Chun Lee - Academia.edu (original) (raw)

Papers by Chun Lee

European Journal of Oncology Nursing, 2015

The aim of the study was to report the psychometric properties of the Arabic version of the Breas... more The aim of the study was to report the psychometric properties of the Arabic version of the Breast Cancer Screening Beliefs Questionnaire (BCSBQ). A convenience sample of 251 Arabic-Australian women was recruited from a number of Arabic community organizations. Construct validity was examined by Cuzick's non-parametric test while Cronbach α was used to assess internal consistency reliability. Explanatory factor analysis was conducted to study the factor structure. The results indicated that the Arabic version of the BCSBQ had satisfactory validity and internal consistency. The Cronbach's alpha of the three subscales ranged between 0.810 and 0.93. The frequency of breast cancer screening practices (breast awareness, clinical breast-examination and mammography) were significantly associated with attitudes towards general health check-up and perceived barriers to mammographic screening. Exploratory factor analysis showed a similar fit for the hypothesized three-factor structure with our data set. The Arabic version of the BCBSQ is a culturally appropriate, valid and reliable instrument for assessing the beliefs, knowledge and attitudes to breast cancer and breast cancer screening practices among Arabic-Australian women.

Proceedings of the National Academy of Sciences, 2015

Chitinases are enzymes that cleave chitin, a component of the exoskeleton of many organisms inclu... more Chitinases are enzymes that cleave chitin, a component of the exoskeleton of many organisms including the house dust mite (HDM). Here we show that knockin mice expressing an enzymatically inactive acidic mammalian chitinase (AMCase), the dominant true chitinase in mouse lung, showed enhanced type 2 immune responses to inhaled HDM. We found that uncleaved chitin promoted the release of IL-33, whereas cleaved chitin could be phagocytosed and could induce the activation of caspase-1 and subsequent activation of caspase-7; this results in the resolution of type 2 immune responses, probably by promoting the inactivation of IL-33. These data suggest that AMCase is a crucial regulator of type 2 immune responses to inhaled chitin-containing aeroallergens.

American journal of respiratory cell and molecular biology, Jan 29, 2015

Virus-induced exacerbations often lead to further impairment of lung function in chronic obstruct... more Virus-induced exacerbations often lead to further impairment of lung function in chronic obstructive pulmonary disease. Interleukin (IL)-15 is critical in antiviral immune responses. Retinoic acid (RA) signaling plays an important role in tissue maintenance and repair, particularly in the lung. We studied RA signaling and its relation to IL-15 in the lung during cigarette smoke (CS) exposure and influenza virus infection. In vivo studies show that RA signaling is diminished by long-term CS exposure or influenza virus infection alone, which is further attenuated during infection following CS exposure. RA receptor β (RARβ) is specifically decreased in the lung of IL-15 transgenic (overexpression; IL-15Tg) mice, and a greater reduction in RARβ is found in these mice compared with wild type (WT) after infection. RARβ is increased in IL-15 knockout (IL-15KO) mice compared with WT after infection and the additive effect of CS and virus on RARβ downregulation is diminished in IL-15KO mice....

C31. MECHANISMS OF INFLAMMATION IN THE AIRWAY, 2009

Allergy, asthma & immunology research, 2010

BRP-39 and its human homolog YKL-40 have been regarded as a prototype of chitinase-like proteins ... more BRP-39 and its human homolog YKL-40 have been regarded as a prototype of chitinase-like proteins (CLP) in mammals. Exaggerated levels of YKL-40 protein and/or mRNA have been noted in a number of diseases characterized by inflammation, tissue remodeling, and aberrant cell growth. Asthma is an inflammatory disease characterized by airway hyperresponsiveness and airway remodeling. Recently, the novel regulatory role of BRP-39/YKL-40 in the pathogenesis of asthma has been demonstrated both in human studies and allergic animal models. The levels of YKL-40 are increased in the circulation and lungs from asthmatics where they correlate with disease severity, and CHI3L1 polymorphisms correlate with serum YKL-40 levels, asthma and abnormal lung function. Animal studies using BRP-39 null mutant mice demonstrated that BRP-39 was required for optimal allergen sensitization and Th2 inflammation. These studies suggest the potential use of BRP-39 as a biomarker as well as a therapeutic target for ...

Proceedings of the American Thoracic Society, 2006

the level of pulmonary artery pressure is a good indicator of prognosis in patients with COPD. Th... more the level of pulmonary artery pressure is a good indicator of prognosis in patients with COPD. The pathogenesis of PH in patients with advanced COPD is incompletely understood. Chronic hypoxemia, morphologic changes in lung parenchyma (2, 3), and inflammation (4) are potential contributing factors. Here, we investigated whether inflammatory cytokines were related to the PH process in COPD. In 50 patients with COPD (age, 62 Ϯ 3 yr), pulmonary artery pressure (Pap) was measured during right heart catheterization, and blood samples were collected for determination of genotypes and serum levels of interleukin (IL)-1␤, IL-6, and monocyte chemoattractant protein-1 (MCP-1). As compared with a control group of 50 smokers, patients with COPD had elevated serum levels of IL-6 (p Ͻ 0.001) and MCP-1 (p Ͻ 0.01) but unchanged levels of IL-1␤. Pap was positively correlated with serum IL-6 levels but not with serum IL-1␤ and MCP-1 levels. The IL-6 G/G polymorphism (-174G/C) correlated with a higher level of IL-6 among patients with COPD but not among control subjects. Patients carrying the IL6 GG genotype showed higher serum levels of IL-6 and higher Pap than those carrying the CC or CG genotype. These results indicate that the inflammatory cytokine IL-6 may contribute to PH in COPD and that IL-6 gene polymorphism confers susceptibility to PH in patients with COPD. Since we previously reported that the serotonin transporter (5-HTT) gene polymorphism was associated with PH in COPD, the combined actions of the allelic variants of these two genes are being examined in a larger population of patients with COPD.

PLOS ONE, 2015

Epithelial cell death is a major contributor to fibrogenesis in the lung. In this study, we sough... more Epithelial cell death is a major contributor to fibrogenesis in the lung. In this study, we sought to determine the function of mitochondria and their clearance (mitophagy) in alveolar epithelial cell death and fibrosis.

Proceedings of the American Thoracic Society, 2006

Alveolar destruction is a cardinal feature of emphysema but is not traditionally believed to cont... more Alveolar destruction is a cardinal feature of emphysema but is not traditionally believed to contribute to the pathogenesis of "classical" asthma. However, the relationship between chronic obstructive pulmonary disease (COPD) and asthma is controversial and the variety of mechanisms that can mediate the alveolar destruction in emphysema have not been adequately defined. To address these issues, we used overexpression transgenic approaches to define the effects of Th1/Tc1 and Th2/Tc2 cytokines in the mature murine lung and compared findings in these transgenic systems to the effects of similar interventions after cigarette smoke (CS) exposure. In these experiments, the Th1/Tc1 and Th2/Tc2 cytokines IFN-gamma and interleukin (IL)-13, respectively, both caused emphysema. The IFN-gamma response was associated with neutrophilia but was not associated with mucus metaplasia or a major fibrotic response. In this setting, IFN-gamma was a potent stimulator of matrix metalloproteinas...

Proceedings of the American Thoracic Society, 2011

The Korean Journal of Internal Medicine, 2014

The FASEB Journal, 2007

Prolonged exposure to hyperoxia results in hyperoxic acute lung injury (HALI). Vascular endotheli... more Prolonged exposure to hyperoxia results in hyperoxic acute lung injury (HALI). Vascular endothelial growth factor (VEGF) has been shown to have cytoprotective effects and prolong survival in an in vivo model of HALI. Heme oxygenase-1 (HO-1) has protective effects in hyperoxia; therefore, we hypothesized that induction of HO-1 would be an important contributor to VEGF-induced cytoprotection. Using inducible, lung-specific VEGF overexpressing transgenic mice, we demonstrated that VEGF is a potent inducer of HO-1 mRNA and protein in mouse lung. To evaluate the effect of inhibition of HO-1 on injury, VEGF transgenic mice were treated with HO-1 short interfering RNA (HO-1 siRNA) and exposed to hyperoxia. Total lung lavage protein concentration, TUNEL staining, lipid peroxidation, and wet-to-dry ratio were all increased, consistent with increased injury. These findings were corroborated by survival studies in which inhibition of HO-1 function using tin-protoporphryin or silencing of HO-1 with lentiviral HO-1 short hairpin RNA (ShRNA) significantly decreased survival in hyperoxia. We conclude from these data that VEGF-induced HO-1 is an important contributor to cytoprotection in this in vivo model of acute lung injury and that alterations in VEGF function in the lung are likely to be important determinants of the outcome of acute lung injury.

Seminars in Cell & Developmental Biology, 2002

Since the first tetracycline-controlled transcriptional activation system was designed nearly a d... more Since the first tetracycline-controlled transcriptional activation system was designed nearly a decade ago, new variants, modifications, and improvements have been steadily added to this powerful set of tools for temporal control of transgene expression in mammalian systems. Tetracycline-based externally regulatable (Tet-based) systems have been successfully used to control the expression of numerous transgenes in cultured cells and in whole organisms, especially in mice. The application of these systems has provided invaluable insights into the function and regulation of a variety of genes under physiological and pathological conditions. Because of the favorable characteristics of the inducing agent doxycycline and the efficiency and effectiveness of the operating mechanism, the Tet-based systems have attracted substantial attention from the transgenic research community and are rapidly gaining popularity. The original tetracycline-controlled transcriptional activator (tTA) is a regulator with tight control of target gene expression and a broad range of inducibility. The reverse tetracycline-controlled transcriptional activator (rtTA) activates the responsive elements only in the presence of doxycycline, giving a convenient control over the target transgene. The recently developed tetracycline-controlled transcriptional silencer (tTS) has been successfully used in cultured cells and in transgenic mice. In combination with rtTA, tTS actively suppresses background expression or "leakiness" without impeding the inducibility of the target gene, providing a true "On/Off" transgenic switch. New variants of Tet-based regulators with improved features are still emerging and the utilities of these systems are constantly being tested.

Proceedings of the National Academy of Sciences, 2006

VEGF, nitric oxide (NO), inflammation, and vascular-and extravascular remodeling coexist in asthm... more VEGF, nitric oxide (NO), inflammation, and vascular-and extravascular remodeling coexist in asthma and other disorders. In these responses, VEGF regulates angiogenesis. VEGF also induces inflammation and remodeling. The mechanisms of the latter responses have not been defined, however. We hypothesized that VEGFinduces extravascular tissue responses via NO-dependent mechanisms. To evaluate this hypothesis, we compared the effects of transgenic VEGF 165 in lungs from normal mice, mice treated with pan-NO synthase (NOS) or endothelial NOS (eNOS) inhibitors, and mice with null mutations of inducible NOS (iNOS) or eNOS. These studies demonstrate that VEGF selectively stimulates eNOS and iNOS. They also demonstrate that VEGF induces pulmonary alterations via NO-dependent and -independent mechanisms with angiogenesis, edema, mucus metaplasia, airway hyperresponsiveness, lymphocyte accumulation, dendritic cell hyperplasia and S-nitrosoglutathione reductase stimulation being NO-dependent and dendritic cell activation being NO-independent. Furthermore, they demonstrate that eNOS and iNOS both contribute to these responses. NO͞NOS-based interventions may be therapeutic in VEGF-driven inflammation and remodeling.

PLoS ONE, 2012

The downstream of kinase (DOK)-1 is involved in the protein tyrosine kinase (PTK) pathway in mast... more The downstream of kinase (DOK)-1 is involved in the protein tyrosine kinase (PTK) pathway in mast cells, but the role of DOK-1 in the pathogenesis of asthma has not been defined. In this study, we have demonstrated a novel regulatory role of DOK-1 in airway inflammation and physiologic responses in a murine model of asthma using lentiviral vector containing DOK-1 cDNA or DOK-1-specific ShRNA. The OVA-induced inflammatory cells, airway hyperresponsiveness, Th2 cytokine expression, and mucus response were significantly reduced in DOK-1 overexpressing mice compared to OVA-challenged control mice. The transgenic introduction of DOK-1 significantly stimulated the activation and expression of STAT-4 and Tbet, while impressively inhibiting the activation and expression of STAT-6 and GATA-3 in airway epithelial cells. On the other hand, DOK-1 knockdown mice enhanced STAT-6 expression and its nuclear translocation compared to OVA-challenged control mice. When viewed in combination, our studies demonstrate DOK-1 regulates allergen-induced Th2 immune responses by selective stimulation and inhibition of STAT-4 and STAT-6 signaling pathways, respectively. These studies provide a novel insight on the regulatory role of DOK-1 in allergen-induced Th2 inflammation and airway responses, which has therapeutic potential for asthma and other allergic diseases.

Palliative Medicine, 2007

This study aimed to test the reliability and validity of the Korean version of McGill Quality of ... more This study aimed to test the reliability and validity of the Korean version of McGill Quality of Life Questionnaire (MQOL-K) for use with 140 palliative care patients in Korea. Our results confirmed the suitability of using the 16 questions of the questionnaire clustered into four domains (physical, psychological, existential and support) as in the original version of the MQOL, although the distribution of items among the domains differed somewhat from the original. The MQOL-K demonstrated moderate to high internal consistency (Cronbach's alpha, 0.62-0.90), convergent validity without scaling error, and a good concurrent validity with European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, sense of dignity, and general health perception. In addition, we tested the clinical validity of the MQOL-K using a known group comparison to quantify sensitivity. Regression results indicated that the existential and psychological domains had independent effects on the overall quality of life of patients in Korea. Therefore, the MQOL-K is deemed suitable for assessing the quality of life in a Korean palliative care setting.

Nucleic Acids Research, 2010

mitochondria contain full-length genome and a single-stranded 7S DNA. Although the copy number of... more mitochondria contain full-length genome and a single-stranded 7S DNA. Although the copy number of mitochondrial DNA (mtDNA) varies depending on the cell type and also in response to diverse environmental stresses, our understanding of how mtDNA and 7S DNA are maintained and regulated is limited, partly due to lack of reliable in vitro assay systems that reflect the in vivo functionality of mitochondria. Here we report an in vitro assay system to measure synthesis of both mtDNA and 7S DNA under a controllable in vitro condition. With this assay system, we demonstrate that the replication capacity of mitochondria correlates with endogenous copy numbers of mtDNA and 7S DNA. Our study also shows that higher nucleotide concentrations increasingly promote 7S DNA synthesis but not mtDNA synthesis. Consistently, the mitochondrial capacity to synthesize 7S DNA but not mtDNA noticeably varied along the cell cycle, reaching its highest level in S phase. These findings suggest that syntheses of mtDNA and 7S DNA proceed independently and that the mitochondrial capacity to synthesize 7S DNA dynamically changes not only with cell-cycle progression but also in response to varying nucleotide concentrations.

Molecular and Cellular Biology, 2002

Cyclin T1, together with the kinase CDK9, is a component of the transcription elongation factor P... more Cyclin T1, together with the kinase CDK9, is a component of the transcription elongation factor P-TEFb which binds the human immunodeficiency virus type 1 (HIV-1) transactivator Tat. P-TEFb facilitates transcription by phosphorylating the carboxy-terminal domain (CTD) of RNA polymerase II. Cyclin T1 is an exceptionally large cyclin and is therefore a candidate for interactions with regulatory proteins. We identified granulin as a cyclin T1-interacting protein that represses expression from the HIV-1 promoter in transfected cells. The granulins, mitogenic growth factors containing repeats of a cysteine-rich motif, were reported previously to interact with Tat. We show that granulin formed stable complexes in vivo and in vitro with cyclin T1 and Tat. Granulin bound to the histidine-rich domain of cyclin T1, which was recently found to bind to the CTD, but not to cyclin T2. Binding of granulin to P-TEFb inhibited the phosphorylation of a CTD peptide. Granulin expression inhibited Tat transactivation, and tethering experiments showed that this effect was due, at least in part, to a direct action on cyclin T1 in the absence of Tat. In addition, granulin was a substrate for CDK9 but not for the other transcription-related kinases CDK7 and CDK8. Thus, granulin is a cellular protein that interacts with cyclin T1 to inhibit transcription.

Marine Biology, 2004

Harsh physical conditions in the intertidal zone are the cause of an ample amount of dead macroin... more Harsh physical conditions in the intertidal zone are the cause of an ample amount of dead macroinvertebrates, which constitute a food source for carrion-feeders. In the European Wadden Sea, this trophic guild includes decapod crustaceans and fish when the tide is in, while during nocturnal low tides the polychaete Phyllodoce mucosa is attracted in large numbers by dead mollusks, crabs or worms on the sediment surface. Within 10 s worms emerged to the surface, crawled as far as 15 m on mucus trails towards the carcass, sucked in tissue up to one-third of their own weight, and then quickly retreated to below the surface. Abundance of P. mucosa was highest in the lower intertidal zone and winter. The seaward high abundance pattern, however, did not continue into the shallow subtidal. In summer, few were attracted during daytime or when the tide was in. However, up to 447 worms aggregated at a single crushed mussel within 20 min at dusk during low-tide exposure. This study suggests that during winter carrion-feeding is an important trophic niche on cold-temperate, intertidal mud flats occupied by a phyllodocid polychaete that is segregated in feeding time from most other scavengers and benefits from cold-sensitive benthic invertebrates.

The Journal of Immunology, 2012

Interstitial lung disease (ILD) with pulmonary fibrosis is an important manifestation in systemic... more Interstitial lung disease (ILD) with pulmonary fibrosis is an important manifestation in systemic sclerosis (SSc, scleroderma) where it portends a poor prognosis. However, biomarkers that predict the development and or severity of SSc-ILD have not been validated, and the pathogenetic mechanisms that engender this pulmonary response are poorly understood. In this study, we demonstrate in two different patient cohorts that the levels of chitotriosidase (Chit1) bioactivity and protein are significantly increased in the circulation and lungs of SSc patients compared with demographically matched controls. We also demonstrate that, compared with patients without lung involvement, patients with ILD show high levels of circulating Chit1 activity that correlate with disease severity. Murine modeling shows that in comparison with wild-type mice, bleomycin-induced pulmonary fibrosis was significantly reduced in Chit1⁻/⁻ mice and significantly enhanced in lungs from Chit1 overexpressing transgenic animals. In vitro studies also demonstrated that Chit1 interacts with TGF-β1 to augment fibroblast TGF-β receptors 1 and 2 expression and TGF-β-induced Smad and MAPK/ERK activation. These studies indicate that Chit1 is potential biomarker for ILD in SSc and a therapeutic target in SSc-associated lung fibrosis and demonstrate that Chit1 augments TGF-β1 effects by increasing receptor expression and canonical and noncanonical TGF-β1 signaling.

Journal of Gastroenterology and Hepatology, 2003

Interindividual genetic differences in susceptibility to chemical carcinogens are among the most ... more Interindividual genetic differences in susceptibility to chemical carcinogens are among the most important host factors in human cancer. The present study was undertaken to reveal the association between the polymorphism of CYP2E1 (CYP2E1/PstI and CYP2E1/DraI) with genetic susceptibility to gastric cancer development in Koreans. In the present study, 120 gastric cancer patients and 145 controls with no history of tumors were analyzed. CYP2E1 was determined by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP), or PCR and direct gel electrophoresis. The overall genotype distribution of CYP2E1 was not significantly different from that of controls. However, the genotype distribution of the patient subgroups with a history of heavy cigarette smoking (>30 pack/year) in the CYP2E1/PstI and CYP2E1/DraI polymorphisms were significantly different from those of non-smoking patients (P = 0.0122 and P = 0.0029, respectively). The difference was also noticeable in the younger patient subgroup (aged </=50 years) compared with normal controls (P = 0.0414) in the CYP2E1/PstI. The relative risk estimation for the combination of the CYP2E1/PstI and CYP2E1/DraI polymorphisms revealed that the odds ratio for individuals with homozygotes of rare alleles (c2/c2, C/C) was 5.6 (95% confidence interval = 0.9-39.1). : These results suggest the possible involvement of the CYP2E1 polymorphism in smoking-induced gastric cancer development in Koreans as one of the risk factors which increases genetic susceptibility.

European Journal of Oncology Nursing, 2015

The aim of the study was to report the psychometric properties of the Arabic version of the Breas... more The aim of the study was to report the psychometric properties of the Arabic version of the Breast Cancer Screening Beliefs Questionnaire (BCSBQ). A convenience sample of 251 Arabic-Australian women was recruited from a number of Arabic community organizations. Construct validity was examined by Cuzick's non-parametric test while Cronbach α was used to assess internal consistency reliability. Explanatory factor analysis was conducted to study the factor structure. The results indicated that the Arabic version of the BCSBQ had satisfactory validity and internal consistency. The Cronbach's alpha of the three subscales ranged between 0.810 and 0.93. The frequency of breast cancer screening practices (breast awareness, clinical breast-examination and mammography) were significantly associated with attitudes towards general health check-up and perceived barriers to mammographic screening. Exploratory factor analysis showed a similar fit for the hypothesized three-factor structure with our data set. The Arabic version of the BCBSQ is a culturally appropriate, valid and reliable instrument for assessing the beliefs, knowledge and attitudes to breast cancer and breast cancer screening practices among Arabic-Australian women.

Proceedings of the National Academy of Sciences, 2015

Chitinases are enzymes that cleave chitin, a component of the exoskeleton of many organisms inclu... more Chitinases are enzymes that cleave chitin, a component of the exoskeleton of many organisms including the house dust mite (HDM). Here we show that knockin mice expressing an enzymatically inactive acidic mammalian chitinase (AMCase), the dominant true chitinase in mouse lung, showed enhanced type 2 immune responses to inhaled HDM. We found that uncleaved chitin promoted the release of IL-33, whereas cleaved chitin could be phagocytosed and could induce the activation of caspase-1 and subsequent activation of caspase-7; this results in the resolution of type 2 immune responses, probably by promoting the inactivation of IL-33. These data suggest that AMCase is a crucial regulator of type 2 immune responses to inhaled chitin-containing aeroallergens.

American journal of respiratory cell and molecular biology, Jan 29, 2015

Virus-induced exacerbations often lead to further impairment of lung function in chronic obstruct... more Virus-induced exacerbations often lead to further impairment of lung function in chronic obstructive pulmonary disease. Interleukin (IL)-15 is critical in antiviral immune responses. Retinoic acid (RA) signaling plays an important role in tissue maintenance and repair, particularly in the lung. We studied RA signaling and its relation to IL-15 in the lung during cigarette smoke (CS) exposure and influenza virus infection. In vivo studies show that RA signaling is diminished by long-term CS exposure or influenza virus infection alone, which is further attenuated during infection following CS exposure. RA receptor β (RARβ) is specifically decreased in the lung of IL-15 transgenic (overexpression; IL-15Tg) mice, and a greater reduction in RARβ is found in these mice compared with wild type (WT) after infection. RARβ is increased in IL-15 knockout (IL-15KO) mice compared with WT after infection and the additive effect of CS and virus on RARβ downregulation is diminished in IL-15KO mice....

C31. MECHANISMS OF INFLAMMATION IN THE AIRWAY, 2009

Allergy, asthma & immunology research, 2010

BRP-39 and its human homolog YKL-40 have been regarded as a prototype of chitinase-like proteins ... more BRP-39 and its human homolog YKL-40 have been regarded as a prototype of chitinase-like proteins (CLP) in mammals. Exaggerated levels of YKL-40 protein and/or mRNA have been noted in a number of diseases characterized by inflammation, tissue remodeling, and aberrant cell growth. Asthma is an inflammatory disease characterized by airway hyperresponsiveness and airway remodeling. Recently, the novel regulatory role of BRP-39/YKL-40 in the pathogenesis of asthma has been demonstrated both in human studies and allergic animal models. The levels of YKL-40 are increased in the circulation and lungs from asthmatics where they correlate with disease severity, and CHI3L1 polymorphisms correlate with serum YKL-40 levels, asthma and abnormal lung function. Animal studies using BRP-39 null mutant mice demonstrated that BRP-39 was required for optimal allergen sensitization and Th2 inflammation. These studies suggest the potential use of BRP-39 as a biomarker as well as a therapeutic target for ...

Proceedings of the American Thoracic Society, 2006

the level of pulmonary artery pressure is a good indicator of prognosis in patients with COPD. Th... more the level of pulmonary artery pressure is a good indicator of prognosis in patients with COPD. The pathogenesis of PH in patients with advanced COPD is incompletely understood. Chronic hypoxemia, morphologic changes in lung parenchyma (2, 3), and inflammation (4) are potential contributing factors. Here, we investigated whether inflammatory cytokines were related to the PH process in COPD. In 50 patients with COPD (age, 62 Ϯ 3 yr), pulmonary artery pressure (Pap) was measured during right heart catheterization, and blood samples were collected for determination of genotypes and serum levels of interleukin (IL)-1␤, IL-6, and monocyte chemoattractant protein-1 (MCP-1). As compared with a control group of 50 smokers, patients with COPD had elevated serum levels of IL-6 (p Ͻ 0.001) and MCP-1 (p Ͻ 0.01) but unchanged levels of IL-1␤. Pap was positively correlated with serum IL-6 levels but not with serum IL-1␤ and MCP-1 levels. The IL-6 G/G polymorphism (-174G/C) correlated with a higher level of IL-6 among patients with COPD but not among control subjects. Patients carrying the IL6 GG genotype showed higher serum levels of IL-6 and higher Pap than those carrying the CC or CG genotype. These results indicate that the inflammatory cytokine IL-6 may contribute to PH in COPD and that IL-6 gene polymorphism confers susceptibility to PH in patients with COPD. Since we previously reported that the serotonin transporter (5-HTT) gene polymorphism was associated with PH in COPD, the combined actions of the allelic variants of these two genes are being examined in a larger population of patients with COPD.

PLOS ONE, 2015

Epithelial cell death is a major contributor to fibrogenesis in the lung. In this study, we sough... more Epithelial cell death is a major contributor to fibrogenesis in the lung. In this study, we sought to determine the function of mitochondria and their clearance (mitophagy) in alveolar epithelial cell death and fibrosis.

Proceedings of the American Thoracic Society, 2006

Alveolar destruction is a cardinal feature of emphysema but is not traditionally believed to cont... more Alveolar destruction is a cardinal feature of emphysema but is not traditionally believed to contribute to the pathogenesis of "classical" asthma. However, the relationship between chronic obstructive pulmonary disease (COPD) and asthma is controversial and the variety of mechanisms that can mediate the alveolar destruction in emphysema have not been adequately defined. To address these issues, we used overexpression transgenic approaches to define the effects of Th1/Tc1 and Th2/Tc2 cytokines in the mature murine lung and compared findings in these transgenic systems to the effects of similar interventions after cigarette smoke (CS) exposure. In these experiments, the Th1/Tc1 and Th2/Tc2 cytokines IFN-gamma and interleukin (IL)-13, respectively, both caused emphysema. The IFN-gamma response was associated with neutrophilia but was not associated with mucus metaplasia or a major fibrotic response. In this setting, IFN-gamma was a potent stimulator of matrix metalloproteinas...

Proceedings of the American Thoracic Society, 2011

The Korean Journal of Internal Medicine, 2014

The FASEB Journal, 2007

Prolonged exposure to hyperoxia results in hyperoxic acute lung injury (HALI). Vascular endotheli... more Prolonged exposure to hyperoxia results in hyperoxic acute lung injury (HALI). Vascular endothelial growth factor (VEGF) has been shown to have cytoprotective effects and prolong survival in an in vivo model of HALI. Heme oxygenase-1 (HO-1) has protective effects in hyperoxia; therefore, we hypothesized that induction of HO-1 would be an important contributor to VEGF-induced cytoprotection. Using inducible, lung-specific VEGF overexpressing transgenic mice, we demonstrated that VEGF is a potent inducer of HO-1 mRNA and protein in mouse lung. To evaluate the effect of inhibition of HO-1 on injury, VEGF transgenic mice were treated with HO-1 short interfering RNA (HO-1 siRNA) and exposed to hyperoxia. Total lung lavage protein concentration, TUNEL staining, lipid peroxidation, and wet-to-dry ratio were all increased, consistent with increased injury. These findings were corroborated by survival studies in which inhibition of HO-1 function using tin-protoporphryin or silencing of HO-1 with lentiviral HO-1 short hairpin RNA (ShRNA) significantly decreased survival in hyperoxia. We conclude from these data that VEGF-induced HO-1 is an important contributor to cytoprotection in this in vivo model of acute lung injury and that alterations in VEGF function in the lung are likely to be important determinants of the outcome of acute lung injury.

Seminars in Cell & Developmental Biology, 2002

Since the first tetracycline-controlled transcriptional activation system was designed nearly a d... more Since the first tetracycline-controlled transcriptional activation system was designed nearly a decade ago, new variants, modifications, and improvements have been steadily added to this powerful set of tools for temporal control of transgene expression in mammalian systems. Tetracycline-based externally regulatable (Tet-based) systems have been successfully used to control the expression of numerous transgenes in cultured cells and in whole organisms, especially in mice. The application of these systems has provided invaluable insights into the function and regulation of a variety of genes under physiological and pathological conditions. Because of the favorable characteristics of the inducing agent doxycycline and the efficiency and effectiveness of the operating mechanism, the Tet-based systems have attracted substantial attention from the transgenic research community and are rapidly gaining popularity. The original tetracycline-controlled transcriptional activator (tTA) is a regulator with tight control of target gene expression and a broad range of inducibility. The reverse tetracycline-controlled transcriptional activator (rtTA) activates the responsive elements only in the presence of doxycycline, giving a convenient control over the target transgene. The recently developed tetracycline-controlled transcriptional silencer (tTS) has been successfully used in cultured cells and in transgenic mice. In combination with rtTA, tTS actively suppresses background expression or "leakiness" without impeding the inducibility of the target gene, providing a true "On/Off" transgenic switch. New variants of Tet-based regulators with improved features are still emerging and the utilities of these systems are constantly being tested.

Proceedings of the National Academy of Sciences, 2006

VEGF, nitric oxide (NO), inflammation, and vascular-and extravascular remodeling coexist in asthm... more VEGF, nitric oxide (NO), inflammation, and vascular-and extravascular remodeling coexist in asthma and other disorders. In these responses, VEGF regulates angiogenesis. VEGF also induces inflammation and remodeling. The mechanisms of the latter responses have not been defined, however. We hypothesized that VEGFinduces extravascular tissue responses via NO-dependent mechanisms. To evaluate this hypothesis, we compared the effects of transgenic VEGF 165 in lungs from normal mice, mice treated with pan-NO synthase (NOS) or endothelial NOS (eNOS) inhibitors, and mice with null mutations of inducible NOS (iNOS) or eNOS. These studies demonstrate that VEGF selectively stimulates eNOS and iNOS. They also demonstrate that VEGF induces pulmonary alterations via NO-dependent and -independent mechanisms with angiogenesis, edema, mucus metaplasia, airway hyperresponsiveness, lymphocyte accumulation, dendritic cell hyperplasia and S-nitrosoglutathione reductase stimulation being NO-dependent and dendritic cell activation being NO-independent. Furthermore, they demonstrate that eNOS and iNOS both contribute to these responses. NO͞NOS-based interventions may be therapeutic in VEGF-driven inflammation and remodeling.

PLoS ONE, 2012

The downstream of kinase (DOK)-1 is involved in the protein tyrosine kinase (PTK) pathway in mast... more The downstream of kinase (DOK)-1 is involved in the protein tyrosine kinase (PTK) pathway in mast cells, but the role of DOK-1 in the pathogenesis of asthma has not been defined. In this study, we have demonstrated a novel regulatory role of DOK-1 in airway inflammation and physiologic responses in a murine model of asthma using lentiviral vector containing DOK-1 cDNA or DOK-1-specific ShRNA. The OVA-induced inflammatory cells, airway hyperresponsiveness, Th2 cytokine expression, and mucus response were significantly reduced in DOK-1 overexpressing mice compared to OVA-challenged control mice. The transgenic introduction of DOK-1 significantly stimulated the activation and expression of STAT-4 and Tbet, while impressively inhibiting the activation and expression of STAT-6 and GATA-3 in airway epithelial cells. On the other hand, DOK-1 knockdown mice enhanced STAT-6 expression and its nuclear translocation compared to OVA-challenged control mice. When viewed in combination, our studies demonstrate DOK-1 regulates allergen-induced Th2 immune responses by selective stimulation and inhibition of STAT-4 and STAT-6 signaling pathways, respectively. These studies provide a novel insight on the regulatory role of DOK-1 in allergen-induced Th2 inflammation and airway responses, which has therapeutic potential for asthma and other allergic diseases.

Palliative Medicine, 2007

This study aimed to test the reliability and validity of the Korean version of McGill Quality of ... more This study aimed to test the reliability and validity of the Korean version of McGill Quality of Life Questionnaire (MQOL-K) for use with 140 palliative care patients in Korea. Our results confirmed the suitability of using the 16 questions of the questionnaire clustered into four domains (physical, psychological, existential and support) as in the original version of the MQOL, although the distribution of items among the domains differed somewhat from the original. The MQOL-K demonstrated moderate to high internal consistency (Cronbach's alpha, 0.62-0.90), convergent validity without scaling error, and a good concurrent validity with European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, sense of dignity, and general health perception. In addition, we tested the clinical validity of the MQOL-K using a known group comparison to quantify sensitivity. Regression results indicated that the existential and psychological domains had independent effects on the overall quality of life of patients in Korea. Therefore, the MQOL-K is deemed suitable for assessing the quality of life in a Korean palliative care setting.

Nucleic Acids Research, 2010

mitochondria contain full-length genome and a single-stranded 7S DNA. Although the copy number of... more mitochondria contain full-length genome and a single-stranded 7S DNA. Although the copy number of mitochondrial DNA (mtDNA) varies depending on the cell type and also in response to diverse environmental stresses, our understanding of how mtDNA and 7S DNA are maintained and regulated is limited, partly due to lack of reliable in vitro assay systems that reflect the in vivo functionality of mitochondria. Here we report an in vitro assay system to measure synthesis of both mtDNA and 7S DNA under a controllable in vitro condition. With this assay system, we demonstrate that the replication capacity of mitochondria correlates with endogenous copy numbers of mtDNA and 7S DNA. Our study also shows that higher nucleotide concentrations increasingly promote 7S DNA synthesis but not mtDNA synthesis. Consistently, the mitochondrial capacity to synthesize 7S DNA but not mtDNA noticeably varied along the cell cycle, reaching its highest level in S phase. These findings suggest that syntheses of mtDNA and 7S DNA proceed independently and that the mitochondrial capacity to synthesize 7S DNA dynamically changes not only with cell-cycle progression but also in response to varying nucleotide concentrations.

Molecular and Cellular Biology, 2002

Cyclin T1, together with the kinase CDK9, is a component of the transcription elongation factor P... more Cyclin T1, together with the kinase CDK9, is a component of the transcription elongation factor P-TEFb which binds the human immunodeficiency virus type 1 (HIV-1) transactivator Tat. P-TEFb facilitates transcription by phosphorylating the carboxy-terminal domain (CTD) of RNA polymerase II. Cyclin T1 is an exceptionally large cyclin and is therefore a candidate for interactions with regulatory proteins. We identified granulin as a cyclin T1-interacting protein that represses expression from the HIV-1 promoter in transfected cells. The granulins, mitogenic growth factors containing repeats of a cysteine-rich motif, were reported previously to interact with Tat. We show that granulin formed stable complexes in vivo and in vitro with cyclin T1 and Tat. Granulin bound to the histidine-rich domain of cyclin T1, which was recently found to bind to the CTD, but not to cyclin T2. Binding of granulin to P-TEFb inhibited the phosphorylation of a CTD peptide. Granulin expression inhibited Tat transactivation, and tethering experiments showed that this effect was due, at least in part, to a direct action on cyclin T1 in the absence of Tat. In addition, granulin was a substrate for CDK9 but not for the other transcription-related kinases CDK7 and CDK8. Thus, granulin is a cellular protein that interacts with cyclin T1 to inhibit transcription.

Marine Biology, 2004

Harsh physical conditions in the intertidal zone are the cause of an ample amount of dead macroin... more Harsh physical conditions in the intertidal zone are the cause of an ample amount of dead macroinvertebrates, which constitute a food source for carrion-feeders. In the European Wadden Sea, this trophic guild includes decapod crustaceans and fish when the tide is in, while during nocturnal low tides the polychaete Phyllodoce mucosa is attracted in large numbers by dead mollusks, crabs or worms on the sediment surface. Within 10 s worms emerged to the surface, crawled as far as 15 m on mucus trails towards the carcass, sucked in tissue up to one-third of their own weight, and then quickly retreated to below the surface. Abundance of P. mucosa was highest in the lower intertidal zone and winter. The seaward high abundance pattern, however, did not continue into the shallow subtidal. In summer, few were attracted during daytime or when the tide was in. However, up to 447 worms aggregated at a single crushed mussel within 20 min at dusk during low-tide exposure. This study suggests that during winter carrion-feeding is an important trophic niche on cold-temperate, intertidal mud flats occupied by a phyllodocid polychaete that is segregated in feeding time from most other scavengers and benefits from cold-sensitive benthic invertebrates.

The Journal of Immunology, 2012

Interstitial lung disease (ILD) with pulmonary fibrosis is an important manifestation in systemic... more Interstitial lung disease (ILD) with pulmonary fibrosis is an important manifestation in systemic sclerosis (SSc, scleroderma) where it portends a poor prognosis. However, biomarkers that predict the development and or severity of SSc-ILD have not been validated, and the pathogenetic mechanisms that engender this pulmonary response are poorly understood. In this study, we demonstrate in two different patient cohorts that the levels of chitotriosidase (Chit1) bioactivity and protein are significantly increased in the circulation and lungs of SSc patients compared with demographically matched controls. We also demonstrate that, compared with patients without lung involvement, patients with ILD show high levels of circulating Chit1 activity that correlate with disease severity. Murine modeling shows that in comparison with wild-type mice, bleomycin-induced pulmonary fibrosis was significantly reduced in Chit1⁻/⁻ mice and significantly enhanced in lungs from Chit1 overexpressing transgenic animals. In vitro studies also demonstrated that Chit1 interacts with TGF-β1 to augment fibroblast TGF-β receptors 1 and 2 expression and TGF-β-induced Smad and MAPK/ERK activation. These studies indicate that Chit1 is potential biomarker for ILD in SSc and a therapeutic target in SSc-associated lung fibrosis and demonstrate that Chit1 augments TGF-β1 effects by increasing receptor expression and canonical and noncanonical TGF-β1 signaling.

Journal of Gastroenterology and Hepatology, 2003

Interindividual genetic differences in susceptibility to chemical carcinogens are among the most ... more Interindividual genetic differences in susceptibility to chemical carcinogens are among the most important host factors in human cancer. The present study was undertaken to reveal the association between the polymorphism of CYP2E1 (CYP2E1/PstI and CYP2E1/DraI) with genetic susceptibility to gastric cancer development in Koreans. In the present study, 120 gastric cancer patients and 145 controls with no history of tumors were analyzed. CYP2E1 was determined by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP), or PCR and direct gel electrophoresis. The overall genotype distribution of CYP2E1 was not significantly different from that of controls. However, the genotype distribution of the patient subgroups with a history of heavy cigarette smoking (>30 pack/year) in the CYP2E1/PstI and CYP2E1/DraI polymorphisms were significantly different from those of non-smoking patients (P = 0.0122 and P = 0.0029, respectively). The difference was also noticeable in the younger patient subgroup (aged </=50 years) compared with normal controls (P = 0.0414) in the CYP2E1/PstI. The relative risk estimation for the combination of the CYP2E1/PstI and CYP2E1/DraI polymorphisms revealed that the odds ratio for individuals with homozygotes of rare alleles (c2/c2, C/C) was 5.6 (95% confidence interval = 0.9-39.1). : These results suggest the possible involvement of the CYP2E1 polymorphism in smoking-induced gastric cancer development in Koreans as one of the risk factors which increases genetic susceptibility.