previous studies demonstrated that nitric oxide inhibitor, $N^{\omega}$-Nitro-L-Arginine(NNA) diminished the hyperdynamic splanchnic and systemic circulation in portal hypertensive rats The present study was done to determine the role of nitric oxide in the development of hyperdynamic circulations in the prehepatic portal hypertensive rat model produced by partial portal vein ligation. Methods: The portal hypertensive rats were divided into water ingestion group and NNA ingestion group. After partial portal vein ligation, NNA ingestion group and water ingestion group received NNA 1mg/kg/day and plain water through the mouth for 14 days, respectively. Cardiac output, mean arterial pressure, organ blood flow and porto-systemic shunting were measured by radioisotope labeled microsphere methods. Vascular resistances were calculated by standard equation. Results: There were significant decreases in mean arterial pressure, increases in cardiac output and cardiac index, and decreases in total systemic and splanchnic vascular resistance in portal hypertensive rats compared to normal control group (p<0.01). Compared to the water ingestion group, significantly increased mean arterial pressure with decreased cardiac output and cardiac index were developed in the NNA ingestion group. Total systemic and splanchnic vascular resistance were significantly increased in the NNA ingestion group compared to water ingestion group (p<0.05). But, there was no significant difference in portal pressure between the two groups. Conclusion: The hemodynamic results of this study indicate that hyperdynamic circulation in prehepatic portal hypertensive rat mode1 was attenuated by ingestion of NNA. Nitric oxide may play an important role in the development of hyperdynamic circulation with splanchnic vasodilation in chronic portal hypertension.

• Childhood Kidney Diseases
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• v.11 no.1
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• pp.24-31
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• 2007

Purpose : Nitric oxide(NO) is a very potent vasodilator synthesized from L-arginine by endothelial cells. We investigated whether urinary NO excretion was altered in various renal diseases in children and whether urinary NO excretion could be used in predicting pathologic causes and fibrosis in renal diseases in children. Methods : We recruited 48 patients(32 minimal change nephrotic syndrome[MCNS] and 16 vesicoureteral reflux[VUR] patients from the pediatric renal clinic in Korea University Guro Hospital. We measured the concentration of nitrite$(NO_2)$ and nitrate$(NO_3)$ by Griess reaction and that of creatinine(Cr) by Jaffe method in randomized spot urines. We then analyzed the urinary$(NO_2+NO_3)/Cr$ ratios and compared the values between each patient group. Urinary $(NO_2+NO_3)/Cr$ ratios were also evaluated according to the recurrence and the degree of proteinuria at sampling in the MCNS group and compared according to the presence of renal scarring and the grade of reflux in the VUR group. Results : The ratios of urinary$(NO_2+NO_3)/Cr$ were significantly increased in the VUR and MCNS groups, as compared to the control group. In the MCNS group, a higher level of urine $(NO_2+NO_3)/Cr$ was observed In frequent relapse patients(relapse over four times within one year after first diagnosis) and the patients with severe proteinuria at sampling, respectively. The VUR group with renal scars also showed a higher level of urinary$(NO_2+NO_3)/Cr$ compared to that without scars. Conclusions : In summary, VUR may play a role in the pathogenesis of VUR and MCNS. NO also seems to affect proteinuria and renal scar formation. (J Korean Soc Pediatr Nephrol 2007;11:24-31)

• Journal of Yeungnam Medical Science
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• v.15 no.1
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• pp.55-66
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• 1998

Pathophysiological mechanism of hemorrhagic fever with renal syndrome (HFRS) is not fully understood. Major clinical findings of HFRS patients are widespread hemorrhage, acute renal failure and shock. Basic lesion is vascular injury with microvascular hemorrhage and relatively little inflammation. According to autopsy findings, renal medulla shows focal hemorrhage, tubular necrosis and interstitial mononuclear infiltrates. The predominant cell type in the renal and pulmonary interstitium is a fibroblast and it participates in the healing process at the injury site by secreting a large amount of extracellular matrix proteins. Cultured human lung fibroblasts and Mongolian gerbil fibroblasts were known to be good host cells for the hantaan virus. It is possible that not only the endothelial cell but also the fibroblast is a target of Hantaan virus and the fibroblast might be involved in the pathogenesis and the healing process in HFRS. Integrins are adhesion molecules, and act as receptors for many extracellular matrix proteins. Recently, there are many reports that cell surface integrins influence on some viral infections or reversely viruses influence on the expression of integrins. The ${\alpha}_5{\beta}_1$ integrin is a major receptor for the fibronectin which is an important extracellular matrix protein secreted by fibroblasts. In this study, the role of ${\alpha}_5{\beta}_1$ integrin in the infection of Hantaan virus was examined by using anti-${\alpha}_5{\beta}_1$, integrin, anti-${\alpha}_5$ integrin and anti-${\beta}_1$, integrin antibodies in chicken embryo fibroblasts (CEF) and Mongolian gerbil fibroblasts(MGF). The treatment of anti-${\alpha}_5{\beta}_1$, integrin antibody in CEF reduced the virion titers 26.8% and the amount of nucleocapsid N protein 32.6% when compared with control CEF. When MGF were treated with anti-${\alpha}_5$, anti-${\beta}_1$ and anti-${\alpha}_5{\beta}_1$ integrin antibodies, virion titers were reduced by 26.5%, 29.4% and 28.7% and the amount of nucleocapsid N protein were reduced by 65.2%, 59.7% and 72.6%. These results suggested that ${\alpha}_5{\beta}_1$ integrin might act as a receptor for the Hantaan virus or blocking of ${\alpha}_5{\beta}_1$ integrin influences on the viral replication in CEF and MGF. It is also possible that the blocking of only one subunit of integrin represents similar results in that of whole molecule.

• Clinical and Experimental Pediatrics
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• v.52 no.5
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• pp.594-602
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• 2009

Purpose : Transforming growth factor (TGF)-${\beta}1$ reportedly increases neuronal survival by inhibiting the induction of inducible nitric oxide synthase (NOS) in astrocytes and protecting neurons after excitotoxic injury. However, the neuroprotective mechanism of $TGF-{\beta}1$ on hypoxic-ischemic (HI) brain injury in neonatal rats is not clear. The aim of this study was to determine whether $TGF-{\beta}1$ has neuroprotective effects via a NO-mediated mechanism and N-methyl-D-aspartate (NMDA) receptor modulation on perinatal HI brain injury. Methods : Cortical cells were cultured using 19-day-pregnant Sprague-Dawley (SD) rats treated with $TGF-{\beta}1$ (1, 5, or 10 ng/mL) and incubated in a 1% O2 incubator for hypoxia. Seven-day-old SD rat pups were subjected to left carotid occlusion followed by 2 h of hypoxic exposure (7.5% $O_2$). $TGF-{\beta}1$ (0.5 ng/kg) was administered intracerebrally to the rats 30 min before HI brain injury. The expressions of NOS and NMDA receptors were measured. Results : In the in vitro model, the expressions of endothelial NOS (eNOS) and neuronal NOS (nNOS) increased in the hypoxic group and decreased in the 1 ng/mL $TGF-{\beta}1-treated$ group. In the in vivo model, the expression of inducible NOS (iNOS) decreased in the hypoxia group and increased in the $TGF-{\beta}1$-treated group. The expressions of eNOS and nNOS were reversed compared with the expression of iNOS. The expressions of all NMDA receptor subunits decreased in hypoxia group and increased in the $TGF-{\beta}1$-treated group except NR2C. Conclusion : The administration of $TGF-{\beta}1$ could significantly protect against perinatal HI brain injury via some parts of the NO-mediated or excitotoxic mechanism.

• Asian-Australasian Journal of Animal Sciences
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• v.31 no.1
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• pp.32-39
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• 2018

Objective: In this study, we investigated the adverse effects of dietary zearalenone (ZEA) (0.5 to 1.5 mg/kg diet) on the localization and expression of the growth hormone receptor (GHR) in the uteri of post-weaning gilts and explored alternative mechanism of the reproductive toxicity of ZEA on piglets. Methods: A total of forty healthy piglets (Duroc${\times}$Landrace${\times}$Large White) aged 28 d were selected for study. Piglets were transferred to single cages after 10 days' adaptation on an obstetric table. The animals were allocated to one of four treatments: a normal basal diet supplemented with 0 (Control), 0.5 (ZEA0.5), 1.0 (ZEA1.0), or 1.5 (ZEA1.5) mg/kg purified ZEA, and fed for 35 d after the 10-d adaptation. Analyzed ZEA concentrations in the diets were 0, $0.52{\pm}0.07$, $1.04{\pm}0.03$, and $1.51{\pm}0.13mg/kg$, respectively. At the end of the feeding trial, piglets were euthanized after being fasted for 12 h. Two samples of uterine tissue from each pig were rapidly collected, one of which was stored at $-80^{\circ}C$ for analysis of the relative mRNA and protein expression of GHR, and the second was promptly fixed in Bouin's solution for immunohistochemical analysis. Results: The relative weight of the uteri and thickness of the myometrium and endometrium increased linearly (p<0.001) and quadratically (p<0.001) with an increasing level of ZEA. The results of immunohistochemical analysis indicated that GHR immunoreactive substance was mainly localizated in the cytoplasm of uterine smooth muscle, glandular epithelial, luminal epithelial, stromal, and vascular endothelial cells. In contrast, nuclear staining was rarely observed. The immunoreactive integrated optic density of GHR in the myometrium, luminal epithelium, glandular epithelium, and whole uteri of weaning gilts increased linearly (p<0.001) and quadratically (p<0.05) with an increasing level of ZEA. The mRNA and protein expression of GHR in the uteri of weaning gilts increased linearly (p<0.001) and quadratically (p<0.05) with an increasing level of ZEA. Conclusion: In conclusion, ZEA at a concentration of 0.5 mg/kg was sufficient to significantly thicken the myometrium and endometrium, and at a concentration of 1.0 mg/kg induced a high level of GHR expression to promote growth and development of the uteri. This revealed an alternative molecular mechanism whereby ZEA induces growth and development of the uteri and provides a theoretical basis for the revision of Chinese feed hygiene standards.

• Tuberculosis and Respiratory Diseases
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• v.39 no.4
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• pp.310-317
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• 1992

Background: Angiotensin converting enzyme is a glycoprotein peptidyldipeptide hydrolase which cleaves the c-terminal dipeptides of several oligopeptides. It is a menbrane-bound protein mainly synthesized by the endothelial cells. Since the lung has the largest capillary bed of any organ in the body, it is here that ACE acts on circulating substrates like angiotensin I and bradykinin. It is well known that ACE correlates with disease activity in sarcoidosis and also there are reports that changes in serum ACE activity are found in many acute and chronic lung diseases. So we planned this study to see if serum ACE activity can act as a prognostic factor in lung cancer. Methods: Forty-one newly diagnosed lung cancer patients were included in the study group. There were 19 patients with squamous cell lung cancer, 13 with adenocarcinoma, and 9 with small cell carcinoma. Patients were excluded from the study if they had high blood pressure, heart disease, liver disease, renal disease, or other lung disease. Serum ACE activity was analyzed according to cell type, staging, mode of treatment, and clinical response to treatment. Results: 1) There was no difference in serum ACE activity between lung cancer patients and the control group. Also no difference in serum ACE activity was found according to cancer cell type or staging. 2) In patients who underwent curative resection of lung cancer, serum ACE activity was decreased significantly after the operation. 3) In patients who were diagnosed as non-small cell lung cancer and were treated with 4 cycles of anti-cancer chemotherapy without clinical improvement, changes in serum ACE activity were not seen after the treatment. 4) In patients diagnosed as small cell lung cancer treated with 4 cycles of anti-cancer chemotherapy with clinical improvement, changes in serum ACE activity were also not observed. Conclusion: Serum ACE activity was decreased after lung resection but had no relation to cell type, staging, or clinical response to treatment in lung cancer patients. Therefore, serum ACE activity is not suitable in predicting clinical outcome of lung cancer patients.

• Applied Microscopy
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• v.34 no.1
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• pp.31-42
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• 2004

Acute respiratory distress syndrome (ARDS) is a kind of acute lung injury characterized by inflammatory disruption of alveolar-capillary barrier and notorious for its high mortality. Neutrophils cause cell damage through the production of free radicals, inflammatory mediators, and proteases in ARDS. $PLA_2$ might serve a primary regulatory role in the activation of neutrophils. This present study was performed to elucidate the effect of rutin known as $PLA_2$ inhibitor on ARDS induced by endotoxin. Endotoxin had increased lung myeloperoxidase (MPO) activity, BAL (bronchoalveolar lavage) protein content, numbers of neutrophils in BALF (bronchoalveolar lavage fluid) compared with those of control rat (p<0.001). In addition, histological evidence of lung injury was correlated with neutrophil influx into alveolar space and cerrous perhydroxide granules were found in lining of endothelial cell, alveolar type I, II cells. In contrast, pretreated group of rutin had significantly decreased all of the parameters (p<0.001). These data suggest that inhibition of $PLA_2$ is one step approach that block the process of ARDS. Accordingly, we conclude that rutin can be used as the prophylactic agent for ARDS on the bases of these experimental results.

• Tuberculosis and Respiratory Diseases
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• v.40 no.2
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• pp.104-111
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• 1993

Background: Gram-negative bacterial endotoxin induced septicemia is known to be a leading cause in the development of adult respiratory distress syndrome(ARDS). The mechanism of endotoxin induced lung injury is mainly due to the activated neutrophils which injure the capillary endothelial cells by releasing oxidant radical and resulted in pulmonary edema. We studied the change of antioxidant enzyme in the case of large or small, intermittant dose of endotoxin infused rat lungs. Methods: Endotoxin was given to the rat through the peritoneal cavity in the dose of 7 mg/kg body weight in the large dose group and 1 mg/kg for 10 days in the small dose group. Bronchoalveolar lavage (BAL) was done and rats were killed at 6, 12, 24 hours after single endotoxin injection in the large dose group and 3, 7, 10 days after daily endotoxin injection for 10 days in the small dose group. The lungs were perfused with normal saline through the pulmonary artery to remove the blood and were homogenized in 5 volume of 50 mM potassium phosphate buffer containing 0.1 mM EDTA. After centrifuging at 100,000 g for 60 minute, the supernatent was removed and stored at $-70^{\circ}C$ until measuring for superoxide dismutase (SOD), catalase, glutathione peroxidase (GSH-Px) and protein. Results: We observed the following results. 1) The lung wet/dry weight ratio and albumin concentration in the BAL fluids were increased to peak at 12 hours and neutrophil number in the BAL fluids were peak at 6 hours after endotoxin injection in the large dose group. 2) Cu, Zn SOD (IU/mg protein) was significantly decreased after 6, 12 hours after endotoxin injection in the large dose group. 3) There were no singnificant change in the level of Mn SOD, catalase, GSH-Px after endotoxin injection in both groups. Conclusion: Endotoxin in the large dose group produced the acute pulmonary edema and decreased the Cu, Zn SOD in the lung tissue after injecting endotoxin at 6 and 12 hours. These phenomenon may be due to the cell membrane damage by endotoxin. Further research would be necessary whther giving SOD by intratracheal route or method to increase the synthesis of SOD may lessen the acute lung injury by endotoxin.

• Radiation Oncology Journal
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• v.20 no.3
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• pp.253-263
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• 2002

Purpose : In order to understand in vivo radiation damage modifying of bFGF on jejunal mucosa, bone marrow and the effect of bFGF on the growth of transplanted mouse sarcoma 180 tumor in mice. Materials and Methods : Mice were treated with $6\;{\mu}g$ of bFGF at 24 hours and 4 hours before exposing to 600 cGy, 800 cGy and 1,000 cGy total body irradiation (TBI), and then exposed to 3,000 cGy local radiation therapy on the tumor bearing thigh. Survival and tumor growth curve were plotted in radiation alone group and combined group of bFGF and irradiation (RT). Histologic examination was performed in another experimental group. Experimental groups consisted of normal control, tumor control, RT (radiation therapy) alone, $6\;{\mu}g$ bFGF alone, combined group of $3\;{\mu}g$ bFGF and irradiation (RT), combined group of $6\;{\mu}g$ bFGF and irradiation (RT). Histologic examination was peformed with H-E staining in marrow, jejunal mucosa, lung and sarcoma 180 bearing tumor. Radiation induced apoptosis was determined in each group with the DNA terminal transferase nick-end labeling method ($ApopTag^{\circledR}$ S7100-kit, Intergen Co.) Results : The results were as follows 1) $6\;{\mu}g$ bFGF given before TBI significantly improved the survival of lethally irradiated mice. bFGF would protect against lethal bone marrow syndrome. 2) $6\;{\mu}g$ bFGF treated group showed a significant higher crypt depth and microvilli length than RT alone group (p<0.05). 3) The bone marrow of bFGF treated group showed less hypocellularity than radiation alone group on day 7 and 14 after TBI (p<0.05), and this protective effect was more evident in $6\;{\mu}g$ bFGF treated group than that of $3\;{\mu}g$ bFGF treated group. 4) bFGF protected against early radiation induced apoptosis in intestinal crypt cell but might have had no antiapoptotic effect in bone marrow stem cell and pulmonary endothelial cells. 5) There was no significant differences in tumor growth rate between tumor control and bFGF alone groups (p>0.05). 6) There were no significant differences in histopathologic findings of lung and mouse sarcoma 180 tumor between radiation alone group and bFGF treated group. Conclusions : Our results suggest that bFGF protects small bowel and bone marrow from acute radiation damage without promoting the inoculated tumor growth in C3H mice. Improved recovery of early responding normal tissue and reduced number of radiation induced apoptosis may be possible mechanism of radioprotective effect of bFGF.

• Journal of Chest Surgery
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• v.37 no.3
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• pp.210-219
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• 2004

Extracellular $K^{+}$ concentration ([ $K^{+}$]$_{0}$ ) can be increased within several mM by the efflux of intracellular $K^{+}$. To investigate the effect of an increase in [ $K^{+}$]$_{0}$ on vascular contractility, we attempted to examine whether extracellular $K^{+}$ might modulate vascular contractility, endothelium-dependent relaxation (EDR) and intracellular $Ca^2$$^{+}$ concentration ([C $a^2$$^{+}$]$_{i}$ ) in endothelial cells (EC). We observed isometric contractions in rabbit carotid, superior mesenteric, basilar arteries and movse aorta. [C $a^2$$^{+}$]$_{i}$ was recorded by microfluorimeter using Fura-2/AM in EC. No change in contractility was recorded by the increase in [ $K^{+}$]$_{0}$ from 6 to 12 mM in conduit artery such as rabbit carotid artery. whereas resistant vessels, such as basilar and branches of superior mesenteric arteries (SMA), were relaxed by the increase. In basilar artery, the relaxation by the increase in [ $K^{+}$]$_{0}$ to from 1 to 3 mM was bigger than that by the increase from 6 to 12 mM. In contrast, in branches of SMA, the relaxation by the increase in [ $K^{+}$]$_{0}$ to from 6 to 12 mM is bigger than that by the increase from 1 to 3 mM. $Ba^2$$^{+}$ (30 $\mu$M) did not inhibit the relaxation by the increase in [ $K^{+}$]$_{0}$ from 1 to 3 mM but did inhibit the relaxation by the increase from 6 to 12 mM. In the mouse aorta without the endothelium or treated with $N^{G}$_nitro-L-arginine (30 $\mu$M), nitric oxide synthesis blocker, the increase in [ $K^{+}$]$_{0}$ from 6 to 12 mM did not change the magnitude of contraction induced either norepinephrine or prostaglandin $F_2$$_{\alpha}$. The increase in [ $K^{+}$]$_{0}$ up to 12 mM did not induce contraction of mouse aorta but the increase more than 12 mM induced contraction. In the mouse aorta, EDR was completely inhibited on increasing [ $K^{+}$]$_{0}$ from 6 to 12 mM. In cultured mouse aorta EC, [C $a^2$$^{+}$]$_{i}$ , was increased by acetylcholine or ATP application and the increased [C $a^2$$^{+}$]$_{i}$ , was reduced by the increase in [ $K^{+}$]$_{0}$ reversibly and concentration-dependently. In human umbilical vein EC, similar effect of extracellular $K^{+}$ was observed. Ouabain, a N $a^{+}$ - $K^{+}$ pump blocker, and N $i^2$$^{+}$, a N $a^{+}$ - $Ca^2$$^{+}$ exchanger blocker, reversed the inhibitory effect of extracellular $K^{+}$. In resistant arteries, the increase in [ $K^{+}$]$_{0}$ relaxes vascular smooth muscle and the underlying mechanisms differ according to the kinds of the arteries; $Ba^2$$^{+}$-insensitive mechanism in basilar artery and $Ba^2$$^{+}$ -sensitive one in branches of SMA. It also inhibits [C $a^2$$^{+}$]$_{i}$ , increase in EC and thereby EDR. The initial mechanism of the inhibition may be due to the activation of N $a^{+}$ - $K^{+}$pump. activation of N $a^{+}$ - $K^{+}$pump.p.p.p.