Browsing by Author "Sorachai Srisuma"
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Publication Metadata only Airway epithelial cell PPARγ modulates cigarette smoke-induced chemokine expression and emphysema susceptibility in mice(2015-01-01) Siva Kumar Solleti; Dawn M. Simon; Sorachai Srisuma; Meltem C. Arikan; Soumyaroop Bhattacharya; Tirumalai Rangasamy; Kaiser M. Bijli; Arshad Rahman; Joseph T. Crossno; Steven D. Shapiro; Thomas J. Mariani; University of Rochester Medical Center; Apnea; Mahidol University; Brigham and Women's Hospital; University of Colorado Health Sciences Center; Emory University; University of Pittsburgh© 2015 the American Physiological Society. Chronic obstructive pulmonary disease (COPD) is a highly prevalent, chronic inflammatory lung disease with limited existing therapeutic options. While modulation of peroxisome proliferator-activating receptor (PPAR)-γ activity can modify inflammatory responses in several models of lung injury, the relevance of the PPARG pathway in COPD pathogenesis has not been previously explored. Mice lacking Pparg specifically in airway epithelial cells displayed increased susceptibility to chronic cigarette smoke (CS)-induced emphysema, with excessive macrophage accumulation associated with increased expression of chemokines, Ccl5, CxcllO, and Cxcl15. Conversely, treatment of mice with a pharmacological PPARγ activator attenuated CxcllO and Cxcl15 expression and macrophage accumulation in response to CS. In vitro, CS increased lung epithelial cell chemokine expression in a PPARγ activation-dependent fashion. The ability of PPARγ to regulate CS-induced chemokine expression in vitro was not specifically associated with peroxisome proliferator response element (PPRE)-mediated transactivation activity but was correlated with PPARγ-mediated transrepression of NF-ΚB activity. Pharmacological or genetic activation of PPARγ activity abrogated CS-dependent induction of NF-ΚB activity. Regulation of NF-ΚB activity involved direct PPARγ-NF-ΚB interaction and PPARγ-mediated effects on IKK activation, IkBiα degradation, and nuclear translocation of p65. Our data indicate that PPARG represents a disease-relevant patho-physiological and pharmacological target in COPD. Its activation state likely contributes to NF-ΚB-dependent, CS-induced chemokine-me-diated regulation of inflammatory cell accumulation.Publication Open Access Apolipoprotein E gene polymorphism: effects on plasma lipids and risk of type 2 diabetes and coronary artery disease(2012) Rajesh Chaudhary; Atip Likidlilid; Thavatchai Peerapatdit; Damras Tresukosol; Sorachai Srisuma; Suphachai Ratanamaneechat; Charn Sriratanasathavorn; Mahidol University. Faculty of Medicine Siriraj Hospital. Department of BiochemistryBackground: The most common apolipoprotein E (apoE) gene polymorphism has been found to influence plasma lipid concentration and its correlation with coronary artery disease (CAD) has been extensively investigated in the last decade. It is, however, unclear whether apoE gene polymorphism is also associated with increased risk of type 2 diabetes mellitus (T2DM). The knowledge of this study may provide the primary prevention for T2DM and CAD development before its initiation and progression. Therefore, this study was carried out to determine the association between apoE gene polymorphism and T2DM with and without CAD and its role in lipid metabolism. Methods: The case-control study was carried out on a total of 451 samples including 149 normal control subjects, 155 subjects with T2DM, and 147 subjects with T2DM complicated with CAD. The apoE gene polymorphism was tested by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Univariable and multivariable logistic regression analyses were used to identify the possible risks of T2DM and CAD. Results: A significantly increased frequency of E3/E4 genotype was observed only in T2DM with CAD group (p = 0.0004), whereas the ε4 allele was significantly higher in both T2DM (p = 0.047) and T2DM with CAD (p = 0.009) as compared with controls. E3/E4 genotype was also the independent risk in developing CAD after adjusting with established risk factors with adjusted odds ratio (OR) 2.52 (95%CI 1.28-4.97, p = 0.008). The independent predictor of individuals carrying ε4 allele still remained significantly associated with both CAD (adjusted OR 2.32, 95%CI 1.17- 4.61, p = 0.016) and T2DM (adjusted OR 2.04, 95%CI 1.07-3.86, p = 0.029). After simultaneously examining the joint association of E3/E4 genotype combined with either obesity or smoking the risk increased to approximately 5-fold in T2DM (adjusted OR 4.93, 95%CI 1.74-13.98, p = 0.003) and 10-fold in CAD (adjusted OR 10.48, 95%CI 3.56-30.79, p < 0.0001). The association between apoE genotypes on plasma lipid levels was compared between E3/E3 as a reference and E4-bearing genotypes. E4-bearing genotypes showed lower HDL-C and higher VLDL-C and TG, whereas other values of plasma lipid concentrations showed no significant difference. Conclusions: These results indicate that ε4 allele has influence on lipid profiles and is associated with the development of both T2DM with and without CAD, and furthermore, it increased the risk among the subjects with obesity and/or smoking, the conditions associated with high oxidative stress.Publication Metadata only Apolipoprotein E gene polymorphism: Effects on plasma lipids and risk of type 2 diabetes and coronary artery disease(2012-04-23) Rajesh Chaudhary; Atip Likidlilid; Thavatchai Peerapatdit; Damras Tresukosol; Sorachai Srisuma; Suphachai Ratanamaneechat; Charn Sriratanasathavorn; Mahidol UniversityBackground: The most common apolipoprotein E (apoE) gene polymorphism has been found to influence plasma lipid concentration and its correlation with coronary artery disease (CAD) has been extensively investigated in the last decade. It is, however, unclear whether apoE gene polymorphism is also associated with increased risk of type 2 diabetes mellitus (T2DM). The knowledge of this study may provide the primary prevention for T2DM and CAD development before its initiation and progression. Therefore, this study was carried out to determine the association between apoE gene polymorphism and T2DM with and without CAD and its role in lipid metabolism.Methods: The case-control study was carried out on a total of 451 samples including 149 normal control subjects, 155 subjects with T2DM, and 147 subjects with T2DM complicated with CAD. The apoE gene polymorphism was tested by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Univariable and multivariable logistic regression analyses were used to identify the possible risks of T2DM and CAD.Results: A significantly increased frequency of E3/E4 genotype was observed only in T2DM with CAD group (p = 0.0004), whereas the ε4 allele was significantly higher in both T2DM (p = 0.047) and T2DM with CAD (p = 0.009) as compared with controls. E3/E4 genotype was also the independent risk in developing CAD after adjusting with established risk factors with adjusted odds ratio (OR) 2.52 (95%CI 1.28-4.97, p = 0.008). The independent predictor of individuals carrying ε4 allele still remained significantly associated with both CAD (adjusted OR 2.32, 95%CI 1.17-4.61, p = 0.016) and T2DM (adjusted OR 2.04, 95%CI 1.07-3.86, p = 0.029). After simultaneously examining the joint association of E3/E4 genotype combined with either obesity or smoking the risk increased to approximately 5-fold in T2DM (adjusted OR 4.93, 95%CI 1.74-13.98, p = 0.003) and 10-fold in CAD (adjusted OR 10.48, 95%CI 3.56-30.79, p < 0.0001). The association between apoE genotypes on plasma lipid levels was compared between E3/E3 as a reference and E4-bearing genotypes. E4-bearing genotypes showed lower HDL-C and higher VLDL-C and TG, whereas other values of plasma lipid concentrations showed no significant difference.Conclusions: These results indicate that ε4 allele has influence on lipid profiles and is associated with the development of both T2DM with and without CAD, and furthermore, it increased the risk among the subjects with obesity and/or smoking, the conditions associated with high oxidative stress. © 2012 Chaudhary et al; licensee BioMed Central Ltd.Publication Metadata only Comparison of immunogenicity between intradermal and intramuscular injections of repeated annual identical influenza virus strains post-pandemic (2011-2012) in COPD patients(2019-01-01) Benjamas Chuaychoo; Uraiwan Kositanont; Parichat Niyomthong; Nuttapol Rittayamai; Sorachai Srisuma; Kanokwan Rattanasaengloet; Walaiporn Wongsrisakunkaew; Julalux Thongam; Thaweesak Songserm; Kasetsart University, Kamphaeng Saen Campus; Naresuan University; Thammasat University; Faculty of Medicine, Siriraj Hospital, Mahidol University© 2019, © 2019 Taylor & Francis Group, LLC. We compared the antibody responses and persistence of the reduced-dose, 9 µg hemagglutinin (HA)/strain intradermal (ID) injection via the Mantoux technique and the 15 μg HA/strain intramuscular (IM) injection of the repeated annual identical trivalent, inactivated, split-virion vaccine 2011–2012 in chronic obstructive pulmonary disease (COPD) patients. Eighty patients were randomized to ID (n = 41) and IM (n = 39) groups. Four weeks post-vaccination, the antibody responses of the two groups were similar; those for influenza A(H1N1)pdm09 and influenza A(H3N2)–but not influenza B–met the criteria of the Committee for Proprietary Medicinal Products (CPMP). The antibody responses for influenza A(H1N1)pdm09 rapidly declined in both groups, especially with the ID injection, whereas those for influenza A(H3N2) maintained above the CPMP criteria throughout 12 months post-vaccination. The geometric mean titres for influenza A(H1N1)pdm09 persisted above the protective threshold (≥ 40) until 6 months post-vaccination in both the ID and IM groups. The seroprotection rates of the ID and IM groups were above 60% until 3 months and 6 months post-vaccination, respectively. In conclusion, the 9 μg HA/strain ID injection of vaccine 2011–2012 elicited antibody responses similar to the standard dose of 15 μg of the HA/strain IM injection at 4 weeks post-vaccination. However, the antibody responses for influenza A(H1N1)pdm09 rapidly declined, especially in the case of the ID injection, whereas they were comparable for influenza A(H3N2). Additional strategies for increasing vaccine durability should be considered, especially for new pandemic strains affecting elderly COPD patients.Publication Metadata only Comparison of immunogenicity between intradermal and intramuscular injections of repeated annual identical influenza virus strains post-pandemic (2011-2012) in COPD patients(2020-06-02) Benjamas Chuaychoo; Uraiwan Kositanont; Parichat Niyomthong; Nuttapol Rittayamai; Sorachai Srisuma; Kanokwan Rattanasaengloet; Walaiporn Wongsrisakunkaew; Julalux Thongam; Thaweesak Songserm; Kasetsart University, Kamphaeng Saen Campus; Naresuan University; Thammasat University; Faculty of Medicine, Siriraj Hospital, Mahidol University© 2019, © 2019 Taylor & Francis Group, LLC. We compared the antibody responses and persistence of the reduced-dose, 9 µg hemagglutinin (HA)/strain intradermal (ID) injection via the Mantoux technique and the 15 μg HA/strain intramuscular (IM) injection of the repeated annual identical trivalent, inactivated, split-virion vaccine 2011–2012 in chronic obstructive pulmonary disease (COPD) patients. Eighty patients were randomized to ID (n = 41) and IM (n = 39) groups. Four weeks post-vaccination, the antibody responses of the two groups were similar; those for influenza A(H1N1)pdm09 and influenza A(H3N2)–but not influenza B–met the criteria of the Committee for Proprietary Medicinal Products (CPMP). The antibody responses for influenza A(H1N1)pdm09 rapidly declined in both groups, especially with the ID injection, whereas those for influenza A(H3N2) maintained above the CPMP criteria throughout 12 months post-vaccination. The geometric mean titres for influenza A(H1N1)pdm09 persisted above the protective threshold (≥ 40) until 6 months post-vaccination in both the ID and IM groups. The seroprotection rates of the ID and IM groups were above 60% until 3 months and 6 months post-vaccination, respectively. In conclusion, the 9 μg HA/strain ID injection of vaccine 2011–2012 elicited antibody responses similar to the standard dose of 15 μg of the HA/strain IM injection at 4 weeks post-vaccination. However, the antibody responses for influenza A(H1N1)pdm09 rapidly declined, especially in the case of the ID injection, whereas they were comparable for influenza A(H3N2). Additional strategies for increasing vaccine durability should be considered, especially for new pandemic strains affecting elderly COPD patients.Publication Metadata only Effect of pursed-lip breathing using a windmill toy model on breathing efficiency in chronic obstructive pulmonary disease patients(2021-12-01) Sarawut Jansang; Parunkul Tungsukruthai; Sorachai Srisuma; Kusuma Sriyakul; Aungkana Krajarng; Somboon Kietinun; Siriraj Hospital; Thammasat UniversityChronic obstructive pulmonary disease (COPD) is the third-highest cause of death in the world, also true in Thailand. There are various methods to treat COPD such as medication and non-drug therapies for respiratory rehabilitation. The aim of this study is to investigate the effectiveness of pursed-lip breathing (PLB) by using a windmill toy in COPD patients. The participants in this randomized controlled trial study were 60 to 75 years old. The total number of 46 participants were equally divided into 2 groups: The intervention group and the control group (23 participants each). The intervention group used breathing training through a windmill toy, whereas the control group received training in standard breathing patterns. The training was performed over sessions in 1 week. Lung function, respiratory muscle strength, and 6-minute walk test (6MWT) were recorded at baseline, and between 6-12 weeks (follow-up). The intervention group and the control group improved significantly in lung function and muscle strength (p < 0.05). In addition, 6MWT in the intervention group increased significantly when compared to the control group (p < 0.05) at week 12. In conclusion, the PLB using a windmill toy is a new form of breathing training that is effective in promoting the strength of the muscles used for breathing, lung performance, and cardiovascular function in COPD patients.Publication Metadata only Effects of Pursed-Lip Breathing by Using a Windmill Toy after 12-Week Training on Maximum Oxygen Efficiency in Chronic Obstructive Pulmonary Disease Patients(2021-08-01) Sarawut Jansang; Somboon Kietinun; Kusuma Sriyakul; Parunkul Tungsukruthai; Aungkana Krajarng; Sorachai Srisuma; Siriraj Hospital; Thammasat UniversityJansang S, Kietinun S, Sriyakul K, Tungsukruthai P, Krajarng A, Srisuma S. Effects of Pursed-Lip Breathing by Using a Windmill Toy after 12-Week Training on Maximum Oxygen Efficiency in Chronic Obstructive Pulmonary Disease Patients. JEPonline 2021;24(4):96-108. Chronic obstructive pulmonary disease (COPD) is an illness that cannot be cured, but breathing capacity can be restored to function effectively. The purpose of this study was to measure the effects of the pursed-lip breathing exercises by using a windmill toy on the maximum oxygen use before and after the intervention and the exertion conditions during the breathing exercises in COPD patients with mild to moderate severity level. This study was a randomized controlled trial. The sample was COPD patients admitted to the COPD clinic of the Pulmonary Medicine Clinic in Rajavithi Hospital, Bangkok, Thailand. A total number of 46 participants were randomly divided into 2 Groups: (a) the Intervention Group (n = 23); and (b) the Control Group (n = 23). The Intervention Group received pursed-lip breathing exercises using a windmill toy for 45 min·session-1, 1 session·d-1, 3 times·wk-1 for 12 weeks while the Control Group received the standard medical care. The measurement tools included Cardiopulmonary Exercise Testing (CPET) to measure cardiopulmonary endurance and St. George’s Respiratory Questionnaire (SGRQ) to evaluate the quality of life in COPD patients. The descriptive statistics consisted of the student's paired t-test and ANOVA. The results showed that both groups improved significantly in respiratory performance. The cardiopulmonary exercise testing results for variables divided into COPD categories in both groups increased significantly (P<0.05). The results demonstrated the positive effects of the pursed-lip breathing exercises by using a windmill toy, an easy-to-train, effective, and user-friendly method in COPD patients, which helped improve breathing efficiency leading to better quality of life.Publication Metadata only Epithelial cell PPARγ contributes to normal lung maturation(2006-07-01) Dawn M. Simon; Meltem C. Arikan; Sorachai Srisuma; Soumyaroop Bhattacharya; Larry W. Tsai; Edward P. Ingenito; Frank Gonzalez; Steven D. Shapiro; Thomas J. Mariani; Brigham and Women's Hospital; Harvard Medical School; Mahidol University; National Cancer InstitutePeroxisome proliferator-activated receptor (PPAR)-γ is a member of the nuclear hormone receptor superfamily that can promote cellular differentiation and organ development. PPARγ expression has been reported in a number of pulmonary cell types, including inflammatory, mesenchymal, and epithelial cells. We find that PPARγ is prominently expressed in the airway epithelium in the mouse lung. In an effort to define the physiological role of PPARγ within the lung, we have ablated PPARγ using a novel line of mice capable of specifically targeting the airway epithelium. Airway epithelial cell PPARγ-targeted mice display enlarged airspaces resulting from insufficient postnatal lung maturation. The increase in airspace size is accompanied by alterations in lung physiology, including increased lung volumes and decreased tissue resistance. Genome-wide expression profiling reveals a reduction in structural extracellular matrix (ECM) gene expression in conditionally targeted mice, suggesting a disruption in epithelial-mesenchymal interactions necessary for the establishment of normal lung structure. Expression profiling of airway epithelial cells isolated from conditionally targeted mice indicates PPARγ regulates genes encoding known PPARγ targets, additional lipid metabolism enzymes, and markers of cellular differentiation. These data reveal airway epithelial cell PPARγ is necessary for normal lung structure and function. © FASEB.Publication Metadata only Experiences and factors that influence potassium hydroxide examination by microscopists(2016-01-01) Sumanas Bunyaratavej; Penvadee Pattanaprichakul; Sorachai Srisuma; Charussri Leeyaphan; Mahidol University© 2016, Japanese Society for Medical Mycology. All rights reserved. Background: Potassium hydroxide (KOH) examination is commonly used in dermatological practice. Despite its simplicity, rapidity, and minimal invasiveness, experience in specimen collection, preparation, and interpretation is extremely important. Aims: To determine the ability to interpret KOH examination of six microscopists with different levels of experience within the Department of Dermatology. Methods: Six volunteer microscopists, who have different experiences in KOH examination in terms of specimens per week (SPW), were assigned to prepare and examine 10 unknown slides of skin scrapings. All participants were then paired into three groups and exchanged the slides set to their partner in each group for a second round of slides interpretation. Results: Results of examinations were classified as correct, false negative, false positive, and misinterpretation. The highly experienced microscopists achieved more correct answers than the fairly experienced group in both sessions. There was a significant positive correlation between SPW (r = 1.0, Spearman rank, p = 0.01) and the correct answers; and a significant negative correlation between SPW and misinterpretation(r = -1.0, Spearman rank, p < 0.01), exclusively for the second session. Limitations: A small number of volunteer microscopists was enrolled in this study. Conclusions: Experience in routine slide examination and time spent during examination were significant factors for accurate interpretation of KOH examination. Positive correlation between experience and correct answers, and negative correlation between experience and misinterpretation were particularly observed under limited examination time.Publication Metadata only Exploratory study of factors related to educational scores of first preclinical year medical students(2014-01-01) Chantacha Sitticharoon; Sorachai Srisuma; Sawita Kanavitoon; Sarawut Summachiwakij; Mahidol UniversityThe relationships among the scores of major subjects taught in the first preclinical year of a Thai medical school, previous academic achievements, and daily life activities are rarely explored. We therefore performed an exploratory study identifying various factors possibly related to the educational scores of these medical students. Questionnaires were sent out to all first preclinical year medical students, with 79.8% being returned (245/307 questionnaires). Positive correlations were revealed between the premedical year grade point average (pre-MD GPA) and anatomy, physiology, and biochemistry scores (R = 0.664, 0.521, and 0.653, respectively, P < 0.001 for all) by Pearson's method. Using multiple linear regression analysis, anatomy scores could be predicted by pre-MD GPA, student satisfaction with anatomy, the percentage of expected reading, monthly earnings, reading after class and near exam time, and duration of sleeping periods near exam time (R = 0.773, R2 = 0.598, P < 0.001). Physiology scores could be estimated by pre-MD GPA, the percentage of expected reading, monthly earnings, and percentage of those who fell asleep during class and near exam time (R = 0.722, R2 = 0.521, P < 0.001). Biochemistry scores could be calculated by pre-MD GPA, the percentage of expected reading, motivation to study medicine, student satisfaction with biochemistry, and exam performance expectations (R = 0.794, R2R2 = 0.630, P < 0.001). In conclusion, pre-MD GPA and the percentage of expected reading are factors involved in producing good academic results in the first preclinical year. Anatomy and biochemistry, but not physiology, scores are influenced by satisfaction. © 2014 The American Physiological Society.Publication Metadata only Fibroblast growth factor receptors control epithelial-mesenchymal interactions necessary for alveolar elastogenesis(2010-04-15) Sorachai Srisuma; Soumyaroop Bhattacharya; Dawn M. Simon; Siva K. Solleti; Shivraj Tyagi; Barry Starcher; Thomas J. Mariani; University of Rochester; Mahidol University; Brigham and Women's Hospital; Emory Children's Center; University of Texas Health Center at TylerRationale: The mechanisms contributing to alveolar formation are poorly understood. A better understanding of these processes will improve efforts to ameliorate lung disease of the newborn and promote alveolar repair in the adult. Previous studies have identified impaired alveogenesis in mice bearing compound mutations of fibroblast growth factor (FGF) receptors (FGFRs) 3 and 4, indicating that these receptors cooperatively promote postnatal alveolar formation. Objectives: To determine the molecular and cellular mechanisms of FGF-mediated alveolar formation. Methods: Compound FGFR3/FGFR4-deficient mice were assessed for temporal changes in lung growth, airspace morphometry, and genome-wide expression. Observed gene expression changes were validated using quantitative real-time RT-PCR, tissue biochemistry, histochemistry, and ELISA. Autocrine and paracrine regulatory mechanisms were investigated using isolated lung mesenchymal cells and type II pneumocytes. Measurements and Main Results: Quantitative analysis of airspace ontogeny confirmed a failure of secondary crest elongation in compound mutant mice. Genome-wide expression profiling identified molecular alterations in these mice involving aberrant expression of numerous extracellular matrix molecules. Biochemical and histochemical analysis confirmed changes in elastic fiber gene expression resulted in temporal increases in elastin deposition with the loss of typical spatial restriction. No abnormalities in elastic fiber gene expression were observed in isolated mesenchymal cells, indicating that abnormal elastogenesis in compound mutant mice is not cell autonomous. Increased expression of paracrine factors, including insulin-like growth factor21, in freshly-isolated type II pneumocytes indicated that these cells contribute to the observed pathology. Conclusions: Epithelial/mesenchymal signaling mechanisms appear to contribute to FGFR-dependent alveolar elastogenesis and proper airspace formation.Publication Metadata only Genome-wide transcriptional profiling reveals connective tissue mast cell accumulation in bronchopulmonary dysplasia(2012-08-15) Soumyaroop Bhattacharya; Diana Go; Daria L. Krenitsky; Heidi L. Huyck; Siva Kumar Solleti; Valerie A. Lunger; Leon Metlay; Sorachai Srisuma; Susan E. Wert; Thomas J. Mariani; Gloria S. Pryhuber; University of Rochester Medical Center; Mahidol University; Cincinnati Children's Hospital Medical CenterRationale: Bronchopulmonary dysplasia (BPD) is a major complication of premature birth. Risk factors for BPD are complex and include prenatal infection and O 2 toxicity. BPD pathology is equally complex and characterized by inflammation and dysmorphic airspaces and vasculature. Due to the limited availability of clinical samples, an understanding of the molecular pathogenesis of this disease and its causal mechanisms and associated biomarkers is limited. Objectives: Apply genome-wide expression profiling to define pathways affected in BPD lungs. Methods: Lung tissue was obtained at autopsy from 11 BPD cases and 17 age-matched control subjects without BPD. RNA isolated from these tissue samples was interrogated using microarrays. Standard gene selection and pathway analysis methods were applied to the data set. Abnormal expression patterns were validated by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. Measurements and Main Results: We identified 159 genes differentially expressed in BPD tissues. Pathway analysis indicated previously appreciated (e.g., DNA damage regulation of cell cycle) as well as novel (e.g., B-cell development) biological functions were affected. Three of the five most highly induced genes were mast cell (MC)-specific markers. We confirmed an increased accumulation of connective tissue MC TC (chymase expressing) mast cells in BPD tissues. Increased expression of MC TC markers was also demonstrated in an animal model of BPD-like pathology. Conclusions: We present a unique genome-wide expression data set from human BPD lung tissue. Our data provide information on gene expression patterns associated with BPD and facilitated the discovery that MC TC accumulation is a prominent feature of this disease. These observations have significant clinical and mechanistic implications. Copyright © 2012 by the American Thoracic Society.Publication Metadata only Molecular biomarkers for quantitative and discrete COPD phenotypes(2009-03-01) Soumyaroop Bhattacharya; Sorachai Srisuma; Dawn L. Demeo; Steven D. Shapiro; Raphael Bueno; Edwin K. Silverman; John J. Reilly; Thomas J. Mariani; Harvard Medical School; Brigham and Women's Hospital; Mahidol University; University of Rochester; University of PittsburghChronic obstructive pulmonary disease (COPD) is an inflammatory lung disorder with complex pathological features and largely unknown etiology. The identification of biomarkers for this disease could aid the development of methods to facilitate earlier diagnosis, the classification of disease subtypes, and provide a means to define therapeutic response. To identify gene expression biomarkers, we completed expression profiling of RNA derived from the lung tissue of 56 subjects with varying degrees of airflow obstruction using the Affymetrix U133 Plus 2.0 array. We applied multiple, independent analytical methods to define biomarkers for either discrete or quantitative disease phenotypes. Analysis of differential expression between cases (n = 15) and controls (n = 18) identified a set of 65 discrete biomarkers. Correlation of gene expression with quantitative measures of airflow obstruction (FEV1%predicted or FEV1/FVC) identified a set of 220 biomarkers. Biomarker genes were enriched in functions related to DNA binding and regulation of transcription. We used this group of biomarkers to predict disease in an unrelated data set, generated from patients with severe emphysema, with 97% accuracy. Our data contribute to the understanding of gene expression changes occurring in the lung tissue of patients with obstructive lung disease and provide additional insight into potential mechanisms involved in the disease process. Furthermore, we present the first gene expression biomarker for COPD validated in an independent data set.Publication Metadata only Peripheral blood gene expression profiles in COPD subjects(2011-04-24) Soumyaroop Bhattacharya; Shivraj Tyagi; Sorachai Srisuma; Dawn L. DeMeo; Steven D. Shapiro; Raphael Bueno; Edwin K. Silverman; John J. Reilly; Thomas J. Mariani; University of Rochester Medical Center; Brigham and Women's Hospital; Mahidol University; University of Pittsburgh Medical CenterTo identify non-invasive gene expression markers for chronic obstructive pulmonary disease (COPD), we performed genome-wide expression profiling of peripheral blood samples from 12 subjects with significant airflow obstruction and an equal number of non-obstructed controls. RNA was isolated from Peripheral Blood Mononuclear Cells (PBMCs) and gene expression was assessed using Affymetrix U133 Plus 2.0 arrays.Tests for gene expression changes that discriminate between COPD cases (FEV 1 < 70% predicted, FEV 1 /FVC < 0.7) and controls (FEV 1 > 80% predicted, FEV 1 /FVC > 0.7) were performed using Significance Analysis of Microarrays (SAM) and Bayesian Analysis of Differential Gene Expression (BADGE). Using either test at high stringency (SAM median FDR = 0 or BADGE p < 0.01) we identified differential expression for 45 known genes. Correlation of gene expression with lung function measurements (FEV 1 & FEV 1 /FVC), using both Pearson and Spearman correlation coefficients (p < 0.05), identified a set of 86 genes. A total of 16 markers showed evidence of significant correlation (p < 0.05) with quantitative traits and differential expression between cases and controls. We further compared our peripheral gene expression markers with those we previously identified from lung tissue of the same cohort. Two genes, RP9and NAPE-PLD, were identified as decreased in COPD cases compared to controls in both lung tissue and blood. These results contribute to our understanding of gene expression changes in the peripheral blood of patients with COPD and may provide insight into potential mechanisms involved in the disease. © 2011 Bhattacharya et al; licensee BioMed Central Ltd.Publication Metadata only Serpine2 deficiency results in lung lymphocyte accumulation and bronchus-associated lymphoid tissue formation(2016-07-01) Siva Kumar Solleti; Sorachai Srisuma; Soumyaroop Bhattacharya; Javier Rangel-Moreno; Kaiser M. Bijli; Troy D. Randall; Arshad Rahman; Thomas J. Mariani; University of Rochester Medical Center; Mahidol University; Atlanta VA Medical Center; University of Alabama at Birmingham© FASEB. Serine proteinase inhibitor, clade E, member 2 (SERPINE2), is a cell- and extracellular matrix-associated inhibitor of thrombin. Although SERPINE2 is a candidate susceptibility gene for chronic obstructive pulmonary disease, the physiologic role of this protease inhibitor in lung development and homeostasis is unknown. We observed spontaneous monocytic-cell infiltration in the lungs of Serpine2-deficient (SE2-/-) mice, beginning at or before the time of lung maturity, which resulted in lesions that resembled bronchus-associated lymphoid tissue (BALT). The initiation of lymphocyte accumulation in the lungs of SE2-/-mice involved the excessive expression of chemokines, cytokines, and adhesion molecules that are essential for BALT induction, organization, and maintenance. BALT-like lesion formation in the lungs of SE2-/-mice was also associated with a significant increase in the activation of thrombin, a recognized target of SE2, and excess stimulation of NF-κB, a major regulator of chemokine expression and inflammation. Finally, systemic delivery of thrombin rapidly stimulated lung chemokine expression in vivo. These data uncover a novel mechanism whereby loss of serine protease inhibition leads to lung lymphocyte accumulation.Publication Metadata only The SERPINE2 gene is associated with chronic obstructive pulmonary disease(2006-01-01) Dawn L. DeMeo; Thomas J. Mariani; Christoph Lange; Sorachai Srisuma; Augusto A. Litonjua; Juan C. Celedón; Stephen L. Lake; John J. Reilly; Harold A. Chapman; Brigham H. Mecham; Kathleen J. Haley; Jody S. Sylvia; David Sparrow; Avrum E. Spira; Jennifer Beane; Victor Pinto-Plata; Frank E. Speizer; Steven D. Shapiro; Scott T. Weiss; Edwin K. Silverman; Brigham and Women's Hospital; Beth Israel Deaconess Medical Center; Boston Medical Center; Caritas St. Elizabeth's Medical Center; Mahidol University; University of California, San Francisco; Channing LaboratoryChronic obstructive pulmonary disease (COPD) is a complex human disease likely influenced by multiple genes, cigarette smoking, and gene-by-smoking interactions, but only severe alpha 1-antitrypsin deficiency is a proven genetic risk factor for COPD. Prior linkage analyses in the Boston Early-Onset COPD Study have demonstrated significant linkage to a key intermediate phenotype of COPD on chromosome 2q. We integrated results from murine lung development and human COPD gene-expression microarray studies with human COPD linkage results on chromosome 2q to prioritize candidate-gene selection, thus identifying SERPINE2 as a positional candidate susceptibility gene for COPD. Immunohistochemistry demonstrated expression of serpinel protein in mouse and human adult lung tissue. In family-based association testing of 127 severe, early-onset COPD pedigrees from the Boston Early-Onset COPD Study, we observed significant association with COPD phenotypes and 18 single-nucleotide polymorphisms (SNPs) in the SERPINE2 gene. Association of five of these SNPs with COPD was replicated in a case-control analysis, with cases from the National Emphysema Treatment Trial and controls from the Normative Aging Study. Family-based and case-control haplotype analyses supported similar regions of association within the SEEPINE2 gene. When significantly associated SNPs in these haplotypic regions were included as covariates in linkage models, LOD score attenuation was observed most markedly in a smokers-only linkage model (LOD 4.41, attenuated to 1.74). After the integration of murine and human microarray data to inform candidate-gene selection, we observed significant family-based association and independent replication of association in a case-control study, suggesting that SERPINE2 is a COPD-susceptibility gene and is likely influenced by gene-by-smoking interaction. © 2005 by The American Society of Human Genetics. All rights reserved.