• 대한약침학회지
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• 제4권1호
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• pp.105-121
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• 2001

Objectives: Herbal acupuncture has been administered with Liriopis Tuber extract on the point of BL 13 (Pyesu) to treat bronchial asthma and a certain degree of clinical benefits have been observed but lacking scientific substantiation. Methods: The present report describes on Th1 cytokine (Interleukin-2, Interferon-gamma), Th2 cytokine, (Interleukin-4, Interleukin-5), and IL-12 in bronchoalveolar lavage fluid (ELISA). Five groups were devised to study the effects of herbal acupuncture with Liriopis Tuber extract at BL 13 (Pyesu) for airway inflammation in the mouse model with bronchial asthma. Results shows that herbal acupuncture with Liriopis Tuber extract at BL 13 increased Th1 cytokine (Interleukin-2) in allergic sensitization and allergic challenge, and decreased Th2 cytokine (Interleukin-2, Interleukin-5) in allergic sensitization.

• 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.

• Tuberculosis and Respiratory Diseases
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• 제42권5호
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• pp.744-751
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• 1995

연구배경: 여러 종류의 자극으로 감각신경(C-fiber)의 말단부에서 분비되는 신경단백질인 substance P와 neurokinin A는 기관지 평활근의 수축, 점막의 혈장 유출 및 점액의 과분비를 일으켜 기관지 천식 발병 기전에 중요한 역활을 한다. 이러한 기도 신경단백질은 $NK_1$, $NK_2$, $NK_3$ 등의 3종류의 수용체를 통하여 작용하며, $NK_1$ 수용체에 주로 작용하는 substance P는 기도의 혈관확장과 혈장 유출에 관여하며 $NK_2$ 수용체에 작용하는 neurokinin A는 기도의 수축에 주로 작용하며 기도혈장 유출에도 관여하는 것으로 알려져 있다. 목적: 저지들은 백서의 미주신경인 비교감 및 비부교감 신경을 전기적 자극으로 유발된 기도 혈장 유출에서 $NK_1$과 $NK_2$ 수용체 차단제인 FK224를 이용하여 기도내 신경성 염증에서 혈장유출에 대한 효과를 기도 부위별로 확인하였다. 대상 및 방법: 백서 21마리를 7마리씩 3군으로 나누어 미주신경에 전기적 자극을 하지 않은 대조군(control group), 2분간 자극한 군(NANC2군)과 신경 단백 수용체 차단제인 FK224를 미주신경 자극 전에 사용한 군(FK224군)에서 Evans blue dye를 이용하여 기도 부위별 혈장 유출의 정도를 각 군간에 비교하여 다음과 같은 결과를 얻었다. 결과: 1) 2분간 신경 자극한 군(NANC2군)은 대조군에 비하여 기관에서 49.7(${\pm}2.5$)ng/mg으로 353%, 주기관지에서 38.7(${\pm}2.8$)ng/mg으로 221%의 증가와 말초기관지 19.1(${\pm}1.6$)ng/mg으로 151%로 혈장 유출이 모두 유의하게 높았으며(p<0.05), 주로 상부 기도에서 혈장 유출 정도가 심하였으나, 폐실질은 13.0(${\pm}1.8$)ng/mg, 76%로 대조군과 차이는 없었다(p>0.05). 2) 신경 단백질 수용체 차단제를 사용한 FK224군은 2분간 신경 자극한 군에 비하여 기관에서 24.3(${\pm}2.2$)ng/mg으로 49%, 주기관지에서 22.3(${\pm}1.6$)ng/mg 으로 58%의 억제와 말초기관지 13.3(${\pm}0.8$) ng/mg으로 70%로 혈장 유출이 모두 유의하게 감소되었다(p<0.05). 결론: 이상의 결과에 의하면 백서에서 미주신경(NANC)의 전기적 자극으로 유발된 혈장유출은 기도에서만 발생되고 주로 상부기도에서 혈장유출이 심하며, $NK_1$과 $NK_2$ 수용체 차단제인 FK224를 전처치하여 substance P와 neurokinin A의 수용체 차단으로 기도 혈장 유출이 억제됨을 알 수 있었다.

• 대한한의학회지
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• 제39권4호
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• pp.126-135
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• 2018

Objectives: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and irreversible airflow. This study aimed to evaluate the effects of GHX02 in a COPD-induced mouse model. Methods: The COPD mouse model was established by exposure to cigarette smoke extract and lipopolysaccharide which were administered by intratracheal injection three times with a 7 day interval. GHX02 (100, 200, 400 mg/kg) and all other drugs were orally administrated for 14 days from Day 7 to Day 21. Results: GHX02 significantly decreased the neutrophil counts in bronchoalveolar lavage fluid (BALF) and the number of $CD4^+$, $CD8^+$, $CD69^+$, and $CD11b^+/GR1^+$ cells in BALF and lung cells. GHX02 also suppressed the secretion of tumor necrosis factor-alpha ($TNF-{\alpha}$), interleukin-17A, macrophage inflammatory protein 2 (MIP2), and chemokine (C-X-C motif) ligand 1 (CXCL-1) in BALF and ameliorated the lung pathological changes. Conclusions: Thus, GHX02 effectively inhibited airway inflammation by inhibiting migration of inflammatory cells and expression of pro-inflammatory cytokines. Therefore, GHX02 may be a promising therapeutic agent for COPD.

• Clinical and Experimental Pediatrics
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• 제53권4호
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• pp.481-487
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• 2010

목 적: 최근 여러 연구결과 천식을 포함한 알레르기질환의 발병에 소아 성장시기에 알레르겐이나 내독소(LPS)등과 같은 물질에 노출이 중요한 역할을 하는 것으로 제시되었다. 이에 연구자들은 출생 초기에 기도 점막을 통한 알레르겐과 내독소에의 노출이 성장한 후에 알레르기 기도염증과 과반응성의 발생에 미치는 효과를 생쥐 모델을 통하여 규명하고자 본 연구를 시행하였다. 방 법: 실험동물은 무균 상태의 생후 1주이내의 암컷 BALB/c 생쥐를 사용하였다. 실험동물들에게는 각각 신생생쥐시기에 생리식염수, 1% ovalbumin (OVA), $1.0{\mu}g$ LPS, $1.0{\mu}g$ LPS in 1% OVA를 각 비공을 통하여 투여하였다. 실험동물은 연구 시작 제 35일부터 10일간 5% OVA로 감작시켰으며 최종 기도 감작 10일 후부터 3일간 1% OVA로 기도 항원유발을 시행하였다. 최종 기도유발 48시간 후 체적검사(plethysmography)를 이용하여 비특이적 기도과반응성 검사(Methcholine challenge test)를 시행하였으며 검사 후 실험동물을 희생시켜 검체를 취하여 BAL액내 세포분획, 사이토카인, 혈청 면역글로불린을 측정하였다. 결 과: 1) 메타콜린에 의한 기도과반응성은 생후 초기에 OVA, LPS, OVA/LPS를 투여한 군에서 생리식염수를 투여한 군에 비해 통계적으로 유의하게 억제되었다. 2) OVA, LPS, OVA/LPS를 투여한 군에서 BAL 액내의 호산구수와 IL-4, IL-5가 유의하게 낮았다. 3) 혈청내 OVA 특이 IgE는 OVA, LPS, OVA/LPS 투여군에서 유의하게 감소되었다. 결 론: 본 연구 결과 신생생쥐 시기의 점막을 통한 항원, 내독소의 노출이 성숙한 후 항원에 의한 기도염증 및 과반응성의 발생을 억제하였으며 향후 이러한 효과의 작용기전에 대한 연구가 필요할 것으로 생각한다.

• 대한본초학회지
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• 제30권3호
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• pp.1-12
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• 2015

Objectives : In this study, we investigated the effects of Agastachis Herba water (AH-W) extract on compound 48/80-induced mast cell degranulation and histamine release in human mast cells and also anti-asthmatic effect of AH-W extract on ovalbumin (OVA)-induced asthma in mice. Methods : Human mast cells, HMC-1 were treated with AH-W extract in the presence or absence of compound 48/80 (C48/80). Mast cell degranulation was observed by microscope, and the histamine release was measured in culture medium by ELISA. For preparation of asthmatic in vivo model, mice were sensitized (0, 7, and 14 days) with OVA and airway challenged (21, 23, 25, 27, and 29 days). AH-W extract at doses of 100 and 300 mg/kg/body weight was orally administered during OVA challenge once per a day. The levels of immunoglobulin (Ig) E, and Th1/Th2 cytokines, IFN-$\gamma$ and IL-4 were measured in the sera of mice by ELISA. The histopathological change of lung tissues was observed by hematoxylin and eosin (H&E) and Periodic Acid Schiff (PAS) staining. Results : The treatment of AH-W extract significantly decreased the mast cell degranulation and histamine release in C48/80-stimulated HMC-1 cells. In addition, The administration of AH-W extract at does of 100 and 300 mg/kg significantly decreased the serum levels of OVA-specific IgE compared with those of OVA control group. In H&E and PAS staining, AH-W extract inhibited OVA-induced airway inflammation, and inflammatory cells infiltration, and also histopathological damages on lung tissues such as bronchiole epithelial desquamation, goblet cells hyperplasia, and mucin releasing. Conclusions : These results indicate that AH-W extract may improve asthmatic symptoms through mast cell stabilization and inhibiting the lung inflammation in bronchial asthma.

• Molecules and Cells
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• 제22권1호
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• pp.104-112
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• 2006

We previously reported that DA-9601, ethanol herbal extract of Artemisia asiatica, inhibited histamine and leukotriene releases in guinea pig lung mast cells activated with specific antigen/antibody reaction. This study aimed to evaluate the inhibitory effect of DA-9601 on the OVA-induced airway inflammation in allergic asthma mouse model. BALB/c mice were sensitized and challenged with OVA. DA-9601 was administered orally 1 h before every local OVA-challenge. OVA-specific serum IgE was measured by ELISA, recruitment of inflammatory cells in BAL fluids and lung tissues by Diff-Quik and H&E staining, respectively, the expressions of CD40, CD40L and VCAM-1 by immunohistochemistry, goblet cell hyperplasia by PAS staining, activities of MMPs by gelatin zymography, expressions of mRNA and proteins of cytokines by RT-PCR and ELISA, activities of MAP kinases by western blot, and activity of NF-${\kappa}B$ by EMSA. DA-9601 reduced IgE level, recruitment of inflammatory cells into the BAL fluid and lung tissues, expressions of CD40, CD40L and VCAM-1 molecules, goblet cell hyperplasia, MMPs activity, expressions of mRNA and productions of various cytokines, activities of MAP kinases and NK-${\kappa}B$ increased from OVA-challenged mice. These data suggest that DA-9601 may be developed as a clinical therapeutic agent in allergic diseases due to suppressing the airway allergic inflammation via regulation of various cellular molecules expressed by MAP kinases/NF-${\kappa}B$ pathway.

• IMMUNE NETWORK
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• 제22권2호
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• pp.15.1-15.16
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• 2022

Foreign molecules, including viruses and bacteria-derived toxins, can also induce airway inflammation. However, to the best of our knowledge, the roles of these molecules in the development of airway inflammation have not been fully elucidated. Herein, we investigated the precise role and synergistic effect of virus-mimicking double-stranded RNA (dsRNA) and staphylococcal enterotoxin B (SEB) in macrophages and epithelial cells. To identify cytokine expression profiles, both the THP-1-derived macrophages and BEAS-2B epithelial cells were stimulated with dsRNA or SEB. A total of 21 cytokines were evaluated in the culture supernatants. We observed that stimulation with dsRNA induced cytokine production in both cell types. However, cytokine production was not induced in SEB-stimulated epithelial cells, compared to the macrophages. The synergistic effect of dsRNA and SEB was evaluated observing cytokine level and intracellular phospho-signaling. Fifteen different types were detected in high-dose dsRNA-stimulated epithelial cells, and 12 distinct types were detected in macrophages; those found in macrophages lacked interferon production compared to the epithelial cells. Notably, a synergistic effect of cytokine induction by co-stimulation of dsRNA and SEB was observed mainly in epithelial cells, via activation of most intracellular phosphor-signaling. However, macrophages only showed an accumulative effect. This study showed that the type and severity of cytokine productions from the epithelium or macrophages could be affected by different intensities and a combination of dsRNA and SEB. Further studies with this approach may improve our understanding of the development and exacerbation of airway inflammation and asthma.

• Tuberculosis and Respiratory Diseases
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• 제85권1호
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• pp.18-24
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• 2022

Background: Neutrophilic asthma (NeuA) is usually resistant to corticosteroids. Tiotropium bromide (TIO) is a bronchodilator that is used as an add-on therapy to inhaled corticosteroid and long-acting β2 agonist in asthma treatment. However, the role of TIO in NeuA is not fully known. Thus, the aim of this study was to evaluate the effect of TIO on NeuA compared to that of corticosteroids. Methods: C57BL/6 female mice were sensitized with ovalbumin and lipopolysaccharide to induce neutrophilic inflammation. Dexamethasone (DEX) was administered on days 14, 17, 20, and 23. TIO was inhaled on days 21, 21, and 23. On day 24, mice were sacrificed. Airway hyper-responsiveness, levels of cytokines in bronchoalveolar lavage (BAL) and lung homogenates, and lung tissue histopathology were compared between the two groups. Results: Neutrophil counts, T helper 2 cells (T_H2)/T_H17 cytokines, and pro-inflammatory cytokine in BAL fluids were elevated in the NeuA group. TIO group showed lower total cells, neutrophil counts, and eosinophil counts in BAL fluids than the DEX group (p<0.001, p<0.05, and p<0.001, respectively). Airway resistance was attenuated in the TIO group but elevated in the NeuA group (p<0.001). Total protein, interleukin (IL)-5, and IL-17A levels in BAL fluids were lower in the TIO group than in the NeuA group (all p<0.05). Conclusion: TIO showed more potent effects than DEX in improving airway inflammation and attenuating airway resistance in NeuA.

• Clinical and Experimental Pediatrics
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• 제56권11호
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• pp.482-489
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• 2013

Purpose: The aim of the present study was to investigate the differences in lower airway inflammatory immune responses, including cellular responses and responses in terms of inflammatory mediators in bronchoalveolar lavage fluid (BALF) and the airway, to rhinovirus (RV) infection on asthma exacerbation by comparing a control and a murine asthma model, with or without RV infection. Methods: BALB/c mice were intraperitoneally injected with a crude extract of Dermatophagoides farinae (Df ) or phosphate buffered saline (PBS) and were subsequently intranasally treated with a crude extract of Df or PBS. Airway responsiveness and cell infiltration, differential cell counts in BALF, and cytokine and chemokine concentrations in BALF were measured 24 hours after intranasal RV1B infection. Results: RV infection increased the enhanced pause (Penh) in both the Df sensitized and challenged mice (Df mice) and PBS-treated mice (PBS mice) (P<0.05). Airway eosinophil infiltration increased in Df mice after RV infection (P<0.05). The levels of interleukin (IL) 13, tumor necrosis factor alpha, and regulated on activation, normal T cells expressed and secreted (RANTES) increased in response to RV infection in Df mice, but not in PBS mice (P<0.05). The level of IL-10 significantly decreased following RV infection in Df mice (P<0.05). Conclusion: Our findings suggest that the augmented induction of proinflammatory cytokines, Th2 cytokines, and chemokines that mediate an eosinophil response and the decreased induction of regulatory cytokines after RV infection may be important manifestations leading to airway inflammation with eosinophil infiltration and changes in airway responsiveness in the asthma model.