• IMMUNE NETWORK
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• 제21권4호
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• pp.26.1-26.28
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• 2021

Asthma exacerbations are a major cause of intractable morbidity, increases in health care costs, and a greater progressive loss of lung function. Asthma exacerbations are most commonly triggered by respiratory viral infections, particularly with human rhinovirus (hRV). Respiratory viral infections are believed to affect the expression of indoleamine 2,3-dioxygenase (IDO), a limiting enzyme in tryptophan catabolism, which is presumed to alter asthmatic airway inflammation. Here, we explored the detailed role of IDO in the progression of asthma exacerbations using a mouse model for asthma exacerbation caused by hRV infection. Our results reveal that IDO is required to prevent neutrophilic inflammation in the course of asthma exacerbation caused by an hRV infection, as corroborated by markedly enhanced Th17- and Th1-type neutrophilia in the airways of IDO-deficient mice. This neutrophilia was closely associated with disrupted expression of tight junctions and enhanced expression of inflammasome-related molecules and mucin-inducing genes. In addition, IDO ablation enhanced allergen-specific Th17- and Th1-biased CD4⁺ T-cell responses following hRV infection. The role of IDO in attenuating Th17- and Th1-type neutrophilic airway inflammation became more apparent in chronic asthma exacerbations after repeated allergen exposures and hRV infections. Furthermore, IDO enzymatic induction in leukocytes derived from the hematopoietic stem cell (HSC) lineage appeared to play a dominant role in attenuating Th17- and Th1-type neutrophilic inflammation in the airway following hRV infection. Therefore, IDO activity in HSC-derived leukocytes is required to regulate Th17- and Th1-type neutrophilic inflammation in the airway during asthma exacerbations caused by hRV infections.

• Tuberculosis and Respiratory Diseases
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• 제81권1호
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• pp.80-87
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• 2018

Background: Asthma is a disease of chronic airway inflammation with heterogeneous features. Neutrophilic asthma is corticosteroid-insensitive asthma related to absence or suppression of $T_H2$ process and increased $T_H1$ and/or $T_H17$ process. Macrolides are immunomodulatory drug that reduce airway inflammation, but their role in asthma is not fully known. The purpose of this study was to evaluate the role of macrolides in neutrophilic asthma and compare their effects with those of corticosteroids. Methods: C57BL/6 female mice were sensitized with ovalbumin (OVA) and lipopolysaccharides (LPS). Clarithromycin (CAM) and/or dexamethasone (DXM) were administered at days 14, 15, 21, 22, and 23. At day 24, the mice were sacrificed. Results: Airway resistance in the OVA+LPS exposed mice was elevated but was more attenuated after treatment with CAM+DXM compared with the monotherapy group (p<0.05 and p<0.01). In bronchoalveolar lavage fluid study, total cells and neutrophil counts in OVA+LPS mice were elevated but decreased after CAM+DXM treatment. In hematoxylin and eosin stain, the CAM+DXM-treated group showed less inflammation additively than the monotherapy group. There was less total protein, interleukin 17 (IL-17), interferon ${\gamma}$, and tumor necrosis factor ${\alpha}$ in the CAM+DXM group than in the monotherapy group (p<0.001, p<0.05, and p<0.001). More histone deacetylase 2 (HDAC2) activity was recovered in the DXM and CAM+DXM challenged groups than in the control group (p<0.05). Conclusion: Decreased IL-17 and recovered relative HDAC2 activity correlated with airway resistance and inflammation in a neutrophilic asthma mouse model. This result suggests macrolides as a potential corticosteroid-sparing agent in neutrophilic 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.

• Tuberculosis and Respiratory Diseases
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• 제54권1호
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• pp.80-90
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• 2003

배경 : 본 연구에서는 세균성 리포다당질(lipopolysac-charide, LPS)로 인한 호중구성 염증이 EGFR 시스템을 통해서 배상 세포의 이형성 및 점액의 과다 분비를 유발할 것이라는 가설 하에, LPS와 MMPs 억제제(matrix metalloproteinase inhibitor, MMPI)를 투여한 후 EGFR 및 MMP-9의 발현을 연구하고자 하였다. 방법 : Pathogen-free Sprague-Dawley 를, 다양한 농도의 LPS를 투여한 군과 투여하지 않은 대조군으로 나누어 기도의 조직학적인 변화를 날짜 별로 관찰하였고, MMPI(CMT-3)를 LPS 투여 3일 전부터 매일 구강을 통해 섭식시켰다. 호중구의 침윤은 다섯 개의 고배율 시야에서 관찰된 호중구의 수로 정량화하여 비교하였고, mucus glycoconjugate에 대한 AB/PAS 염색 및 MUC5AC, EGFR, MMP-9에 대한 면역조직화학 염색 (immunohistochemical stain)을 시행하였다 결과 : LPS를 투여한 경우 기도 상피의 AB/PAS 및 MUC5AC의 염색 정도는 시간 및 용량 의존적으로 증가하였고, MMPI를 치료할 경우에 LPS로 인한 배상세포의 과형성이 유의하게 감소하였다. LPS를 주입할 경우 호중구의 침윤이 증가하였고 기도 상피에서 EGFR의 발현을 증가시켰다. MMPI로 치료할 경우 LPS로 인한 호중구의 침윤 및 EGFR의 발현 그리고 배상세포의 과형성이 현저하게 감소되었다. 결론 : Matrix metalloproteinase는 호중구성 염증 및 EGFR에 의해 발생하는 LPS에 의한 배상 세포의 과형성 및 점액 과다분비의 기전에 있어서 밀접하게 관련되고, 따라서 점액 과다분비를 특징으로 하는 세균 감염으로 인한 기도 질환의 치료에 있어서 MMPI가 잠재적인 임상적 효과가 있을 것으로 사료된다.

• 대한수의학회지
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• 제46권4호
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• pp.405-408
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• 2006

A 4-year-old male Miniature Pinscher was referred because of head tilt, nystagmus, and ataxia. The hemogram revealed a moderate neutrophilic leukocytosis. On magnetic resonance imaging, cerebellar inflammation was detected. And cerebrospinal fluid analysis indicated marked neutrophilic pleocytosis. Based on these results, bacterial meningoencephalitis was suspected. The clinical signs were well controlled by a combination antibiotics therapy of the third generation cephalosporins (cefotaxime and cefixime) and metronidazole. We tentatively diagnosed this case as a bacterial meningoencephalitis because clinical signs were improved after only antibiotics therapy and relapsed when stopped antibiotics administrations, even though the result of bacterial culture on communication of cerebrospinal fluid (CSF) was negative.

• Tuberculosis and Respiratory Diseases
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• 제85권1호
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• pp.67-73
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• 2022

Background: Bronchiectasis patients with neutrophilic airway inflammation develop symptoms of chronic cough, sputum production, and recurrent exacerbations. Roflumilast has anti-inflammatory actions via decreased neutrophilic airway inflammation. The effectiveness of roflumilast to reduce bronchiectasis exacerbation has never been evaluated. Methods: We conducted a double-blinded, randomized, placebo-controlled trial. Our primary objective was to assess the effect of roflumilast compared with that of a placebo in reducing exacerbation rates in bronchiectasis patients. The secondary objectives were the changes in forced expiratory volume in 1 second (FEV₁) and St. George's Respiratory Questionnaire (SGRQ). Bronchiectasis patients older than 18 years who had had two exacerbations during the previous 12 months were randomly assigned to receive either 500 ㎍ of either roflumilast or a placebo once daily for 6 months in a 1:1 ratio. Results: Forty bronchiectasis patients who had experienced exacerbations were screened. Thirty patients completed the study after 6 months of treatment: roflumilast group (n=15) and placebo group (n=15). The rates of exacerbations were 0.57 and 0.59 per patient in the roflumilast and placebo groups, respectively. Prebronchodilator FEV₁ increased by 0.07 L from baseline in the roflumilast group and decreased by 0.015 L in the placebo group, but the difference was not significant. No significant differences were observed in the change of SGRQ scores between the roflumilast and placebo groups. Roflumilast had significant side effects, including loss of appetite and headache. Conclusion: Roflumilast did not significantly affect the rate of exacerbations or quality of life. However, FEV₁ tended to improve more in the roflumilast group than in the placebo group.

• IMMUNE NETWORK
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• 제22권6호
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• pp.45.1-45.15
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• 2022

Asthma is a chronic airway inflammatory disease characterized by reversible airway obstruction and airway hyperreactivity to various environmental stimuli, leading to recurrent cough, dyspnea, and wheezing episodes. Regarding inflammatory mechanisms, type 2/eosinophilic inflammation along with activated mast cells is the major one; however, diverse mechanisms, including structural cells-derived and non-type 2/neutrophilic inflammations are involved, presenting heterogenous phenotypes. Although most asthmatic patients could be properly controlled by the guided treatment, patients with severe asthma (SA; classified as a treatment-refractory group) suffer from uncontrolled symptoms with frequent asthma exacerbations even on regular anti-inflammatory medications, raising needs for additional controllers, including biologics that target specific molecules found in asthmatic airway, and achieving the precision medicine for asthma. This review summarizes the immunologic basis of airway inflammatory mechanisms and current biologics for SA in order to address unmet needs for future targets.

• 한국독성학회:학술대회논문집
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• 한국독성학회 2005년도 춘계 국제심포지엄 및 학술대회
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• pp.51-82
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• 2005

To compare the pulmonary toxicity between ultrafine colloidal silica particles (UFCSs) and fine colloidal silica particles (FCSs), mice were intratracheally instilled with 3 mg of 14-nm UFCSs and 230-nm FCSs and pathologically examined from 30 mill to 24 hr post-exposure. Histopathologically, lungs exposed to both sizes of particles showed bronchiolar degeneration and necrosis, neutrophilic inflammation in alveoli with alveolar type II cell proliferation and particle-laden alveolar macrophage accumulation. UFCSs, however, induced extensive alveolar hemorrhage compared to FCSs from 30 min onwards. UFCSs also caused more severe bronchiolar epithelial cell necrosis and neutrophil influx in alveoli than FCSs at 12 and 24 hr post-exposure. Laminin positive immunolabellings in basement membranes of bronchioles and alveoli of UFCSs treated animals was weaker than those of FCSs treated animals in all observation times. Electron microscopy demonstrated UFCSs and FCSs on bronchiolar and alveolar wall surface as well as in the cytoplasm of alveolar epithelial cells, alveolar macrophages and neutrophils. Type I alveolar epithelial cell erosion with basement membrane damage in UFCSs treated animals was more severe than those in FCSs treated animals. At 12 and 24 hr post-exposure, bronchiolar epithelia cells in UFCSs treated animals showed more intense vacuolation and necrosis compared to FCSs treated animals. These findings suggest that UFCSs has greater ability to induce lung inflammation and tissue damages than FCSs.

• 통합자연과학논문집
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• 제9권2호
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• pp.121-127
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• 2016

CXC chemokine receptor 2 (CXCR2) is a prominent chemokine receptor on neutrophils. The neutrophilic inflammation in the lung diseases is found to be largely regulated through CXCR2 receptor. Antagonist of CXCR2 may reduce the neutrophil chemotaxis and alter the inflammatory response. Hence, in the present study, ligand based Comparative molecular field analysis (CoMFA) was performed on a series of CXCR2 antagonist named pyrimidine-5-carbonitrile-6-alkyl derivatives. The optimum CoMFA model was obtained with statistically significant cross-validated coefficients ($q^2$) of 0.568 and conventional coefficients ($r^2$) of 0.975. The contour maps suggest the important structural modifications and this study can be used to guide the development of potent CXCR2 antagonist.

• 대한수의학회지
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• 제36권2호
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• pp.447-451
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• 1996

A case of enteric pythiosis in the jejunum is reported in a 28-month-old, male Jindo dog. Grossly, a 20cm segment of the cranial jejunal wall was markedly thickened to a thickness of 10cm and the lumen was narrowed. Histological examination of the jejunum reveals transmurally affected multifocal to coalescing granulomatous inflammation. The granulomatous foci were composed of a necrotic center with neutrophilic infiltration and occasionally non-parallel, branching, septate hyphae surrounded by numerous epithelioid macrophages, multinucleated giant cells, lymphocytes and fibrosis. Multinucleated giant cells occasionally contain fragment of hyphae. The diagnosis was based on light microscopical studies and positive PAS and immunostaining for Pythium insidiosum. This is believed to be the first reported case of canine enteric pythiosis in Korea.