Osteopontin contributes to late-onset asthma phenotypes in adult asthma patients

Hoang Kim Tu Trinh,Thuy Van Thao Nguyen,Seo-Hee Kim,Thi Bich Tra Cao,Quoc Quang Luu,김승현,박해심 생화학분자생물학회 2020 Experimental and molecular medicine Vol.52 No.-

Patients with late-onset asthma (LOA) have poor clinical outcomes. Osteopontin (OPN) is associated with airway inflammation and remodeling. To investigate the role of OPN in LOA compared to early-onset asthma (EOA), serum OPN levels were compared between 131 adult asthma patients (48 LOA and 83 EOA patients) and 226 healthy controls (HCs). BALB/c mice were sensitized with ovalbumin with/without polyinosinic-polycytidylic acid (poly(I:C)) from week 6 (A6 mice) or week 12 (A12 mice) after birth. Airway hyperresponsiveness (AHR), bronchoalveolar lavage fluid (BALF), cell counts, histology, and Spp1 expression were assessed. The levels of OPN, transforming growth factor β1 (TGF-β1), chitinase 3-like 1 (CH3L1), and interleukin (IL) 5 were measured by ELISA. The expression of Smad3 phosphorylation and tissue transglutaminase 2 (TGM2) was evaluated by Western blot. The serum OPN levels were significantly higher in asthma patients than in HCs and in LOA patients than in those with EOA (P < 0.05) and were positively correlated with serum TGF-β1 and CH3L1 (r = 0.174, r = 0.264; P < 0.05). A12 mice showed elevated AHR with increased levels of OPN/TGF-β1/IL-5 in BALF and Spp1 compared to A6 mice. Poly(I:C) induced remarkable TGF-β1, CH3L1, Th2 cytokine, and OPN levels in BALF and the expression of phosphorylated Smad3, TGM2, and Spp1 in the lungs. OPN triggered TGF-β1/Smad3 signaling in the lungs, which was suppressed by dexamethasone and anti-IL5 antibody. In conclusion, aging and exposure to viral infections may induce OPN release and consequently modulate inflammation and TGF-β1/ Smad3-related remodeling, contributing to the development of LOA.

The synergistic effects of clopidogrel with montelukast may be beneficial for asthma treatment

Trinh, Hoang Kim Tu,Nguyen, Thuy Van Thao,Choi, Youngwoo,Park, Hae‐,Sim,Shin, Yoo Seob John Wiley and Sons Inc. 2019 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.23 No.5

<P><B>Abstract</B></P><P>Platelets modulate asthma pathogenesis by forming the platelet‐eosinophil aggregation (PEA), which facilitates the activation of eosinophils. Platelets exhibit the purinergic receptor (P2Y12R), which responds to cysteinyl leukotriene E4 (LTE<SUB>4</SUB>). We have suggested that the combination of an antiplatelet drug (clopidogrel, [Clo]) and montelukast (Mon) would synergistically suppress asthma. BALB/c mice were intraperitoneally sensitized with ovalbumin (OVA) on days 0 and 14 and subsequently challenged on days 28‐30 and 42‐44. Mice were administered with Clo (10 mg/kg), Mon (10 mg/kg) or both drugs (Clo/Mon) orally 30 minutes before the OVA (1%) challenge on days 42‐44. Mice were assayed for airway hyper‐responsiveness (AHR) to methacholine and airway inflammation. Clopidogrel and montelukast attenuated the increased AHR; the combined treatment was more effective than a single treatment for total and eosinophil counts (all <I>P < </I>0.05). Levels of interleukin (IL)‐4, IL‐5, IL‐13, platelet factor 4, eosinophil peroxidase and LTE<SUB>4</SUB> increased in the bronchoalveolar lavage fluid of asthmatic mice, but these levels decreased in mice treated with Clo/Mon (all <I>P < </I>0.05). Goblet cell hyperplasia decreased in response to Clo/Mon. Mouse platelets and eosinophils were isolated and co‐cultured for an in vitro assay with 10 µmol/L adenosine diphosphate (ADP), LTE<SUB>4</SUB> (200 nmol/L), Mon (1 µmol/L), Clo (1 µmol/L) and Clo/Mon (1 µmol/L). Flow cytometry revealed that the increased formation of the PEA (%) was fully mediated by ADP and partly mediated by LTE<SUB>4</SUB>. Clo/Mon reduced ADP‐induced PEA formation and P‐selectin expression (<I>P < </I>0.05). In conclusion, Clo/Mon synergistically relieved asthma by inhibiting ADP‐mediated PEA formation.</P>

Automated annotation of web page contents for rapid creation of Semantic web contents

Tu Minh Phuong,Pham Hoang Duy,Trinh Huu Kien 대한전자공학회 2004 International Conference on Electronics, Informati Vol.2004 No.8

Role of clusterin/progranulin in toluene diisocyanate-induced occupational asthma

최길순,Hoang Kim Tu Trinh,양은미,예영민,신유섭,김승현,박해심 생화학분자생물학회 2018 Experimental and molecular medicine Vol.50 No.-

Toluene diisocyanate (TDI) exposure induces oxidative stress and epithelial cell-derived inflammation, which affect the pathogenesis of TDI-induced occupational asthma (TDI-OA). Recent studies suggested a role for clusterin (CLU) and progranulin (PGRN) in oxidative stress-mediated airway inflammation. To evaluate CLU and PGRN involvement in airway inflammation in TDI-OA, we measured their serum levels in patients with TDI-OA, asymptomatic exposed controls (AECs), and unexposed healthy normal controls (NCs). Serum CLU and PGRN levels were significantly lower in the TDI-OA group than in the AEC and NC groups (P < 0.05). The sensitivity and specificity for predicting the TDI-OA phenotype were 72.4% and 53.4% when either CLU or PGRN levels were below the cutoff values (≤125 μg/mL and ≤68.4 ng/mL, respectively). If both parameters were below the cutoff levels, the sensitivity and specificity were 58.6% and 89.8%, respectively. To investigate CLU and PGRN function, we evaluated their production by human airway epithelial cells (HAECs) in response to TDI exposure and co-culturing with neutrophils. TDI-human serum albumin stimulation induced significant CLU/PGRN release from HAECs in a dose-dependent manner, which positively correlated with IL-8 and folliculin levels. Co-culturing with neutrophils significantly decreased CLU/PGRN production by HAECs. Intracellular ROS production in epithelial cells co-cultured with neutrophils tended to increase initially, but the ROS production decreased gradually at a higher ratio of neutrophils. Our results suggest that CLU and PGRN may be involved in TDI-OA pathogenesis by protecting against TDI-induced oxidative stress-mediated inflammation. The combined CLU/PGRN serum level may be used as a potential serological marker for identifying patients with TDI-OA among TDI-exposed workers.

A Study on the Human Resources Development of Korean Tour Guide in Vietnam

Bui Kim Luan,Trinh Tu Hoang 한국문화관광학회 2015 문화관광연구 Vol.17 No.2

The successful cooperation on almost of fields to increase the demand of exchanges between South Korea and Vietnam, especially in tourism industry as Korean customers visit Vietnam. However, the rapid growth could not satisfy the requirement of tour guides as Korean language. In this research, the authors focus on the evaluation of tour guides resources as Korean language in Vietnam, particularly in Da Nang city. Through this study, we suggest some solutions of tour guides resources as Korean language for Vietnam and Da Nang a well.

A Role of the ABCC4 Gene Polymorphism in Airway Inflammation of Asthmatics

Palikhe, Sailesh,Uuganbayar, Udval,Trinh, Hoang Kim Tu,Ban, Ga-Young,Yang, Eun-Mi,Park, Hae-Sim,Kim, Seung-Hyun Carfax 2017 MEDIATORS OF INFLAMMATION Vol.2017 No.-

<P>The ATP-binding cassette subfamily C member 4 gene encodes a transmembrane protein involved in the export of proinflammatory molecules, including leukotriene, prostaglandin, and sphingosine-1-phosphate across the plasma membrane. Those metabolites play important roles in asthma. We investigated the potential associations between <I>ABCC4</I> gene polymorphisms and asthma phenotype. In total, 270 asthma patients and 120 normal healthy controls were enrolled for a genetic association study. Two polymorphisms (−1508A>G and −642C>G) in the <I>ABCC4</I> promoter were genotyped. The functional variability of the promoter polymorphisms was analyzed by luciferase reporter assay. Inflammatory cytokine levels were measured by enzyme-linked immunosorbent assay. Serum and urinary eicosanoid metabolites, sphingosine-1-phosphate, were evaluated by quadrupole time-of-flight mass spectrometry. Asthma patients carrying the G allele at −1508A>G had significantly higher serum levels of periostin, myeloperoxidase, and urinary levels of 15-hydroxyeicosatetraenoic acid and sphingosine-1-phosphate (<I>P</I> = 0.016, <I>P</I> = 0.027, <I>P</I> = 0.032, and <I>P</I> = 0.010, resp.) compared with noncarrier asthma patients. Luciferase activity was significantly enhanced in human epithelial A549 cells harboring a construct containing the −1508G allele (<I>P</I> < 0.01 for each) compared with a construct containing the −1508A allele. A functional polymorphism in the <I>ABCC4</I> promoter, −1508A>G, may increase extracellular 15-hydroxyeicosatetraenoic acid, sphingosine-1-phosphate, and periostin levels, contributing to airway inflammation in asthmatics.</P>

Serum Periostin Levels: A Potential Serologic Marker for Toluene Diisocyanate-Induced Occupational Asthma

이지호,김상하,최영우,Hoang Kim Tu Trinh,양은미,반가영,신유섭,예영민,Kenji Izuhara,박해심 연세대학교의과대학 2018 Yonsei medical journal Vol.59 No.10

Purpose: Toluene diisocyanate (TDI) is a leading cause of occupational asthma (OA). Periostin is a matricellular protein implicatedin type 2 immunity-driven asthma. Its pathogenic role in TDI-OA has not been completely elucidated. The present study was performed to investigate the role of periostin in TDI-OA. Materials and Methods: Serum periostin levels were measured in subjects with TDI-OA, asymptomatic TDI-exposure controls (AECs), non-occupational asthmatics (NAs), and unexposed normal controls (NCs). To understand the mechanism by which TDI induces periostin production, primary small airway epithelial cells (SAECs) were cultured under stimulation of TDI and neutrophilsfrom asthmatic patients. Results: Fifty-three subjects with TDI-OA, 71 AECs, 67 NAs, and 83 NCs were enrolled. Serum periostin levels were significantly higher in TDI-OA subjects than in AECs (p=0.001), NAs (p<0.001), and NCs (p<0.001). In TDI-exposed subjects (TDI-OA and AEC), the PC20 methacholine levels were significantly lower in subjects with a higher periostin level than in those with a lower periostin level. TDI exposure did not increase periostin production directly by SAECs; however, periostin production increased significantly after co-culture with TDI and neutrophils, which was suppressed by an antioxidant. In addition, increased release of TGF-β1 was noted from SAECs when exposed to TDI and neutrophils, which was also suppressed by an antioxidant. Conclusion: These results suggest that an increased periostin level may contribute to the progression of airway inflammation to remodeling in TDI-exposed workers. A high serum periostin level is a potential serologic marker of the phenotype of TDI-OA.

A Role of the ABCC4 Gene Polymorphism in Airway Inflammation of Asthmatics

Palikhe, Sailesh,Uuganbayar, Udval,Trinh, Hoang Kim Tu,Ban, Ga-Young,Yang, Eun-Mi,Park, Hae-Sim,Kim, Seung-Hyun Carfax 2017 MEDIATORS OF INFLAMMATION Vol.2017 No.3

P2Y12 antagonist attenuates eosinophilic inflammation and airway hyperresponsiveness in a mouse model of asthma

Suh, Dong‐,Hyeon,Trinh, Hoang Kim Tu,Liu, Jing‐,Nan,Pham, Le Duy,Park, Sang Myun,Park, Hae‐,Sim,Shin, Yoo Seob CAROL DAVILA UNIVERSITY PRESS 2016 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.20 No.2

<P><B>Abstract</B></P><P>Leukotriene E4 (LTE4) that plays a key role in airway inflammation is expressed on platelets and eosinophils. We investigated whether blocking of the P2Y12 receptor can suppress eosinophilic inflammation in a mouse model of asthma because platelets and eosinophils share this receptor to be activated. BALB/c mice were sensitized by intraperitoneal injection of ovalbumin (OVA), followed by OVA nebulization. On each challenge day, clopidogrel, a P2Y12 antagonist was administered 30 min. before each challenge. Forty‐eight hours after the last OVA challenge, mice were assessed for airway hyperresponsiveness (AHR), cell composition and cytokine levels, including chemokine ligand 5 (CCL5), in bronchoalveolar lavage (BAL) fluid. EOL cells were treated with LTE4, with or without clopidogrel treatment, and intracellular and extracellular eosinophil cationic protein (ECP) expressions were measured to find the inhibiting function of P2Y12 antagonist on eosinophilic activation. The levels of P2Y12 expression were increased markedly in the lung homogenates of OVA‐sensitized and ‐challenged mice after platelet depletion. Administration of clopidogrel decreased AHR and the number of airway inflammatory cells, including eosinophils, in BAL fluid following OVA challenge. These results were associated with decreased levels of Th2 cytokines and CCL5. Histological examination showed that inflammatory cells as well as mucus‐containing goblet cells were reduced in clopidogrel‐administered mice compared to vehicle‐treated mice. Clopidogrel inhibited extracellular ECP secretion after LTE4 stimulation in EOL‐1 cells. Clopidogrel could prevent development of AHR and airway inflammation in a mouse model of asthma. P2Y12 can be a novel therapeutic target to the suppression of eosinophils in asthma.</P>

The role of autophagy in allergic inflammation: a new target for severe asthma

Jing-Nan Liu,서동현,Hoang Kim Tu Trinh,채용준,박해심,신유섭 생화학분자생물학회 2016 Experimental and molecular medicine Vol.48 No.-

Autophagy has been investigated for its involvement in inflammatory diseases, but its role in asthma has been little studied. This study aimed to explore the possible role of autophagy and its therapeutic potential in severe allergic asthma. BALB/c mice were sensitized with ovalbumin (OVA) on days 0 and 14, followed by primary OVA challenge on days 28–30. The mice received a secondary 1 or 2% OVA challenge on days 44–46. After the final OVA challenge, the mice were assessed for airway responsiveness (AHR), cell composition and cytokine levels in bronchoalveolar lavage fluid (BALF). LC3 expression in lung tissue was measured by western blot and immunofluorescence staining. Autophagosomes were detected by electron microscopy. 3-Methyladenine (3-MA) treatment and Atg5 knockdown were applied to investigate the potential role of autophagy in allergic asthma mice. AHR, inflammation in BALF and LC3 expression in lung tissue were significantly increased in the 2% OVA-challenged mice compared with the 1% OVA-challenged mice (Po0.05). In addition, eosinophils showed prominent formation of autophagosomes and increased LC3 expression compared with other inflammatory cells in BALF and lung tissue. After autophagy was inhibited by 3-MA and Atg5 shRNA treatment, AHR, eosinophilia, interleukin (IL)-5 levels in BALF and histological inflammatory findings were much improved. Finally, treatment with an anti-IL-5 antibody considerably reduced LC3 II expression in lung homogenates. Our findings suggest that autophagy is closely correlated with the severity of asthma through eosinophilic inflammation, and its modulation may provide novel therapeutic approaches for severe allergic asthma.