• 대한본초학회지
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• 제34권5호
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• pp.21-28
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• 2019

Objectives : In present study, we investigated a therapeutic effect and optimum dose of Socheongryong-Tang (SCT) on LPS-induced lung inflammation rats model. Methods : Male Sprague-Dawley rats ($260{\pm}10g$) were divided into 12 groups : Group 1 included the normal rats, and Group 2-12 were administrated LPS by intranasal injection to induce experimental lung inflammation. After 1 day of LPS administration, Group 3-9 were treated with SCT ${\times}1/4$, ${\times}1/2$, ${\times}1$, ${\times}3$, ${\times}6$, ${\times}12$ or ${\times}18$, respectively. Group 10-12 (positive control) were treated with dexamethasone 1 mg/kg or acetylcystein 1.5 mg/kg or diclofenac sodium 0.4 mg/kg, respectively. After sacrifice, bronchoalveolar lavage fluid (BALF) was isolated. The levels of IL-$1{\beta}$, TNF-${\alpha}$, mucin glycoprotein 5AC (MUG5AC) were measured in BALF using enzyme-linked immunosorbent assay (ELISA). Results : LPS injected rats exhibited outstanding lung inflammation manifestations, including increased amount of total cells and neutrophil, and upregulated inflammatory cytokines level in BALF. However, the administration of SCT ${\times}1/4$, ${\times}1/2$ and ${\times}1$ decreased total cells and neutrophil, and suppressed the production of inflammatory cytokines, including $IL-1{\beta}$ and TNF-${\alpha}$, and MUG5AC in BALF. Notably, inhibitory effect of SCT ${\times}1/2$ and ${\times}1$ on the level of TNF-${\alpha}$ was markedly better than that of positive controls, dexamethasone and acetylcystein. Conclusions : Taken together, these results suggest that SCT ${\times}1/2$ and ${\times}1$ has therapeutic effects on LPS-induced lung inflammation rats model.

• Biomolecules & Therapeutics
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• 제28권4호
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• pp.344-353
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• 2020

This study aims to develop new potential therapeutic moracin M prodrugs acting on lung inflammatory disorders. Potential moracin M prodrugs (KW01-KW07) were chemically synthesized to obtain potent orally active derivatives, and their pharmacological activities against lung inflammation were, for the first time, examined in vivo using lipopolysaccharide (LPS)-induced acute lung injury model. In addition, the metabolism of KW02 was also investigated using microsomal stability test and pharmacokinetic study in rats. When orally administered, some of these compounds (30 mg/kg) showed higher inhibitory action against LPS-induced lung inflammation in mice compared to moracin M. Of them, 2-(3,5-bis((dimethylcarbamoyl)oxy)phenyl)benzofuran-6-yl acetate (KW02) showed potent and dose-dependent inhibitory effect on the same animal model of lung inflammation at 1, 3, and 10 mg/kg. This compound at 10 mg/kg also significantly reduced IL-1β concentration in the bronchoalveolar lavage fluid of the inflamed-lungs. KW02 was rapidly metabolized to 5-(6-hydroxybenzofuran-2-yl)-1,3-phenylene bis(dimethylcarbamate) (KW06) and moracin M when it was incubated with rat serum and liver microsome as expected. When KW02 was administered to rats via intravenous or oral route, KW06 was detected in the serum as a metabolite. Thus, it is concluded that KW02 has potent inhibitory action against LPS-induced lung inflammation. It could behave as a potential prodrug of moracin M to effectively treat lung inflammatory disorders.

• Biomolecules & Therapeutics
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• 제19권3호
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• pp.324-330
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• 2011

Broussonetia papyrifera and Lonicera japonica have long been used in the treatment of inflammatory disorders, especially respiratory inflammation, in Chinese medicine. Previously, phytoformula (BL) containing B. papyrifera and L. japonica was found to exert strong anti-inflammatory activity in vitro and in vivo. In this study, the effects of BL on lung inflammation including bronchitis were examined in vitro and in vivo. BL (10-100 ${\mu}g$/ml) inhibited nitric oxide (NO) production of lipopolysaccharide (LPS)-treated alveolar macrophages, MH-S cells, primarily by down-regulating inducible NO synthase. BL also inhibited production of the proinflammatory cytokines, TNF-${\alpha}$ and IL-6. Against an animal model of pleural cavity inflammation, BL (200-400 mg/kg) significantly inhibited 5 h and 24 h carrageenan-induced pleurisy in rats when administered orally. Additionally, BL inhibited experimental bronchitis induced by intratracheal instillation of LPS to rats. Taken together, these results indicate that BL may be effective for the treatment of human lung inflammation as well as bronchitis.

• Clinical and Experimental Pediatrics
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• 제64권1호
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• pp.37-43
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• 2021

Background: Animal studies have shown that a leukocyte influx precedes the development of bronchopulmonary dysplasia (BPD) in premature sheep. The CXC chemokine receptor 2 (CXCR2) pathway has been implicated in the pathogenesis of BPD because of the predominance of CXCR2 ligands in tracheal aspirates of preterm infants who later developed BPD. Purpose: To test the effect of CXCR2 antagonist on postnatal systemic and pulmonary inflammation and alveolarization in a newborn Sprague-Dawley rat model of BPD. Methods: Lipopolysaccharide (LPS) was injected intraperitoneally (i.p.) into the newborn rats on postnatal day 1 (P1), P3, and P5 to induce systemic inflammation and inhibit alveolarization. In the same time with LPS administration, CXCR2 antagonist (SB-265610) or vehicle was injected i.p. to investigate whether CXCR2 antagonist can alleviate the detrimental effect of LPS on alveolarization by attenuating inflammation. On P7 and P14, bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) were collected from the pups. To assess alveolarization, mean cord length and alveolar surface area were measured on 4 random nonoverlapping fields per animal in 2 distal lung sections at ×100 magnification. Results: Early postnatal LPS administration significantly increased neutrophil counts in BALF and PB and inhibited alveolarization, which was indicated by a greater mean cord length and lesser alveolar surface area. CXCR2 antagonist significantly attenuated the increase of neutrophil counts in BALF and PB and restored alveolarization as indicated by a decreased mean cord length and increased alveolar surface area in rat pups exposed to early postnatal systemic LPS. Conclusion: CXCR2 antagonist preserved alveolarization by alleviating pulmonary and systemic inflammation induced by early postnatal systemic LPS administration. These results suggest that CXCR2 antagonist can be considered a potential therapeutic agent for BPD that results from disrupted alveolarization induced by inflammation.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제26권1호
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• pp.5-17
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• 2000

To evaluate the possible therapeutic effects of growth hormone and vitamin C on multiorgan failure, a rat model was developed for LPS-induced sepsis. Using this model, the effects of growth hormone and vitamin C on tissue damages, catalase and i-NOS activities, and MDA levels were examined in the lung and liver. The level of TNF- in plasm was also examined. Male, Sprague-Dawley rats were injected with LPS intraperitoneally then divided into 3 groups : positive controls injected with LPS only, the ones injected with growth hormone or vitamin C immediately after the LPS injections. The lung and the liver were then isolated, blood samples were collected at 24 or 48 hours after the LPS injection, then examined for histopathological and biochemical changes. The results obtained were as follows. 1. LPS induced sinusoid vasodilation and mild destruction of lobular structure in the liver. In the lung, alveolar structure appeared to be thickened and interstitial edema was observed. The levels of MDA in the liver and the lung was increased by LPS, while the activity of catalase was decreased. The activity of i-NOS of those tissues was also increased, which was more pronounced at 24 hr. The level of TNF- in plasm was increased by LPS 2. In the lung, vitamin C suppressed lymphocyte and neutrophil infiltration, alveolar wall thickening and interstitial edema. In the liver, vitamin C protected against the destruction of the lobular structure. The activity of catalase reduced by LPS was reversed partly by vitamin C. The activity of i-NOS enhanced by LPS was also reversed by vitamin C. The level of TNF- in plasm reduced in some animals by vitamin C, which however was not significant statistically(p<0.05). 3. Growth hormone showed similar protective effects against inflammation and damages in the liver and lung tissues. Growth hormone reversed partly the LPS effects on the level of MDA, the activity of catalase and i-NOS induction in the liver and the lung. Growth hormone reduced plasma level of TNF-${\alpha}$ substantially, which contrasted from vitamin C. Besides this, overall protective effects of growth hormone against LPS-induced experimental sepsis were similar to those of vitamin C. From this results, the mechanism of growth hormone on suppression of LPS-induced tissue damage might be associated with production of antioxidative enzyme and suppression of plasma TNF- level.

• Journal of Trauma and Injury
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• 제21권2호
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• pp.120-127
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• 2008

Purpose: Many studies on the time course of inducible nitric oxide synthase (iNOS) gene expression have been performed in the LPS (Lipopolysaccharide)-induced endotoxemic model, but there have been few experimental approaches to continuous peritonitis-induced sepsis model. We conducted this study to establish basic data for future sepsis-related research by investigating the time course of iNOS gene expression and the relationship with the production of inflammatory mediators in the early sepsis model induced by cecal ligation and puncture (CLP). Methods: Male Sprague-Dawley rats were operated on by sing the CLP method to induce of peritonitis; and then, they were sacrificed and samples of blood and lung tissues were obtained at various times (1,2,3,6,9 and 12 h after CLP). We observed the expression of iNOS mRNA from lung tissues and measured the synthesis of nitric oxide, $IL-1{\beta}$, and $TNF-{\alpha}$ from the blood. Results: iNOS mRNA began to be expressed at 3 h and was maintained untill 12 h after CLP. The nitric oxide concentration was increased significantly at 6 h, reached its peak level at 9 h, and maintained a plateau untill 12 h after CLP. $TNF-{\alpha}$ began to be detected at 3 h, increased gradually, and decreased steeply from 9 h after CLP. $IL-1{\beta}$ showed its peak level at 6 h after CLP, and tended to decrease without significance. Conclusion: We observed that the iNOS gene was expressed later in peritonitis-induced sepsis than in LPS-induced sepsis. Nitric oxide and key inflammatory mediators were also expressed later in peritonitis-induced sepsis than in LPS-induced sepsis.

• Biomolecules & Therapeutics
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• 제21권1호
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• pp.66-71
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• 2013

Broussonetia papyrifera and Lonicera japonica have long been used in the treatment of inflammatory disorders in Chinese medicine, especially respiratory inflammation. Previously, a new phytoformula (BL) containing B. papyrifera and L. japonica was found to exert strong anti-inflammatory activity against several animal models of inflammation, especially against an animal model of acute bronchitis. In the present investigation, the effects of BL on animal models of septic inflammation and chronic bronchitis are examined. Against lipopolysaccharide (LPS)-induced septic inflammation in mice, BL (200-400 mg/kg) reduced the induction of some important proinflammatory cytokines. At 1 h after LPS treatment, BL was found to considerably inhibit TNF-${\alpha}$ production when measured by cytokine array. At 3 h after LPS treatment, BL inhibited the induction of several proinflammatory cytokines, including IFN-${\gamma}$ and IL-$1{\beta}$, although dexamethasone, which was used as a reference, showed a higher inhibitory action on these biomarkers. Against chronic bronchitis induced by LPS/elastase instillation in rats for 4 weeks, BL (200-400 mg/kg/day) significantly inhibited cell recruitment in bronchoalveolar lavage fluid. Furthermore, BL considerably reduced lung injury, as revealed by histological observation. Taken together, these results indicate that BL may have a potential to treat systemic septic inflammation as well as chronic bronchitis.

• Tuberculosis and Respiratory Diseases
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• 제48권4호
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• pp.487-499
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• 2000

연구배경 : 급성호흡곤란증후군은 다양한 원인으로 유발된 폐포와 모세혈관 사이의 투과성 증가로 폐부종이 발생하여 저산소성 호흡부전이 유발되는 증후군으로, 여러 종류의 surfactant의 이상이 관찰되어 외부에서 기관을 통해 surfactant를 공급하는 치료방법이 많이 시도되었다. 본 연구에서는 흰쥐를 대상으로 기판내로 내독소를 주입하여 급성 폐손상을 유발한 다음 기관내로 surfactant를 투여하여 치료효과를 알아보았다. 방 법 : 흰쥐를 각각 5마리씩 네 군으로 나누어 제1군은 기관대로 생리식염수를 30분 간격으로 주입하였고, 제2군은 기관내로 내독소를 주입한 이후 30분 뒤에 기관내로 생리식염수를 주입하였으며, 제3군과 4군은 기관내로 내독소를 주입한 후 각각 30분과 5시간 뒤에 기관내로 surfactant를 주입하였다. 결 과 : 생리식영수만 기관내로 주입한 제1군에 비해서 내독소를 기관내로 주입한 제2군과 3군, 4군에서는 호흡수가 증가하고, 흡기유량이 감소하였으며, 기도저항을 나타내는 지표인 Penh은 제2군에서만 증가되었다. 동맥혈액산소분압은 제 2군에서만 유의하게 감소하였다. 기관내 내독소 투여후 24시간에 얻은 기관지폐포세척액의 단백농도는 제 2군에서만 증가하였다. 기관지폐포세척액내의 세포수는 내독소를 투여받은 제2군과 3군, 4군에서 모두 증가하였고 구성세포는 다형백혈구가 다수를 이루고 있었다. 폐조직검사에서 제2군의 폐포내로 다형백혈구를 위주로하는 염증세포의 침윤과 폐포벽의 비후소견이 관찰되었으며, 제3군 및 제4군에서도 비슷한 염증소견이 관찰되었으나 염증의 정도는 제2군에서 제일 심하였다. 결 론 : 기관내 sufactant 투여는 기관내 내독소 투여로 유발된 흰쥐의 급성폐손상에서 의미있는 치료효과를 나타내었다.

• Tuberculosis and Respiratory Diseases
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• 제53권5호
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• pp.519-529
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• 2002

연구배경 : 급성폐손상의 치료로 시도되는 표면활성물질의 효과는 허탈된 폐포를 재환기시키는 작용 외에 표면 활성물질 자제가 가지고 있는 항염증작용이 중요한 기전으로 생각되고 있다. 본 연구에서는 백서의 급성폐손상 모델을 이용하여 기관 내로 표면활성물질을 투여하였을 때, 기관지폐포세척액의 백혈구수와, 염증매개 사이토카인인 IL-$1{\beta}$ 그리고 IL-6의 농도에 변화가 있는지를 살펴보고, surfactant의 항염증작용이 전사인자인 NF-${\kappa}B$의 활성의 억제를 통하여 이루어지는지 여부를 Electrophoretic mobility shift assay (EMSA) 법으로 확인하였다. 방 법 : 대상동물은 300g 내외의 수컷 백서를 이용하였으며, 대상동물을 각각 6 마리씩 세 군으로 나누었다. 대조군은 기관 내로 생리식염수(3ml/kg)를 30분 간격으로 투여하였다. 나머지 두 군은 기관 내로 내독소(5mg/kg)를 투여하여 급성폐손상을 유발하고, 30 분 후에 표변활성 물질 치료군은 surfactant(30mg/kg)을 그리고 비치료군은 생리식염수(3ml/kg)을 각각 기관 내로 투여하였다. 생리식염수나 내독소를 투여한 24 시간 후에 기관지폐포세척술을 시행하였고, 기관지폐포세척액 내의 백혈구수와 IL-$1{\beta}$ 그리고 IL-6의 농도를 측정하였다. 또한 기관지폐포세척액에서 호중구를 분리하고 핵 단백질을 추출하여 NF-${\kappa}B$의 활성을 EMSA법으로 측정하였다. 결 과 : 대조군, 표면활성물질 치료군, 그리고 비치료군의 기관지폐포세척액의 백혈구 수는 각각 $356{\pm}275{\times}10^3/{\mu}1$, $3,221{\pm}1,914{\times}10^3/{\mu}1$, 그리고 $5,561{\pm}1,757{\times}10^3/{\mu}l$으로 비치료군의 백혈구 수가 가장 높았고, 다음으로 표면활성물질 치료군, 비치료군의 순서였다(p<0.05). 기관지폐포세척액의 IL-$1{\beta}$ 농도는 대조군은 0pg/ml, 표면활성물질 치료군은 $360{\pm}234pg/ml$, 그리고 비치료군은 $2,064{\pm}1,082pg/ml$로 대조군에 비해 표면활성물질 치료군이, 그리고 표면활성물질 치료군에 비해 비치료군의 IL-$1{\beta}$농도가 높았다(p<0.05). 기관지폐포세척액의 IL-6 농도는 대조군, 표면활성물질 치료군, 비치료군에서 각각 $49{\pm}62pg/ml$, $1,754{\pm}1,340pg/ml$, 그리고 $3,621{\pm}567pg/ml$으로 대조군에 비해 표면활성물질 치료군이, 그리고 표면활성물질 치료군에 비해 비치료군의 농도가 높았다(p<0.05). 표면활성물질 치료군과 비치료군 사이에서 호중구의 NF-${\kappa}B$ 활성화에는 차이가 없었다. 결 론 : 이상의 연구로 내독소의 기관 내 투여로 유발한 백서의 급성폐손상에서 기관 내로 투여한 표면활성물질은 기관지폐포세척액의 백혈구수와 염증매개 사이토카인인 IL-$1{\kappa}$ 그리고 IL-6의 농도를 감소시켜 폐포 내의 염증을 감소시켰으며, 표면활성 물질의 항염증작용은 NF-${\kappa}B$의 활성의 억제를 통하여 이루어지지는 않는 것으로 판단된다.