Publications by authors named "Suzy A A Comhair"

67 Publications

The Precision Interventions for Severe and/or Exacerbation-Prone (PrecISE) Asthma Network: an overview of Network organization, procedures and interventions.

J Allergy Clin Immunol 2021 Nov 27. Epub 2021 Nov 27.

Department of Radiology, University of Iowa, Iowa City.

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here we describe the Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the U.S. The PrecISE Network was designed to conduct phase II/proof of concept clinical trials of precision interventions in the severe asthma population, and is supported by the National Heart Lung and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the Network will evaluate up to six interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for of severe asthma.
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http://dx.doi.org/10.1016/j.jaci.2021.10.035DOI Listing
November 2021

The systemic inflammatory landscape of COVID-19 in pregnancy: Extensive serum proteomic profiling of mother-infant dyads with SARS-CoV-2.

Cell Rep Med 2021 Nov 27;2(11):100453. Epub 2021 Oct 27.

Instituto Fernades Figueira, Fiocruz, Flamengo, Rio de Janeiro 20140-360, Brazil.

While pregnancy increases the risk for severe COVID-19, the clinical and immunological implications of COVID-19 on maternal-fetal health remain unknown. Here, we present the clinical and immunological landscapes of 93 COVID-19 mothers and 45 of their SARS-CoV-2-exposed infants through comprehensive serum proteomics profiling for >1,400 cytokines of their peripheral and cord blood specimens. Prenatal SARS-CoV-2 infection triggers NF-κB-dependent proinflammatory immune activation. Pregnant women with severe COVID-19 show increased inflammation and unique IFN-λ antiviral signaling, with elevated levels of IFNL1 and IFNLR1. Furthermore, SARS-CoV-2 infection re-shapes maternal immunity at delivery, altering the expression of pregnancy complication-associated cytokines, inducing MMP7, MDK, and ESM1 and reducing BGN and CD209. Finally, COVID-19-exposed infants exhibit induction of T cell-associated cytokines (IL33, NFATC3, and CCL21), while some undergo IL-1β/IL-18/CASP1 axis-driven neonatal respiratory distress despite birth at term. Our findings demonstrate COVID-19-induced immune rewiring in both mothers and neonates, warranting long-term clinical follow-up to mitigate potential health risks.
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http://dx.doi.org/10.1016/j.xcrm.2021.100453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549189PMC
November 2021

Resting Energy Expenditure Is Elevated in Asthma.

Nutrients 2021 Mar 25;13(4). Epub 2021 Mar 25.

Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Asthma physiology affects respiratory function and inflammation, factors that may contribute to elevated resting energy expenditure (REE) and altered body composition. We hypothesized that asthma would present with elevated REE compared to weight-matched healthy controls. Adults with asthma ( = 41) and healthy controls ( = 20) underwent indirect calorimetry to measure REE, dual-energy X-ray absorptiometry (DEXA) to measure body composition, and 3-day diet records. Clinical assessments included spirometry, fractional exhaled nitric oxide (FENO), and a complete blood count. Asthmatics had greater REE than controls amounting to an increase of ~100 kcals/day, even though body mass index (BMI) and body composition were similar between groups. Inclusion of asthma status and FENO in validated REE prediction equations led to improved estimates. Further, asthmatics had higher white blood cell (control vs. asthma (mean ± SD): 4.7 ± 1.1 vs. 5.9 ± 1.6, < 0.01) and neutrophil (2.8 ± 0.9 vs. 3.6 ± 1.4, = 0.02) counts that correlated with REE (both < 0.01). Interestingly, despite higher REE, asthmatics reported consuming fewer calories (25.1 ± 7.5 vs. 20.3 ± 6.0 kcals/kg/day, < 0.01) and carbohydrates than controls. REE is elevated in adults with mild asthma, suggesting there is an association between REE and the pathophysiology of asthma.
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http://dx.doi.org/10.3390/nu13041065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064324PMC
March 2021

PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment.

J Allergy Clin Immunol 2021 05 2;147(5):1594-1601. Epub 2021 Mar 2.

Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wis.

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.
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http://dx.doi.org/10.1016/j.jaci.2021.01.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113113PMC
May 2021

Comparison of whole genome sequencing and targeted sequencing for mitochondrial DNA.

Mitochondrion 2021 05 26;58:303-310. Epub 2021 Jan 26.

Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address:

Mitochondrial dysfunction has emerged to be associated with a broad spectrum of diseases, and there is an increasing demand for accurate detection of mitochondrial DNA (mtDNA) variants. Whole genome sequencing (WGS) has been the dominant sequencing approach to identify genetic variants in recent decades, but most studies focus on variants on the nuclear genome. Whole genome sequencing is also costly and time consuming. Sequencing specifically targeted for mtDNA is commonly used in the diagnostic settings and has lower costs. However, there is a lack of pairwise comparisons between these two sequencing approaches for calling mtDNA variants on a population basis. In this study, we compared WGS and mtDNA-targeted sequencing (targeted-seq) in analyzing mitochondrial DNA from 1499 participants recruited into the Severe Asthma Research Program (SARP). Our study reveals that targeted-sequencing and WGS have comparable capacity to determine genotypes and to call haplogroups and homoplasmies on mtDNA. However, there exists a large variability in calling heteroplasmies, especially for low-frequency heteroplasmies, which indicates that investigators should be cautious about heteroplasmies acquired from different sequencing methods. Further research is highly desired to improve variant detection methods for mitochondrial DNA.
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http://dx.doi.org/10.1016/j.mito.2021.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354572PMC
May 2021

O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension.

Int J Mol Sci 2019 Dec 13;20(24). Epub 2019 Dec 13.

Department of Inflammation & Immunity, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA.

Idiopathic pulmonary arterial hypertension (IPAH) is considered a vasculopathy characterized by elevated pulmonary vascular resistance due to vasoconstriction and/or lung remodeling such as plexiform lesions, the hallmark of the PAH, as well as cell proliferation and vascular and angiogenic dysfunction. The serine/threonine hydroxyl-linked N-Acetylglucosamine (O-GlcNAc) transferase (OGT) has been shown to drive pulmonary arterial smooth muscle cell (PASMC) proliferation in IPAH. OGT is a cellular nutrient sensor that is essential in maintaining proper cell function through the regulation of cell signaling, proliferation, and metabolism. The aim of this study was to determine the role of OGT and O-GlcNAc in vascular and angiogenic dysfunction in IPAH. Primary isolated human control and IPAH patient PASMCs and pulmonary arterial endothelial cells (PAECs) were grown in the presence or absence of OGT inhibitors and subjected to biochemical assessments in monolayer cultures and tube formation assays, in vitro vascular sprouting 3D spheroid co-culture models, and de novo vascularization models in NODSCID mice. We showed that knockdown of OGT resulted in reduced vascular endothelial growth factor (VEGF) expression in IPAH primary isolated vascular cells. In addition, specificity protein 1 (SP1), a known stimulator of VEGF expression, was shown to have higher O-GlcNAc levels in IPAH compared to control at physiological (5 mM) and high (25 mM) glucose concentrations, and knockdown resulted in decreased VEGF protein levels. Furthermore, human IPAH PAECs demonstrated a significantly higher degree of capillary tube-like structures and increased length compared to control PAECs. Addition of an OGT inhibitor, OSMI-1, significantly reduced the number of tube-like structures and tube length similar to control levels. Assessment of vascular sprouting from an in vitro 3D spheroid co-culture model using IPAH and control PAEC/PASMCs and an in vivo vascularization model using control and PAEC-embedded collagen implants demonstrated higher vascularization in IPAH compared to control. Blocking OGT activity in these experiments, however, altered the vascular sprouting and de novo vascularization in IPAH similar to control levels when compared to controls. Our findings in this report are the first to describe a role for the OGT/O-GlcNAc axis in modulating VEGF expression and vascularization in IPAH. These findings provide greater insight into the potential role that altered glucose uptake and metabolism may have on the angiogenic process and the development of plexiform lesions. Therefore, we believe that the OGT/O-GlcNAc axis may be a potential therapeutic target for treating the angiogenic dysregulation that is present in IPAH.
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http://dx.doi.org/10.3390/ijms20246299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941156PMC
December 2019

Integrative proteomics and phosphoproteomics in pulmonary arterial hypertension.

Sci Rep 2019 12 9;9(1):18623. Epub 2019 Dec 9.

Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.

Pulmonary arterial endothelial cells (PAEC) are mechanistically linked to origins of pulmonary arterial hypertension (PAH). Here, global proteomics and phosphoproteomics of PAEC from PAH (n = 4) and healthy lungs (n = 5) were performed using LC-MS/MS to confirm known pathways and identify new areas of investigation in PAH. Among PAH and control cells, 170 proteins and 240 phosphopeptides were differentially expressed; of these, 45 proteins and 18 phosphopeptides were located in the mitochondria. Pathologic pathways were identified with integrative bioinformatics and human protein-protein interactome network analyses, then confirmed with targeted proteomics in PAH PAEC and non-targeted metabolomics and targeted high-performance liquid chromatography of metabolites in plasma from PAH patients (n = 30) and healthy controls (n = 12). Dysregulated pathways in PAH include accelerated one carbon metabolism, abnormal tricarboxylic acid (TCA) cycle flux and glutamate metabolism, dysfunctional arginine and nitric oxide pathways, and increased oxidative stress. Functional studies in cells confirmed abnormalities in glucose metabolism, mitochondrial oxygen consumption, and production of reactive oxygen species in PAH. Altogether, the findings indicate that PAH is typified by changes in metabolic pathways that are primarily found in mitochondria.
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http://dx.doi.org/10.1038/s41598-019-55053-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901481PMC
December 2019

Endothelial Phenotype Evoked by Low Dose Carvedilol in Pulmonary Hypertension.

Front Cardiovasc Med 2018 12;5:180. Epub 2018 Dec 12.

Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States.

The therapeutic benefits of β-blockers are well established in left heart failure. The Pulmonary Arterial Hypertension Treatment with Carvedilol for Heart Failure [PAHTCH] study showed safety and possible benefit of carvedilol in pulmonary arterial hypertension (PAH) associated right heart failure over 6 months. This study aims at evaluating the short-term cardiovascular effects and early mechanistic biomarkers of carvedilol therapy. Thirty patients with pulmonary hypertension (PH) received low dose carvedilol (3.125 mg twice daily) for 1 week prior to randomization to placebo, low-dose, or dose-escalating carvedilol therapy. Echocardiography was performed at baseline and 1 week. Exercise capacity was assessed by 6 min walk distance (6MWD). The L-arginine/nitric oxide pathway and other biological markers of endothelial function were measured. All participants tolerated 1 week of carvedilol without adverse effects. After 1 week of carvedilol, 6MWD and heart rate at peak exercise did not vary (both > 0.1). Heart rate at rest and 1 min post walk dropped significantly (both < 0.05) with a trend for increase in heart rate recovery ( = 0.08). Right ventricular systolic pressure (RVSP) decreased by an average of 13 mmHg ( = 0.002). Patients who had a decrease in RVSP of more than 10 mm Hg were defined as responders ( = 17), and those with a lesser drop as non-responders ( = 13). Responders had a significant drop in pulmonary vascular resistance (PVR) after 1 week of carvedilol ( = 0.004). In addition, responders had a greater decrease in heart rate at rest and 1 min post walk compared to non-responders (both < 0.05). Responders had higher plasma arginine and global bioavailability of arginine at baseline compared to non-responders ( = 0.03 and = 0.05, respectively). After 1 week of carvedilol, responders had greater increase in urinary nitrate ( = 0.04). Responders treated with carvedilol had a sustained drop in RVSP and PVR after 6 months of carvedilol with no change in cardiac output. Low-dose carvedilol for 1 week can potentially identify a PH responder phenotype that may benefit from β-blockers that is associated with less endothelial dysfunction. http://www.clinicaltrials.gov. identifier: NCT01586156.
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http://dx.doi.org/10.3389/fcvm.2018.00180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299019PMC
December 2018

The utility of biomarkers in diagnosis of aspirin exacerbated respiratory disease.

Respir Res 2018 Oct 30;19(1):210. Epub 2018 Oct 30.

Department of Internal Medicine, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.

Background: Aspirin-exacerbated respiratory disease (AERD) is a distinct eosinophilic phenotype of severe asthma with accompanying chronic rhinosinusitis, nasal polyposis, and hypersensitivity to aspirin. Urinary 3-bromotyrosine (uBrTyr) is a noninvasive marker of eosinophil-catalyzed protein oxidation. The lack of in vitro diagnostic test makes the diagnosis of AERD difficult. We aimed to determine uBrTyr levels in patients with AERD (n = 240) and aspirin-tolerant asthma (ATA) (n = 226) and to assess whether its addition to urinary leukotriene E (uLTE) levels and blood eosinophilia can improve the prediction of AERD diagnosis.

Methods: Clinical data, spirometry and blood eosinophilis were evaluated. UBrTyr and uLTE levels were measured in urine by HPLC and ELISA, respectively.

Results: Both groups of asthmatics (AERD, n = 240; ATA, n = 226) had significantly higher uBrTyr, uLTE levels, and blood eosinophils than healthy controls (HC) (n = 71) (p < 0.05). ULTE levels and blood eosinophils were significantly higher in AERD as compared to ATA (p = 0.004, p < 0.0001, respectively). whereas uBrTyr levels were not significantly different between both asthma phenotypes (p = 0.34). Asthmatics with high levels of uBrTyr (> 0.101 ng/mg Cr), uLTE levels (> 800 pg/mg Cr) and blood eosinophils (> 300 cells/ul) were 7 times more likely to have AERD.. However, uBrTyr did not increase the benefit for predicting AERD when uLTE and blood eosinophils were already taken into account (p = 0.57).

Conclusion: UBrTyr levels are elevated both in AERD and ATA as compared to HC, but they could not differentiate between these asthma phenotypes suggesting a similar eosinophilic activation. The addition of uBrTyr to elevated uLTE4 levels and blood eosinophils did not statistically enhance the prediction of AERD diagnosis.
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http://dx.doi.org/10.1186/s12931-018-0909-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208044PMC
October 2018

PVDOMICS: A Multi-Center Study to Improve Understanding of Pulmonary Vascular Disease Through Phenomics.

Circ Res 2017 10;121(10):1136-1139

From the Vanderbilt University, Nashville, TN (A.R.H., J.H.N.); Cleveland Clinic, OH (G.J.B., M.A.A., J.B., S.A.A.C., S.C.E., B.H., J.K.L., M.A.O., W.H.W.T.); Wayne State University/John D. Dingell VAMC, Detroil, MI (A.A.); Columbia University, New York, NY (E.B.R., W.K.C.); Mayo Clinic, Rochester, MN (B.A.B., R.P.F.); Pulmonary Hypertension Association, Silver Spring, MD (M.P.G.); New York University Medical Center (G.G.); Johns Hopkins Hospital, Baltimore, MD (P.M.H., S.C.M.); Tufts Medical Center, Boston, MA (N.S.H.); Weill Cornell Medicine, New York, NY (E.M.H.); Brigham and Women's Hospital, Boston, MA (B.A.M., D.M.S., A.B.W., J.A.L.); The University of Arizona, Tucson (F.P.R., J.X.-J.Y.); and National Heart, Lung and Blood Institute, Bethesda, MD (L.X.).

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http://dx.doi.org/10.1161/CIRCRESAHA.117.311737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685561PMC
October 2017

Baseline Features of the Severe Asthma Research Program (SARP III) Cohort: Differences with Age.

J Allergy Clin Immunol Pract 2018 Mar - Apr;6(2):545-554.e4. Epub 2017 Aug 31.

Harvard University School of Medicine, Boston, Mass.

Background: The effect of age on asthma severity is poorly understood.

Objectives: The objective of this study was to compare the baseline features of severe and nonsevere asthma in the Severe Asthma Research Program (SARP) III cohort, and examine in cross section the effects of age on those features.

Methods: SARP III is a National Institutes of Health/National Heart Lung Blood Institute multisite 3-year cohort study conducted to investigate mechanisms of severe asthma. The sample included 188 children (111 severe, 77 nonsevere) and 526 adults (313 severe, 213 nonsevere) characterized for demographic features, symptoms, health care utilization, lung function, and inflammatory markers compared by age and severity.

Results: Compared with children with nonsevere asthma, children with severe asthma had more symptoms and more historical exacerbations, but no difference in body weight, post-bronchodilator lung function, or inflammatory markers. After childhood, and increasing with age, the cohort had a higher proportion of women, less allergen sensitization, and overall fewer blood eosinophils. Enrollment of participants with severe asthma was highest in middle-aged adults, who were older, more obese, with greater airflow limitation and higher blood eosinophils, but less allergen sensitization than adults with nonsevere asthma.

Conclusions: The phenotypic features of asthma differ by severity and with advancing age. With advancing age, patients with severe asthma are more obese, have greater airflow limitation, less allergen sensitization, and variable type 2 inflammation. Novel mechanisms besides type 2 inflammatory pathways may inform the severe asthma phenotype with advancing age.
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http://dx.doi.org/10.1016/j.jaip.2017.05.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832534PMC
November 2019

Arginine metabolic endotypes related to asthma severity.

PLoS One 2017 10;12(8):e0183066. Epub 2017 Aug 10.

Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.

Aims: Arginine metabolism via inducible nitric oxide synthase (iNOS) and arginase 2 (ARG2) is higher in asthmatics than in healthy individuals. We hypothesized that a sub-phenotype of asthma might be defined by the magnitude of arginine metabolism categorized on the basis of high and low fraction of exhaled nitric oxide (FENO).

Methods: To test this hypothesis, asthmatics (n = 52) were compared to healthy controls (n = 51) for levels of FENO, serum arginase activity, and airway epithelial expression of iNOS and ARG2 proteins, in relation to clinical parameters of asthma inflammation and airway reactivity. In parallel, bronchial epithelial cells were evaluated for metabolic effects of iNOS and ARG2 expression in vitro.

Results: Asthmatics with high FENO (≥ 35 ppb; 44% of asthmatics) had higher expression of iNOS (P = 0.04) and ARG2 (P = 0.05) in the airway, indicating FENO is a marker of the high arginine metabolic endotype. High FENO asthmatics had the lowest FEV1% (P < 0.001), FEV1/FVC (P = 0.0002) and PC20 (P < 0.001) as compared to low FENO asthmatics or healthy controls. Low FENO asthmatics had near normal iNOS and ARG2 expression (both P > 0.05), and significantly higher PC20 (P < 0.001) as compared to high FENO asthmatics. In vitro studies to evaluate metabolic effects showed that iNOS overexpression and iNOS+ARG2 co-expression in a human bronchial epithelial cell line led to greater reliance on glycolysis with higher rate of pyruvate going to lactate.

Conclusions: The high FENO phenotype represents a large portion of the asthma population, and is typified by greater arginine metabolism and more severe and reactive asthma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183066PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552347PMC
October 2017

Antioxidant defense and oxidative damage vary widely among high-altitude residents.

Am J Hum Biol 2017 Nov 20;29(6). Epub 2017 Jul 20.

Department of Anthropology, Case Western Reserve University, Cleveland, Ohio, 44106.

Objectives: People living at high altitude experience unavoidable low oxygen levels (hypoxia). While acute hypoxia causes an increase in oxidative stress and damage despite higher antioxidant activity, the consequences of chronic hypoxia are poorly understood. The aim of the present study is to assess antioxidant activity and oxidative damage in high-altitude natives and upward migrants.

Methods: Individuals from two indigenous high-altitude populations (Amhara, n = 39), (Sherpa, n = 34), one multigenerational high-altitude population (Oromo, n = 42), one upward migrant population (Nepali, n = 12), and two low-altitude reference populations (Amhara, n = 29; Oromo, n = 18) provided plasma for measurement of superoxide dismutase (SOD) activity as a marker of antioxidant capacity, and urine for measurement of 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a marker of DNA oxidative damage.

Results: High-altitude Amhara and Sherpa had the highest SOD activity, while highland Oromo and Nepalis had the lowest among high-altitude populations. High-altitude Amhara had the lowest DNA damage, Sherpa intermediate levels, and high-altitude Oromo had the highest.

Conclusions: High-altitude residence alone does not associate with high antioxidant defenses; residence length appears to be influential. The single-generation upward migrant sample had the lowest defense and nearly the highest DNA damage. The two high-altitude resident samples with millennia of residence had higher defenses than the two with multiple or single generations of residence.
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http://dx.doi.org/10.1002/ajhb.23039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865391PMC
November 2017

Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations.

Am J Respir Crit Care Med 2017 02;195(3):302-313

7 Wake Forest University, Winston-Salem, North Carolina.

Rationale: Reducing asthma exacerbation frequency is an important criterion for approval of asthma therapies, but the clinical features of exacerbation-prone asthma (EPA) remain incompletely defined.

Objectives: To describe the clinical, physiologic, inflammatory, and comorbidity factors associated with EPA.

Methods: Baseline data from the NHLBI Severe Asthma Research Program (SARP)-3 were analyzed. An exacerbation was defined as a burst of systemic corticosteroids lasting 3 days or more. Patients were classified by their number of exacerbations in the past year: none, few (one to two), or exacerbation prone (≥3). Replication of a multivariable model was performed with data from the SARP-1 + 2 cohort.

Measurements And Main Results: Of 709 subjects in the SARP-3 cohort, 294 (41%) had no exacerbations and 173 (24%) were exacerbation prone in the prior year. Several factors normally associated with severity (asthma duration, age, sex, race, and socioeconomic status) did not associate with exacerbation frequency in SARP-3; bronchodilator responsiveness also discriminated exacerbation proneness from asthma severity. In the SARP-3 multivariable model, blood eosinophils, body mass index, and bronchodilator responsiveness were positively associated with exacerbation frequency (rate ratios [95% confidence interval], 1.6 [1.2-2.1] for every log unit of eosinophils, 1.3 [1.1-1.4] for every 10 body mass index units, and 1.2 [1.1-1.4] for every 10% increase in bronchodilatory responsiveness). Chronic sinusitis and gastroesophageal reflux were also associated with exacerbation frequency (1.7 [1.4-2.1] and 1.6 [1.3-2.0]), even after adjustment for multiple factors. These effects were replicated in the SARP-1 + 2 multivariable model.

Conclusions: EPA may be a distinct susceptibility phenotype with implications for the targeting of exacerbation prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 01760915).
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http://dx.doi.org/10.1164/rccm.201602-0419OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328178PMC
February 2017

Distal vessel stiffening is an early and pivotal mechanobiological regulator of vascular remodeling and pulmonary hypertension.

JCI Insight 2016 Jun;1(8)

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Pulmonary arterial (PA) stiffness is associated with increased mortality in patients with pulmonary hypertension (PH); however, the role of PA stiffening in the pathogenesis of PH remains elusive. Here, we show that distal vascular matrix stiffening is an early mechanobiological regulator of experimental PH. We identify cyclooxygenase-2 (COX-2) suppression and corresponding reduction in prostaglandin production as pivotal regulators of stiffness-dependent vascular cell activation. Atomic force microscopy microindentation demonstrated early PA stiffening in experimental PH and human lung tissue. Pulmonary artery smooth muscle cells (PASMC) grown on substrates with the stiffness of remodeled PAs showed increased proliferation, decreased apoptosis, exaggerated contraction, enhanced matrix deposition, and reduced COX-2-derived prostanoid production compared with cells grown on substrates approximating normal PA stiffness. Treatment with a prostaglandin I analog abrogated monocrotaline-induced PA stiffening and attenuated stiffness-dependent increases in proliferation, matrix deposition, and contraction in PASMC. Our results suggest a pivotal role for early PA stiffening in PH and demonstrate the therapeutic potential of interrupting mechanobiological feedback amplification of vascular remodeling in experimental PH.
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http://dx.doi.org/10.1172/jci.insight.86987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918638PMC
June 2016

Increased mitochondrial arginine metabolism supports bioenergetics in asthma.

J Clin Invest 2016 07 23;126(7):2465-81. Epub 2016 May 23.

High levels of arginine metabolizing enzymes, including inducible nitric oxide synthase (iNOS) and arginase (ARG), are typical in asthmatic airway epithelium; however, little is known about the metabolic effects of enhanced arginine flux in asthma. Here, we demonstrated that increased metabolism sustains arginine availability in asthmatic airway epithelium with consequences for bioenergetics and inflammation. Expression of iNOS, ARG2, arginine synthetic enzymes, and mitochondrial respiratory complexes III and IV was elevated in asthmatic lung samples compared with healthy controls. ARG2 overexpression in a human bronchial epithelial cell line accelerated oxidative bioenergetic pathways and suppressed hypoxia-inducible factors (HIFs) and phosphorylation of the signal transducer for atopic Th2 inflammation STAT6 (pSTAT6), both of which are implicated in asthma etiology. Arg2-deficient mice had lower mitochondrial membrane potential and greater HIF-2α than WT animals. In an allergen-induced asthma model, mice lacking Arg2 had greater Th2 inflammation than WT mice, as indicated by higher levels of pSTAT6, IL-13, IL-17, eotaxin, and eosinophils and more mucus metaplasia. Bone marrow transplants from Arg2-deficient mice did not affect airway inflammation in recipient mice, supporting resident lung cells as the drivers of elevated Th2 inflammation. These data demonstrate that arginine flux preserves cellular respiration and suppresses pathological signaling events that promote inflammation in asthma.
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http://dx.doi.org/10.1172/JCI82925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922712PMC
July 2016

Bone Morphogenic Protein Type 2 Receptor Mutation-Independent Mechanisms of Disrupted Bone Morphogenetic Protein Signaling in Idiopathic Pulmonary Arterial Hypertension.

Am J Respir Cell Mol Biol 2016 Oct;55(4):564-575

Departments of 1 Pathobiology and.

Altered bone morphogenic protein (BMP) signaling, independent of BMPR2 mutations, can result in idiopathic pulmonary arterial hypertension (IPAH). Glucose dysregulation can regulate multiple processes in IPAH. However, the role of glucose in BMP antagonist expression in IPAH has not been characterized. We hypothesized that glucose uptake regulates BMP signaling through stimulation of BMP antagonist expression in IPAH. Using human plasma, lung tissue, and primary pulmonary arterial smooth muscle cells (PASMCs), we examined the protein expression of BMP2, BMP-regulated Smads, and Smurf-1 in patients with IPAH and control subjects. Gremlin-1 levels were elevated in patients with IPAH compared with control subjects, whereas expression of BMP2 was not different. We demonstrate increased Smad polyubiquitination in IPAH lung tissue and PASMCs that was further enhanced with proteasomal inhibition. Examination of the Smad ubiquitin-ligase, Smurf-1, showed increased protein expression in IPAH lung tissue and localization in the smooth muscle of the pulmonary artery. Glucose dose dependently increased Smurf-1 protein expression in control PASMCs, whereas Smurf-1 in IPAH PASMCs was increased and sustained. Conversely, phospho-Smad1/5/8 levels were reduced in IPAH compared with control PASMCs at physiological glucose concentrations. Interestingly, high glucose concentrations decreased phosphorylation of Smad1/5/8 in control PASMCs. Blocking glucose uptake had opposing effects in IPAH PASMCs, and inhibition of Smurf-1 activity resulted in partial rescue of Smad1/5/8 activation and cell migration rates. Collectively, these data suggest that BMP signaling can be regulated through BMPR2 mutation-independent mechanisms. Gremlin-1 (synonym: induced-in-high-glucose-2 protein) and Smurf-1 may function to inhibit BMP signaling as a consequence of the glucose dysregulation described in IPAH.
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http://dx.doi.org/10.1165/rcmb.2015-0402OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070111PMC
October 2016

Phosphorylation inactivation of endothelial nitric oxide synthesis in pulmonary arterial hypertension.

Am J Physiol Lung Cell Mol Physiol 2016 06 29;310(11):L1199-205. Epub 2016 Apr 29.

Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Respiratory Institute, Cleveland Clinic, Cleveland, Ohio

The impairment of vasodilator nitric oxide (NO) production is well accepted as a typical marker of endothelial dysfunction in vascular diseases, including in the pathophysiology of pulmonary arterial hypertension (PAH), but the molecular mechanisms accounting for loss of NO production are unknown. We hypothesized that low NO production by pulmonary arterial endothelial cells in PAH is due to inactivation of NO synthase (eNOS) by aberrant phosphorylation of the protein. To test the hypothesis, we evaluated eNOS levels, dimerization, and phosphorylation in the vascular endothelial cells and lungs of patients with PAH compared with controls. In mechanistic studies, eNOS activity in endothelial cells in PAH lungs was found to be inhibited due to phosphorylation at T495. Evidence pointed to greater phosphorylation/activation of protein kinase C (PKC) α and its greater association with eNOS as the source of greater phosphorylation at T495. The presence of greater amounts of pT495-eNOS in plexiform lesions in lungs of patients with PAH confirmed the pathobiological mechanism in vivo. Transfection of the activating mutation of eNOS (T495A/S1177D) restored NO production in PAH cells. Pharmacological blockade of PKC activity by β-blocker also restored NO formation by PAH cells, identifying one mechanism by which β-blockers may benefit PAH and cardiovascular diseases through recovery of endothelial functions.
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http://dx.doi.org/10.1152/ajplung.00092.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935470PMC
June 2016

Soluble guanylate cyclase as an alternative target for bronchodilator therapy in asthma.

Proc Natl Acad Sci U S A 2016 Apr 11;113(17):E2355-62. Epub 2016 Apr 11.

Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;

Asthma is defined by airway inflammation and hyperresponsiveness, and contributes to morbidity and mortality worldwide. Although bronchodilation is a cornerstone of treatment, current bronchodilators become ineffective with worsening asthma severity. We investigated an alternative pathway that involves activating the airway smooth muscle enzyme, soluble guanylate cyclase (sGC). Activating sGC by its natural stimulant nitric oxide (NO), or by pharmacologic sGC agonists BAY 41-2272 and BAY 60-2770, triggered bronchodilation in normal human lung slices and in mouse airways. Both BAY 41-2272 and BAY 60-2770 reversed airway hyperresponsiveness in mice with allergic asthma and restored normal lung function. The sGC from mouse asthmatic lungs displayed three hallmarks of oxidative damage that render it NO-insensitive, and identical changes to sGC occurred in human lung slices or in human airway smooth muscle cells when given chronic NO exposure to mimic the high NO in asthmatic lung. Our findings show how allergic inflammation in asthma may impede NO-based bronchodilation, and reveal that pharmacologic sGC agonists can achieve bronchodilation despite this loss.
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http://dx.doi.org/10.1073/pnas.1524398113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855555PMC
April 2016

Protein disulfide isomerase-endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness.

J Allergy Clin Immunol 2016 Mar 4;137(3):822-32.e7. Epub 2015 Oct 4.

Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT. Electronic address:

Background: Evidence for association between asthma and the unfolded protein response is emerging. Endoplasmic reticulum resident protein 57 (ERp57) is an endoplasmic reticulum-localized redox chaperone involved in folding and secretion of glycoproteins. We have previously demonstrated that ERp57 is upregulated in allergen-challenged human and murine lung epithelial cells. However, the role of ERp57 in asthma pathophysiology is unknown.

Objectives: Here we sought to examine the contribution of airway epithelium-specific ERp57 in the pathogenesis of allergic asthma.

Methods: We examined the expression of ERp57 in human asthmatic airway epithelium and used murine models of allergic asthma to evaluate the relevance of epithelium-specific ERp57.

Results: Lung biopsy specimens from asthmatic and nonasthmatic patients revealed a predominant increase in ERp57 levels in epithelium of asthmatic patients. Deletion of ERp57 resulted in a significant decrease in inflammatory cell counts and airways resistance in a murine model of allergic asthma. Furthermore, we observed that disulfide bridges in eotaxin, epidermal growth factor, and periostin were also decreased in the lungs of house dust mite-challenged ERp57-deleted mice. Fibrotic markers, such as collagen and α smooth muscle actin, were also significantly decreased in the lungs of ERp57-deleted mice. Furthermore, adaptive immune responses were dispensable for house dust mite-induced endoplasmic reticulum stress and airways fibrosis.

Conclusions: Here we show that ERp57 levels are increased in the airway epithelium of asthmatic patients and in mice with allergic airways disease. The ERp57 level increase is associated with redox modification of proinflammatory, apoptotic, and fibrotic mediators and contributes to airways hyperresponsiveness. The strategies to inhibit ERp57 specifically within the airways epithelium might provide an opportunity to alleviate the allergic asthma phenotype.
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http://dx.doi.org/10.1016/j.jaci.2015.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597791PMC
March 2016

Reply: To PMID 25488689.

J Allergy Clin Immunol 2015 Aug 9;136(2):515-6. Epub 2015 Jun 9.

Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2015.04.038DOI Listing
August 2015

Metabolomic Endotype of Asthma.

J Immunol 2015 Jul 5;195(2):643-50. Epub 2015 Jun 5.

Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Cleveland Clinic, Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195;

Metabolomics, the quantification of small biochemicals in plasma and tissues, can provide insight into complex biochemical processes and enable the identification of biomarkers that may serve as therapeutic targets. We hypothesized that the plasma metabolome of asthma would reveal metabolic consequences of the specific immune and inflammatory responses unique to endotypes of asthma. The plasma metabolomic profiles of 20 asthmatic subjects and 10 healthy controls were examined using an untargeted global and focused metabolomic analysis. Individuals were classified based on clinical definitions of asthma severity or by levels of fraction of exhaled NO (FENO), a biomarker of airway inflammation. Of the 293 biochemicals identified in the plasma, 25 were significantly different among asthma and healthy controls (p < 0.05). Plasma levels of taurine, lathosterol, bile acids (taurocholate and glycodeoxycholate), nicotinamide, and adenosine-5-phosphate were significantly higher in asthmatics compared with healthy controls. Severe asthmatics had biochemical changes related to steroid and amino acid/protein metabolism. Asthmatics with high FENO, compared with those with low FENO, had higher levels of plasma branched-chain amino acids and bile acids. Asthmatics have a unique plasma metabolome that distinguishes them from healthy controls and points to activation of inflammatory and immune pathways. The severe asthmatic and high FENO asthmatic have unique endotypes that suggest changes in NO-associated taurine transport and bile acid metabolism.
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http://dx.doi.org/10.4049/jimmunol.1500736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490949PMC
July 2015

Coenzyme Q in asthma.

Am J Respir Crit Care Med 2015 Jun;191(11):1336-8

1 Cleveland Clinic Cleveland, Ohio.

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http://dx.doi.org/10.1164/rccm.201412-2259LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476517PMC
June 2015

Arginine metabolic endotypes in pulmonary arterial hypertension.

Pulm Circ 2015 Mar;5(1):124-34

Lerner Research Institute and Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Decreased synthesis of nitric oxide (NO) by NO synthases (NOS) is believed to play an important role in the pathogenesis of pulmonary arterial hypertension (PAH). Multiple factors may contribute to decreased NO bioavailability, including increased activity of arginase, the enzyme that converts arginine to ornithine and urea, which may compete with NOS for arginine; inadequate de novo arginine production from citrulline; and increased concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS. We hypothesized that PAH patients with the lowest arginine availability secondary to increased arginase activity and/or inadequate de novo arginine synthesis might have a slower rate of NO synthesis and greater pulmonary vascular resistance. Nine patients with group 1 PAH and 10 healthy controls were given primed, constant intravenous infusions of (15)N2-arginine, (13)C,(2)H4-citrulline, (15)N2-ornithine, and (13)C-urea in the postabsorptive state. The results showed that, compared with healthy controls, PAH patients had a tendency toward increased arginine clearance and ornithine flux but no difference in arginine and citrulline flux, de novo arginine synthesis, or NO synthesis. Arginine-to-ADMA ratio was increased in PAH patients. Two endotypes of patients with low and high arginase activity were identified; compared with the low-arginase group, the patients with high arginase had increased arginine flux, slower NO synthesis, and lower plasma concentrations of ADMA. These results demonstrate that increased breakdown of arginine by arginase occurs in PAH and affects NO synthesis. Furthermore, there is no compensatory increase in de novo arginine synthesis to overcome this increased utilization of arginine by arginase.
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http://dx.doi.org/10.1086/679720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405713PMC
March 2015

Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension.

Am J Respir Crit Care Med 2015 Jul;192(2):219-28

1 Genomic Medicine Institute and.

Rationale: Pulmonary arterial hypertension (PAH) is a serious lung condition characterized by vascular remodeling in the precapillary pulmonary arterioles. We and others have demonstrated chromosomal abnormalities and increased DNA damage in PAH lung vascular cells, but their timing and role in disease pathogenesis is unknown.

Objectives: We hypothesized that if DNA damage predates PAH, it might be an intrinsic cell property that is present outside the diseased lung.

Methods: We measured DNA damage, mutagen sensitivity, and reactive oxygen species (ROS) in lung and blood cells from patients with Group 1 PAH, their relatives, and unrelated control subjects.

Measurements And Main Results: Baseline DNA damage was significantly elevated in PAH, both in pulmonary artery endothelial cells (P < 0.05) and peripheral blood mononuclear cells (PBMC) (P < 0.001). Remarkably, PBMC from unaffected relatives showed similar increases, indicating this is not related to PAH treatments. ROS levels were also higher (P < 0.01). DNA damage correlated with ROS production and was suppressed by antioxidants (P < 0.001). PBMC from patients and relatives also showed markedly increased sensitivity to two chemotherapeutic drugs, bleomycin and etoposide (P < 0.001). Results were consistent across idiopathic, heritable, and associated PAH groups.

Conclusions: Levels of baseline and mutagen-induced DNA damage are intrinsically higher in PAH cells. Similar results in PBMC from unaffected relatives suggest this may be a genetically determined trait that predates disease onset and may act as a risk factor contributing to lung vascular remodeling following endothelial cell injury. Further studies are required to fully characterize mutagen sensitivity, which could have important implications for clinical management.
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http://dx.doi.org/10.1164/rccm.201411-2128OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532823PMC
July 2015

Carboxyhemoglobin and methemoglobin in asthma.

Lung 2015 Apr 14;193(2):183-7. Epub 2015 Feb 14.

Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave/NC22, Cleveland, OH, 44195, USA.

Nitric oxide (NO) and carbon monoxide (CO) are synthesized at high levels in asthmatic airways. NO can oxidize hemoglobin (Hb) to methemoglobin (MetHb). CO binds to heme to produce carboxyhemoglobin (COHb). We hypothesized that MetHb and COHb may be increased in asthma. COHb, MetHb, and Hb were measured in venous blood of healthy controls (n = 32) and asthmatics (n = 31). Arterial COHb and oxyhemoglobin were measured by pulse CO-oximeter. Hb, oxyhemoglobin, and deoxyhemoglobin were similar among groups, but arterial COHb was higher in asthmatics than controls (p = 0.04). Venous COHb was similar among groups, and thus, arteriovenous COHb (a-v COHb) concentration difference was greater in asthma compared with controls. Venous MetHb was lower in asthma compared to controls (p = 0.01) and correlated to venous NO (p = 0.009). The greater a-v COHb in asthma suggests CO offloading to tissues, but lower than normal MetHb suggests countermeasures to avoid adverse effects of high NO on gas transfer.
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http://dx.doi.org/10.1007/s00408-015-9686-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500073PMC
April 2015

O-linked β-N-acetylglucosamine transferase directs cell proliferation in idiopathic pulmonary arterial hypertension.

Circulation 2015 Apr 6;131(14):1260-8. Epub 2015 Feb 6.

From Department of Pathobiology, Lerner Research Institute (J.W.B., L.T., K.A., S.A.A.C., K.S.A. R.A.D.), Pulmonary and Critical Care Medicine, Respiratory Institute (G.A.H., R.A.D.), and Department of Pathology (C.F.F.), Cleveland Clinic, OH.

Background: Idiopathic pulmonary arterial hypertension (IPAH) is a cardiopulmonary disease characterized by cellular proliferation and vascular remodeling. A more recently recognized characteristic of the disease is the dysregulation of glucose metabolism. The primary link between altered glucose metabolism and cell proliferation in IPAH has not been elucidated. We aimed to determine the relationship between glucose metabolism and smooth muscle cell proliferation in IPAH.

Methods And Results: Human IPAH and control patient lung tissues and pulmonary artery smooth muscle cells (PASMCs) were used to analyze a specific pathway of glucose metabolism, the hexosamine biosynthetic pathway. We measured the levels of O-linked β-N-acetylglucosamine modification, O-linked β-N-acetylglucosamine transferase (OGT), and O-linked β-N-acetylglucosamine hydrolase in control and IPAH cells and tissues. Our data suggest that the activation of the hexosamine biosynthetic pathway directly increased OGT levels and activity, triggering changes in glycosylation and PASMC proliferation. Partial knockdown of OGT in IPAH PASMCs resulted in reduced global O-linked β-N-acetylglucosamine modification levels and abrogated PASMC proliferation. The increased proliferation observed in IPAH PASMCs was directly impacted by proteolytic activation of the cell cycle regulator, host cell factor-1.

Conclusions: Our data demonstrate that hexosamine biosynthetic pathway flux is increased in IPAH and drives OGT-facilitated PASMC proliferation through specific proteolysis and direct activation of host cell factor-1. These findings establish a novel regulatory role for OGT in IPAH, shed a new light on our understanding of the disease pathobiology, and provide opportunities to design novel therapeutic strategies for IPAH.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.114.013878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390469PMC
April 2015

Biomarker-based asthma phenotypes of corticosteroid response.

J Allergy Clin Immunol 2015 Apr 6;135(4):877-883.e1. Epub 2014 Dec 6.

Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Background: Asthma is a heterogeneous disease with different phenotypes. Inhaled corticosteroid (ICS) therapy is a mainstay of treatment for asthma, but the clinical response to ICSs is variable.

Objective: We hypothesized that a panel of inflammatory biomarkers (ie, fraction of exhaled nitric oxide [Feno], sputum eosinophil count, and urinary bromotyrosine [BrTyr] level) might predict steroid responsiveness.

Methods: The original study from which this analysis originates comprised 2 phases: a steroid-naive phase 1 and a 28-day trial of ICSs (phase 2) during which Feno values, sputum eosinophil counts, and urinary BrTyr levels were measured. The response to ICSs was based on clinical improvements, including a 12% or greater increase in FEV1, a 0.5-point or greater decrease in Asthma Control Questionnaire score, and 2 doubling dose or greater increase in provocative concentration of adenosine 5'-monophosphate causing a 20% decrease in FEV1 (PC20AMP). Healthy control subjects were also evaluated in this study for comparison of biomarkers with those seen in asthmatic patients.

Results: Asthmatic patients had higher than normal Feno values, sputum eosinophil counts, and urinary BrTyr levels during the steroid-naive phase and after ICS therapy. After 28-day trial of ICSs, Feno values decreased in 82% of asthmatic patients, sputum eosinophil counts decreased in 60%, and urinary BrTyr levels decreased in 58%. Each of the biomarkers at the steroid-naive phase had utility for predicting steroid responsiveness, but the combination of high Feno values and high urinary BrTyr levels had the best power (13.3-fold, P < .01) to predict a favorable response to ICS therapy. However, the magnitude of the decrease in biomarker levels was unrelated to the magnitude of clinical response to ICS therapy.

Conclusion: A noninvasive panel of biomarkers in steroid-naive asthmatic patients predicts clinical responsiveness to ICS therapy.
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http://dx.doi.org/10.1016/j.jaci.2014.10.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388771PMC
April 2015

Role of hypoxia-induced transglutaminase 2 in pulmonary artery smooth muscle cell proliferation.

Am J Physiol Lung Cell Mol Physiol 2014 Oct 15;307(7):L576-85. Epub 2014 Aug 15.

Pulmonary, Critical Care and Sleep Division, Tufts Medical Center, Tupper Research Institute, Boston, Massachusetts;

We previously reported that transglutaminase 2 (TG2) activity is markedly elevated in lungs of hypoxia-exposed rodent models of pulmonary hypertension (PH). Since vascular remodeling of pulmonary artery smooth muscle cells (PASMCs) is important in PH, we undertook the present study to determine whether TG2 activity is altered in PASMCs with exposure to hypoxia and whether that alteration participates in their proliferative response to hypoxia. Cultured distal bovine (b) and proximal human (h) PASMCs were exposed to hypoxia (3% O2) or normoxia (21% O2). mRNA and protein expression were determined by PCR and Western blot analyses. TG2 activity and function were visualized and determined by fluorescent labeled 5-pentylamine biotin incorporation and immunoblotting of serotonylated fibronectin. Cell proliferation was assessed by [(3)H]thymidine incorporation assay. At 24 h, both TG2 expression and activity were stimulated by hypoxia in bPASMCs. Activation of TG2 by hypoxia was blocked by inhibition of the extracellular calcium-sensing receptor or the transient receptor potential channel V4. In contrast, TG2 expression was blocked by inhibition of the transcription factor hypoxia-inducible factor-1α, supporting the presence of separate mechanisms for stimulation of activity and expression of TG2. Pulmonary arterial hypertension patient-derived hPASMCs were found to proliferate significantly more rapidly and respond to hypoxia more strongly than control-derived hPASMCs. Similar to bovine cells, hypoxia-induced proliferation of patient-derived cells was blocked by inhibition of TG2 activity. Our results suggest an important role for TG2, mediated by intracellular calcium fluxes and HIF-1α, in hypoxia-induced PASMC proliferation and possibly in vascular remodeling in PH.
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http://dx.doi.org/10.1152/ajplung.00162.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187037PMC
October 2014
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