• Tuberculosis and Respiratory Diseases
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• v.42 no.5
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• pp.744-751
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• 1995

Background: Asthma is an inflammatory disease because there are many inflammatory changes in the asthmatic airways. Axon reflex mechanisms may be involved in the pathogenesis of asthma. Sensory neuropeptides are involved in this inflammation, which is defined as neurogenic inflammation. Substance p, neurokinin A, and neurokinin B may be main neuropeptides of neurogenic inflammation in airways. These tachykinins act on neurokinin receptors. Three types of neurokinin receptors, such as $NK_1$, $NK_2$, and $NK_3$, are currently recognized, at which substance p, neurokinin A, and neurokinin B may be the most relevant natural agonist of neurogenic inflammation in airways. The receptor subtypes present in several tissues have been characterized on the basis of differential sensitivity to substance p, neurokinin A, and neurokinin B. Plasma extravasation and vasodilation are induced by substance p more potently than by neurokinin A, indicating NK1 receptors on endothelial cells mediate the response. But airway contraction is induced by neurokinin A more potently than by substance P, indicating the $NK_2$ receptors in airway smooth muscles. These receptors are used to evaluate the pathogenesis of brochial asthma. FK224 was identified from the fermentation products of Streptomyces violaceoniger. FK224 is a dual antagonist of both $NK_1$ and $NK_2$ receptors. Purpose: For a study of pathogenesis of bronchial asthma, the effect of FK224 on plasma extravasation induced by vagal NANC electrical stimulation was evaluated in rat airway. Method: Male Sprague-Dawley rats weighing 180~450gm were anesthetized by i.p. injection of urethane. Plasma extravasation was induced by electrical stimulation of cervical vagus NANC nerves with 5Hz, 1mA, and 5V for 2 minutes(NANC2 group) and for sham operation without nerve stimulation(control group). To evaluate the effect of FK224 on plasma extravasation in neurogenic inflammation, FK224(1mg/kg, Fujisawa Pharmaceutical Co., dissolved in dimethylsulphoxide; DMSO, Sigma Co.) was injected 1 min before nerve stimulation(FK224 group). To assess plasma exudation, Evans blue dye(20mg/kg, dissolved in saline) was used as a plasma marker and was injected before nerve stimulation. After removal of intravascular dye, the evans blue dye in the tissue was extracted in formamide($37^{\circ}C$, 24h) and quantified spectrophotometrically by measuring dye absorbance at 629nm wavelength. Tissue dye content was expressed as ng of dye per mg of wet weight tissue. The amount of plasma extravasation was measured on the part of airways in each groups. Results: 1) Vagus nerve(NANC) stimulation significantly increased plasma leakage in trachea, main bronchus, and peripheral bronchus compared with control group, $14.1{\pm}1.6$ to $49.7{\pm}2.5$, $17.5{\pm}2.0$ to $38.7{\pm}2.8$, and $12.7{\pm}2.2$ to $19.1{\pm}1.6ng$ of dye per mg of tissue(mean ${\pm}$ SE), respectively(p<0.05). But there was not significantly changed in lung parenchyma(p>0.05) 2) FK224 had significant inhibitory effect upon vagal nerve stimulation-induced airway plasma leakage in any airway tissues of rat,such as trachea, main bronchus, and peripheral bronchus compared with vagus nerve stimulation group, 49%, 58%, and 70%, respectively(p<0.05). Inhibitory effect of FK224 on airway plasma leakage in neurogenic inflammation was revealed the more significant in peripheral bronchus, but no significant in lung parenchyma. Conclusion: These results suggest that FK224 is a selective NK receptor antagonist which effectively inhibits airway plasma leakage induced by the endogenous neurotransmitters relased by neurogenic inflammation in rat airway. Tachykinin receptor antagonists may be useful in the treatment of brochial asthma.

• Tuberculosis and Respiratory Diseases
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• v.54 no.1
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• pp.80-90
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• 2003

Background : Goblet cell hyperplasia is a critical pathological feature in hypersecretory diseases of the airways. A bacterial infection of the lung is also known to induce inflammatory responses, which can lead to the overproduction of mucus. Recently, mucin synthesis in the airways has been reported to be regulated by neutrophilic inflammation-induced epidermal growth factor receptor (EGFR) expression and activation. In addition, it was reported that migration of the activated neutrophils is dependent on the matrix metalloproteinases (MMPs), especially MMP-9. In this study, bacterial lipopolysaccharide (LPS)-induced goblet cell hyperplasia and mucus hypersecretion by EGFR cascade, resulting from the MMPs-dependent neutrophilic inflammation were investigated in the rat airways. Methods : Pathogen-free Sprague-Dawley rats were studied in vivo. Various concentrations of LPS were instilled into the trachea in $300{\mu}{\ell}$ PBS (LPS group). Sterile PBS ($300{\mu}{\ell}$) was instilled into the trachea of the control animals (control group). The airways were examined on different days after instilling LPS. For an examination of the relationship between the LPS-induced goblet cell hyperplasia and MMPs, the animals were pretreated 3 days prior to the LPS instillation and daily thereafter with the matrix metalloproteinase inhibitor (MMPI; 20 mg/Kg/day of CMT-3; Collagenex Pharmaceuticals, USA). The neutrophilic infiltration was quantified as a number in five high power fields (HPF). The alcian blue/periodic acid-Schiff (AB/PAS) stain were performed for the mucus glycoconjugates and the immunohistochemical stains were performed for MUC5AC, EGFR and MMP-9. Their expressions were quantified by an image analysis program and were expressed by the percentage of the total bronchial epithelial area. Results : The instillation of LPS induced AB/PAS and MUC5AC staining in the airway epithelium in a time- and dose-dependent manner. Treatment with the MMPI prevented the LPS-induced goblet cell hyperplasia significantly. The instillation of LPS into the trachea induced also EGFR expression in the airway epithelium. The control airway epithelium contained few leukocytes, but the intratracheal instillation of LPS resulted in a neutrophilic recruitment. A pretreatment with MMPI prevented neutrophilic recruitment, EGFR expression, and goblet cell hyperplasia in the LPS-instilled airway epithelium. Conclusion : Matrix metalloproteinase is involved in LPS-induced mucus hypersecretion, resulting from a neutrophilic inflammation and EGFR cascade. These results suggest a potential therapeutic role of MMPI in the treatment of mucus hypersecretion that were associated with a bacterial infection of the airways.

• The Korean Journal of Pharmacology
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• v.30 no.2
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• pp.227-242
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• 1994

The general pharmacological effects of a new anthracycline anticancer agent, DA-125 $[7-0-(2,\;6-dideoxy-2-fluoro-{\alpha}-L-talopyranosyl)-adriamycinone-14-{\beta}-alaninate{\cdot}HCI]$ were investigated in mice, rats, guinea pigs, rabbits and dogs. Intravenous administration of DA-125 presented no significant effects on the central and peripheral nervous systems of ICR mice except a decrease in the numbers of acetic acid-induced writhing response at a dose of 10 mg/kg. In anesthetized rats and dogs, DA-125 produced a transient depression of blood pressure and an increase in heart rate, but did not affect the peripheral blood flow in the isolated ear vessels of rabbits and the mechanical functions of the isolated hearts of guinea pigs. No significant effects were observed on the gastrointestinal functions and the contractilities of smooth muscle preparations obtained from guinea pig trachea, rabbit ileum, pregnant and non-pregnant uterus and vas deferens of rats. DA-125 Increased the contractility of the isolated ileum of guinea pigs in a dose range of $10^{-6}{\sim}10^{-9}g/ml$, and also increased, but weaker than adriamycin, the vascular permeability in rat skin. DA-125 had no effect on the kallikrein-induced increase in permeability and the permeability of the visceral organs. DA-125 did not adversely affect the liver function and the blood coagulation system, and did not induce hemolysis in vitro. It is concluded from the results that the general pharmachological effects of DA-125 are similar to or weaker than those of adriamycin, and that little adverse effects are anticipated with a therapeutic dose range.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.35 no.5
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• pp.342-351
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• 2013

Advances in immunosuppressive treatments and microsurgical techniques have rendered composite tissues allotransplantation (CTA), such as heteregeneous or non-organ tissues, possible in humans. CTA has evolved dramatically since the first successful rat hind limb allotransplantation. Numerous clinical applications including face, hand, trachea, larynx, and vascularized joint have been performed. Although composite tissue allografts are still in their infancy, they have opened a new era in the field of transplantation surgery and pathology, so that maxillofacial reconstructive surgeons may occasionally be faced with the challenge of diagnosing skin refection of a composite tissue allograft. Facial allotransplantation (FAT) is a new surgical technique that could be considered as a new paradigm in facial reconstruction. Since the first human FAT had been achieved in 2005, 17 cases have been reported in the world up to date. However, many problems such as life-long immunosuppression, immune rejection, ethical problems and psychological problems are remained, so facial CTA is new reconstructive option with no general acceptance. The authors reviewed the indications, the results of 17 cases and their complications, and additional consideration factors in this article, and intended to raise the awareness of oral and maxillofacial surgeons in this type of facial transplantation.

• Journal of Physiology & Pathology in Korean Medicine
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• v.16 no.2
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• pp.322-326
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• 2002

Artemisia iwayomogi has been used in Korea for many centuries as a treatment for anemia. The effect of Artemisia iwayomogi on tracheal smooth muscle is not known. The purpose of the present study is to determine the effect of Artemisia iwayomogi on histamine induced tracheal smooth muscle contraction in guinea pigs. Guinea pigs(500g, male) were killed by CO₂ exposure and a segment (8-10mm) of the thoracic trachea from each rat and guinea pig was cut into equal segments and mounted ‘in pairs’ in a tissue bath. Contractile force was measured with force displacement transducers under 0.5g loading tension. The dose of histamine (His) which evoked 50% of maximal response (ED/sub 50/) was obtained from cumulative dose response curves for histamine (10/sup -7/～10/sup -4/M). Contractions evoked by His (ED/sub 50/) were inhibited significantly by Artemisia iwayomogi. In guinea pig tracheal smooth muscle, the mean percent inhibition of histamine induced contraction was 31.9% (p<0.05) after 100㎕/㎖ Artemisia iwayomogi. L-NNA slightly but significantly attenuated the inhibitory effects of Artemisia iwayomogi. Following treatment with L-NNA, the mean percent inhibition caused by 100㎕/㎖ Artemisia iwayomogi fell to 44.6% in guinea pig induced by histamine contraction. Propranolol, indomethacin and methylene blue did not significantly alter the inhibitory effect of Artemisia iwayomogi. These results indicate that Artemisia iwayomogi can relax histamine induced contraction of guinea pig, and that this inhibition related to nitric oxide formation.

• YAKHAK HOEJI
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• v.36 no.1
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• pp.17-25
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• 1992

The general and some other pharmacological actions of growth hormone without N-terminal methionine(rhGH) were investigated in animals. The hormone had no influences on the central nervous system and on body temperature at a high oral dose of 40 IU/kg in animals. It had neither analgesic nor antiepileptic actions at the high doses. In the isolated ileum and trachea of guinea-pig and isolated stomach fundus and uterus of rat, it showed neither contractive nor relaxing effects at a concentration of $1{\times}10^{-3}\;IU/ml$ in bath, and no inhibitory action at a dose of $1{\times}10^{-3}\;IU/ml$ against the contractions produced by histamine ($5{\times}10^{-5}\;g/ml$), serotonin($1{\times}10^{-5}\;g/ml$), acetylcholine($1{\times}10^{-5}\;g/ml$) and oxytocin($5{\times}10^{-3}\;IU/ml$). Furthermore, the intravenous injection of 20 IU/kg rhGH had no influences on the normal blood pressure and respiration in rabbits. These negative results in pharmacological profile are thought that the hormone may not elicit serious side effects. On the other hand, the rhGH exhibited a weak inhibitory action of glucose tolerance in normal rats, significantly lowered the blood glucose contents in adrenalectomized rats 20 min after i.v. administration of 80 IU/kg, and showed a significant inhibitory effect on in vitro glycerol release in epinephrine-stimulated epididymal fat pad segments of rats.

• The Journal of Korean Medicine
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• v.19 no.2
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• pp.86-99
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• 1998

Antiallergic action and the effect on normal immune function of an oriental medical prescription Gegangjochohwangsinbutang (GJHB) water extract were examined in several experimental models. GJHB water extract at 600-1,800 mg/kg/day administered orally for one week significantly recuded the passive cutaneous anaphylaxis in rats in a dose-dependent manner. Whereas the extravasation induced by intradermal leukotriene D4 in rats was significantly inhibited by GJHB water extract at 600-1,800 mg/kg/day, po, for one week, but that by histamine or serotonin was not influenced. In a rat asthma model, the delayed airway resistance in ovalbumin-induced asthmatic response was significantly attenuated by GJHB water extract of 1,800 mg/kg/day, po, administered for one week. It was also found that GJHB water extract at 1 mg/kg concentration in vitro relaxed the isolated uinea pig trachea contracted by leukotrien D4, but not that by histamine. The above findings indicate that GJHB water extract can ameliorate the adverse effect of type Ⅰ allergy such as asthma. This pharmacological action seems to derive from an inhibition of GJHB water extract on leukotriene D4-related physiological change.

• The Journal of Internal Korean Medicine
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• v.18 no.2
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• pp.83-93
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• 1997

Rhizoma Coptidis, a traditional herb medicine, has been used in Korea and China for many centuries as a treatment for many disease. The purpose of the present study was to determine the effect of Rhizoma Coptidis on histamine-induced tracheal smooth muscle contraction in guinea pigs and rats. Guinea pigs(500g, male) and rats(250g, male) were killed by $CO_2$ exposure and a segment (8-10mm) of the thoracic trachea from each guinea pig was cut into equal segments and mounted 'in pairs' in a tissue bath. Contractile force was measured with force displacement transducers under 0.5g loading tension. The dose of histamine which evoked 50% of maximal response ($ED_{50}$) was obtained from cumulative dose response curves for histamine ($10^{-7}-10^{-3}M$). Contractions evoked by histamine($ED_{50}$) were inhibited significantly by Rhizoma Coptidis. The mean percent inhibition was 33.2% after 1.5mg/ml Rhizoma Coptidis, and 69.5% after 5.0mg/ml Rhizoma Coptidis in guinea pigs, and the mean percent inhibition was 25.3% after 1.5mg/ml Rhizoma Coptidis, and 65.8% after 5.0mg/ml Rhizoma Coptidis in rats. Indomethacin ($10^{-7}M$) slightly but significantly attenuated the inhibitory effects of Rhizoma Coptidis. But propranolol and methylene blue ($10^{-7}M$) did not significantly alter the inhibitory effect of Rhizoma Coptidis. These results indicate that Rhizoma Coptidis can relax histamine-induced contraction of guinea pig and rat tracheal smooth muscle, and that this inhibition involves, in part, cyclooxygenese inhibitor.

• Journal of Pharmacopuncture
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• v.25 no.3
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• pp.209-215
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• 2022

Objectives: Aqueous leaf extract of Tridax procumbens (ALETP) has potent relaxant activity. However, this relaxant activity in respiratory smooth muscle remains uninvestigated. This study investigates the effect of ALETP on the contractile activity of tracheal smooth muscle (TSM) in adult male Wistar rats. Methods: Twelve male Wistar rats divided into 2 groups and were treated with either 100 mg/kg of ALETP (ALETP treatment group) or vehicle (distilled water; control group) through oral gavage for 4 weeks. Dose responses of TSM from the 2 groups to acetylcholine (10^-9 to 10^-5 M), phenylephrine (10^-9 to 10^-5 M), and potassium chloride (KCl; 10^-9 to 10^-4 M) were determined cumulatively. Furthermore, cumulative dose responses to acetylcholine (10^-9 to 10^-5 M) after pre-incubation of TSM with atropine (10^-5 M), L-NAME (10^-4 M), indomethacin (10^-4 M), and nifedipine (10^-4 M), were determined. Results: Treatment with ALETP substantially inhibited TSM contraction stimulated by cumulative doses of acetylcholine, phenylephrine, and KCl. Furthermore, preincubation of TSM from the 2 groups in atropine significantly inhibited contractility in TSM. Incubation in L-NAME and indomethacin also significantly inhibited contractility in TSM of ALETP-treated rats compared to that of controls. Contractile activity of the TSM was also inhibited significantly with incubation in nifedipine in ALETP-treated rats. Conclusion: ALETP enhanced relaxant activity in rat TSM primarily by blocking the L-type calcium channel and promoting endothelial nitric oxide release. ALETP contains agents that may be useful in disorders of the respiratory tract.

• Tuberculosis and Respiratory Diseases
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• v.48 no.4
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• pp.487-499
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• 2000

Background : Acute lung injury is an hypoxic respiratory failure resulting from damage to the alveolar-capillary membrane, which can be developed by a variety of systemic inflammatory diseases. In this study the therapeutic effects of intra-tracheal pulmonary surfactant instillation was evaluated in the intratracheal endotoxin induced acute lung injury model of a rat. Methods : Twenty Sprague-Dawley rats were divided into 4 groups, and normal saline (2 ml/kg, for group 1) or LPS (5 mg/kg, for group 2, 3, and 4) was instilled into the trachea respectively. Either normal saline (2 ml/kg, for group 1 & 2, 30 min later) or bovine surfactant (15 mg/kg, 30 min later for group 3, 5 hr later for group 5) was instilled into the trachea. The therapeutic effect of intratracheal surfactant therapy was evaluated with one chamber body plethysmography (respiratory frequency, tidal volume and enhanced pause), ABGA, BAL fluid analysis (cell count with differential, protein concentration) and pathologic examination of the lung. Results : Intratracheal endotoxin instillation increased the respiration rate decreased the tidal volume and int creased the Penh in all group of rats. Intratracheal instillation of surfactant decreased Penh, increased arterial oxygen tension, decreased protein concentration of BAL fluid and decreased lung inflammation at both times of administration (30 minute and 5 hour after endotoxin instillation). Conclusion : Intratracheal instillation of surfactant can be a beneficial therapeutic modality as discovered in the acute lung injury model of rats induced by intratracheal LPS intillation. It deserves to be evaluated for treatment of human acute lung injury.