Showing papers by "Serpil C. Erzurum published in 2012"

Asthma outcomes: Biomarkers

Abstract: Background Measurement of biomarkers has been incorporated within clinical research studies of asthma to characterize the population and associate the disease with environmental and therapeutic effects. Objective National Institutes of Health institutes and federal agencies convened an expert group to propose which biomarkers should be assessed as standardized asthma outcomes in future clinical research studies. Methods We conducted a comprehensive search of the literature to identify studies that developed and/or tested asthma biomarkers. We identified biomarkers relevant to the underlying disease process progression and response to treatment. We classified the biomarkers as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an National Institutes of Health–organized workshop convened in March 2010 and finalized in September 2011. Results Ten measures were identified; only 1, multiallergen screening to define atopy, is recommended as a core asthma outcome. Complete blood counts to measure total eosinophils, fractional exhaled nitric oxide (Feno), sputum eosinophils, urinary leukotrienes, and total and allergen-specific IgE are recommended as supplemental measures. Measurement of sputum polymorphonuclear leukocytes and other analytes, cortisol measures, airway imaging, breath markers, and system-wide studies (eg, genomics, proteomics) are considered as emerging outcome measures. Conclusion The working group participants propose the use of multiallergen screening in all asthma clinical trials to characterize study populations with respect to atopic status. Blood, sputum, and urine specimens should be stored in biobanks, and standard procedures should be developed to harmonize sample collection for clinical trial biorepositories.

Severe asthma: lessons learned from the National Heart, Lung, and Blood Institute Severe Asthma Research Program.

Abstract: The National Heart, Lung, and Blood Institute Severe Asthma Research Program (SARP) has characterized over the past 10 years 1,644 patients with asthma, including 583 individuals with severe asthma. SARP collaboration has led to a rapid recruitment of subjects and efficient sharing of samples among participating sites to conduct independent mechanistic investigations of severe asthma. Enrolled SARP subjects underwent detailed clinical, physiologic, genomic, and radiological evaluations. In addition, SARP investigators developed safe procedures for bronchoscopy in participants with asthma, including those with severe disease. SARP studies revealed that severe asthma is a heterogeneous disease with varying molecular, biochemical, and cellular inflammatory features and unique structure-function abnormalities. Priorities for future studies include recruitment of a larger number of subjects with severe asthma, including children, to allow further characterization of anatomic, physiologic, biochemical, and genetic factors related to severe disease in a longitudinal assessment to identify factors that modulate the natural history of severe asthma and provide mechanistic rationale for management strategies.

Genome-wide association studies of asthma indicate opposite immunopathogenesis direction from autoimmune diseases

Abstract: Background Genome-wide association studies (GWASs) of asthma have consistently implicated the ORM1-like 3 and gasdermin B (ORMDL3-GSDMB) , IL33 , IL-1 receptor–like 1 and IL-18 receptor 1 (IL1RL1-IL18R1) , RAD50-IL13 , thymic stromal lymphopoietin and WD repeat domain 36 region (TSLP-WDR36) , and HLA-DR/DQ regions. Objective A GWAS of asthma was performed in a non-Hispanic white population. Methods A GWAS was performed in 813 Severe Asthma Research Program/Collaborative Studies on the Genetics of Asthma/Chicago Asthma Genetics Study cases and 1564 control subjects. The GWAS results were compared with those of the published GWASs of autoimmune diseases. Results Multiple single nucleotide polymorphisms in the TNFAIP3 interacting protein 1 (TNIP1) gene, which interacts with TNFAIP3 and inhibits the TNF-α–induced nuclear factor κB inflammation pathway, were associated with asthma: rs1422673 ( P = 3.44 × 10 −7 ) and rs10036748 ( P = 1.41 × 10 −6 , r 2 = 0.67). rs1422673 was also associated with asthma in the published GABRIEL ( P = .018) and EVE ( P = 1.31 × 10 −5 ) studies. The minor allele T of rs20541 in IL13 is the risk allele for asthma but the protective allele for psoriasis. The minor allele T of rs2395185 in HLA-DRA is the risk allele for asthma but the protective allele for ulcerative colitis. The minor allele A of rs2872507 in GSDMB is the protective allele for asthma but the risk allele for rheumatoid arthritis, Crohn disease, and ulcerative colitis. The T allele of rs10036748 in the TNIP1 gene is the minor protective allele for asthma but the minor or major risk allele for systemic lupus erythematosus and systemic sclerosis in non-Hispanic white or Chinese subjects, respectively. Conclusions Our study suggests that single nucleotide polymorphisms associated with both asthma and autoimmune diseases might have opposite effects on immunopathogenesis.

Sleep quality and asthma control and quality of life in non-severe and severe asthma.

Abstract: Purpose The effect of sleep quality on asthma control independent from common comorbidities like gastroesophageal reflux disease (GERD) and obstructive sleep apnea (OSA) is unknown. This study examined the association between sleep quality and asthma control and quality of life after accounting for OSA and GERD in non-severe (NSA) and severe (SA) asthma.

High Mobility Group Box 1 Contributes to the Pathogenesis of Experimental Pulmonary Hypertension via Activation of Toll-like Receptor 4

Abstract: Survival rates for patients with pulmonary hypertension (PH) remain low, and our understanding of the mechanisms involved are incomplete. Here we show in a mouse model of chronic hypoxia (CH)-induced PH that the nuclear protein and damage-associate molecular pattern molecule (DAMP) high mobility group box 1 (HMGB1) contributes to PH via a Toll-like receptor 4 (TLR4)-dependent mechanism. We demonstrate extranuclear HMGB1 in pulmonary vascular lesions and increased serum HMGB1 in patients with idiopathic pulmonary arterial hypertension. The increase in circulating HMGB1 correlated with mean pulmonary artery pressure. In mice, we similarly detected the translocation and release of HMGB1 after exposure to CH. HMGB1-neutralizing antibody attenuated the development of CH-induced PH, as assessed by measurement of right ventricular systolic pressure, right ventricular hypertrophy, pulmonary vascular remodeling and endothelial activation and inflammation. Genetic deletion of the pattern recognition receptor TLR4, but not the receptor for advanced glycation end products, likewise attenuated CH-induced PH. Finally, daily treatment of mice with recombinant human HMGB1 exacerbated CH-induced PH in wild-type (WT) but not Tlr4−/− mice. These data demonstrate that HMGB1-mediated activation of TLR4 promotes experimental PH and identify HMGB1 and/or TLR4 as potential therapeutic targets for the treatment of PH.

Human Primary Lung Endothelial Cells in Culture

Abstract: Pulmonary endothelial functions are critical to maintain the low pressure of the pulmonary circulation and effective diffusion capacity of the lung. To investigate pulmonary endothelial cell biology in healthy or diseased lungs, we developed methods to harvest and culture pure populations of primary pulmonary arterial endothelial cells and microvascular endothelial cells from human lung explanted at time of transplantation or from donor lungs not used in transplantation. The purity and characteristics of cultured endothelial cells is ascertained by morphologic criteria using phase contrast and electron microscopy; phenotypic expression profile for endothelial specific proteins such as endothelial nitric oxide synthase, platelet/endothelial cell adhesion molecule, and von Willbrand factor; and endothelial function assays such as Dil-acetylated low-density lipoprotein uptake and tube formation. This detailed method provides researchers with the ability to establish cells for molecular, genetic, and biochemical investigation of human pulmonary vascular diseases.

The IL6R variation Asp358Ala is a potential modifier of lung function in subjects with asthma

Abstract: Background The IL6R single nucleotide polymorphism (SNP) rs4129267 has recently been identified as an asthma susceptibility locus in subjects of European ancestry but has not been characterized with respect to asthma severity. The SNP rs4129267 is in linkage disequilibrium ( r 2 = 1) with the IL6R coding SNP rs2228145 (Asp 358 Ala). This IL6R coding change increases IL-6 receptor (IL-6R) shedding and promotes IL-6 transsignaling. Objectives We sought to evaluate the IL6R SNP rs2228145 with respect to asthma severity phenotypes. Methods The IL6R SNP rs2228145 was evaluated in subjects of European ancestry with asthma from the Severe Asthma Research Program (SARP). Lung function associations were replicated in the Collaborative Study on the Genetics of Asthma (CSGA) cohort. Serum soluble IL-6R levels were measured in subjects from SARP. Immunohistochemistry was used to qualitatively evaluate IL-6R protein expression in bronchoalveolar lavage cells and endobronchial biopsies. Results The minor C allele of IL6R SNP rs2228145 was associated with a lower percent predicted FEV 1 in the SARP cohort ( P = .005), the CSGA cohort ( P = .008), and in a combined cohort analysis ( P = .003). Additional associations with percent predicted forced vital capacity (FVC), FEV 1 /FVC ratio, and PC 20 were observed. The rs2228145 C allele (Ala 358 ) was more frequent in severe asthma phenotypic clusters. Elevated serum soluble IL-6R levels were associated with lower percent predicted FEV 1 ( P = .02) and lower percent predicted FVC ( P = .008) (n = 146). IL-6R protein expression was observed in bronchoalveolar lavage macrophages, airway epithelium, vascular endothelium, and airway smooth muscle. Conclusions The IL6R coding SNP rs2228145 (Asp 358 Ala) is a potential modifier of lung function in subjects with asthma and might identify subjects at risk for more severe asthma. IL-6 transsignaling might have a pathogenic role in the lung.

Mast Cell Number, Phenotype, and Function in Human Pulmonary Arterial Hypertension:

Abstract: A proliferation of mast cells around the small pulmonary blood vessels and the alveolar septae has been noted in models of pulmonary hypertension, and in plexiform lesions of pulmonary arterial hypertension (PAH) in patients. Here, we hypothesize that total mast cell numbers and activation are increased in PAH and that they contribute to vascular remodeling through cellular and soluble proangiogenic effectors. To test this, blood and urine were collected from patients with PAH (N=44), asthma (N=18) and healthy controls (N=29) to quantitate biomarkers of total body mast cell numbers and activation (total and mature tryptase, N-methyl histamine, leukotriene LTE4 and prostaglandin PGD-M). Serum total tryptase was higher in PAH than that in controls suggesting greater numbers of mast cells, but indicators of mast cell activation (mature tryptase, LTE4 and PGD-M) were similar among PAH, asthma, and controls. Immunohistochemistry of lung tissues identified mast cells as primarily perivascular and connec...

Serotonylated fibronectin is elevated in pulmonary hypertension.

Abstract: Serotonin (5-HT) and fibronectin (FN) have been associated with pulmonary hypertension (PH). We previously reported that FN is posttranslationally modified by tissue transglutaminase (TGase) to for...

The C11orf30-LRRC32 region is associated with total serum IgE levels in asthmatic patients.

Abstract: Xingnan Li, PhD, MS1, Elizabeth J. Ampleford, PhD1, Timothy D. Howard, PhD1, Wendy C. Moore, MD1, Huashi Li, MS1, William W. Busse, MD2, Mario Castro, MD3, Serpil C. Erzurum, MD4, Anne M. Fitzpatrick, PhD5, Benjamin Gaston, MD6, Elliot Israel, MD7, Nizar N. Jarjour, MD8, W. Gerald Teague, MD6, Sally E. Wenzel, MD9, Gregory A. Hawkins, PhD1, Eugene R. Bleecker, MD1, and Deborah A. Meyers, PhD1 1Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston Salem, NC

Small-animal imaging using clinical positron emission tomography/computed tomography and super-resolution.

Abstract: Considering the high cost of dedicated small-animal positron emission tomography/computed tomography (PET/CT), an acceptable alternative in many situations might be clinical PET/CT. However, spatial resolution and image quality are of concern. The utility of clinical PET/CT for small-animal research and image quality improvements from super-resolution (spatial subsampling) were investigated. National Electrical Manufacturers Association (NEMA) NU 4 phantom and mouse data were acquired with a clinical PET/CT scanner, as both conventional static and stepped scans. Static scans were reconstructed with and without point spread function (PSF) modeling. Stepped images were postprocessed with iterative deconvolution to produce super-resolution images. Image quality was markedly improved using the super-resolution technique, avoiding certain artifacts produced by PSF modeling. The 2 mm rod of the NU 4 phantom was visualized with high contrast, and the major structures of the mouse were well resolved. Although not a perfect substitute for a state-of-the-art small-animal PET/CT scanner, a clinical PET/CT scanner with super-resolution produces acceptable small-animal image quality for many preclinical research studies.

Genome-wide ancestry association testing identifies a common European variant on 6q14.1 as a risk factor for asthma in African American subjects.

Abstract: Background Genetic variants that contribute to asthma susceptibility might be present at varying frequencies in different populations, which is an important consideration and advantage for performing genetic association studies in admixed populations. Objective We sought to identify asthma-associated loci in African American subjects. Methods We compared local African and European ancestry estimated from dense single nucleotide polymorphism genotype data in African American adults with asthma and nonasthmatic control subjects. Allelic tests of association were performed within the candidate regions identified, correcting for local European admixture. Results We identified a significant ancestry association peak on chromosome 6q. Allelic tests for association within this region identified a single nucleotide polymorphism (rs1361549) on 6q14.1 that was associated with asthma exclusively in African American subjects with local European admixture (odds ratio, 2.2). The risk allele is common in Europe (42% in the HapMap population of Utah residents with Northern and Western European ancestry from the Centre d'Etude du Polymorphisme Humain collection) but absent in West Africa (0% in the HapMap population of Yorubans in Ibadan, Nigeria), suggesting the allele is present in African American subjects because of recent European admixture. We replicated our findings in Puerto Rican subjects and similarly found that the signal of association is largely specific to subjects who are heterozygous for African and non-African ancestry at 6q14.1. However, we found no evidence for association in European American or Puerto Rican subjects in the absence of local African ancestry, suggesting that the association with asthma at rs1361549 is due to an environmental or genetic interaction. Conclusion We identified a novel asthma-associated locus that is relevant to admixed populations with African ancestry and highlight the importance of considering local ancestry in genetic association studies of admixed populations.