Showing papers by "Serpil C. Erzurum published in 2015"

Asthma is Different in Women

Abstract: Gender differences in asthma incidence, prevalence and severity have been reported worldwide. After puberty, asthma becomes more prevalent and severe in women, and is highest in women with early menarche or with multiple gestations, suggesting a role for sex hormones in asthma genesis. However, the impact of sex hormones on the pathophysiology of asthma is confounded by and difficult to differentiate from age, obesity, atopy, and other gender associated environmental exposures. There are also gender discrepancies in the perception of asthma symptoms. Understanding gender differences in asthma is important to provide effective education and personalized management plans for asthmatics across the lifecourse.

Oxidation increases mucin polymer cross-links to stiffen airway mucus gels.

Abstract: Airway mucus in cystic fibrosis (CF) is highly elastic, but the mechanism behind this pathology is unclear. We hypothesized that the biophysical properties of CF mucus are altered because of neutrophilic oxidative stress. Using confocal imaging, rheology, and biochemical measures of inflammation and oxidation, we found that CF airway mucus gels have a molecular architecture characterized by a core of mucin covered by a web of DNA and a rheological profile characterized by high elasticity that can be normalized by chemical reduction. We also found that high levels of reactive oxygen species in CF mucus correlated positively and significantly with high concentrations of the oxidized products of cysteine (disulfide cross-links). To directly determine whether oxidation can cross-link mucins to increase mucus elasticity, we exposed induced sputum from healthy subjects to oxidizing stimuli and found a marked and thiol-dependent increase in sputum elasticity. Targeting mucin disulfide cross-links using current thiol-amino structures such as N-acetylcysteine (NAC) requires high drug concentrations to have mucolytic effects. We therefore synthesized a thiol-carbohydrate structure (methyl 6-thio-6-deoxy-α-D-galactopyranoside) and found that it had stronger reducing activity than NAC and more potent and fast-acting mucolytic activity in CF sputum. Thus, oxidation arising from airway inflammation or environmental exposure contributes to pathologic mucus gel formation in the lung, which suggests that it can be targeted by thiol-modified carbohydrates.

Biomarker-based asthma phenotypes of corticosteroid response

Abstract: 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 FEV 1 , 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 FEV 1 (PC 20 AMP). 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 Conclusion A noninvasive panel of biomarkers in steroid-naive asthmatic patients predicts clinical responsiveness to ICS therapy.

Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension.

Abstract: 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). ...

eQTL of bronchial epithelial cells and bronchial alveolar lavage deciphers GWAS-identified asthma genes.

Abstract: Background Genome-wide association studies (GWASs) have identified various genes associated with asthma, yet, causal genes or single nucleotide polymorphisms (SNPs) remain elusive. We sought to dissect functional genes/SNPs for asthma by combining expression quantitative trait loci (eQTLs) and GWASs. Methods Cis-eQTL analyses of 34 asthma genes were performed in cells from human bronchial epithelial biopsy (BEC, n = 107) and from bronchial alveolar lavage (BAL, n = 94). Results For TSLP-WDR36 region, rs3806932 (G allele protective against eosinophilic esophagitis) and rs2416257 (A allele associated with lower eosinophil counts and protective against asthma) were correlated with decreased expression of TSLP in BAL (P = 7.9 × 10−11 and 5.4 × 10−4, respectively) and BEC, but not WDR36. Surprisingly, rs1837253 (consistently associated with asthma) showed no correlation with TSLP expression levels. For ORMDL3-GSDMB region, rs8067378 (G allele protective against asthma) was correlated with decreased expression of GSDMB in BEC and BAL (P = 1.3 × 10−4 and 0.04) but not ORMDL3. rs992969 in the promoter region of IL33 (A allele associated with higher eosinophil counts and risk for asthma) was correlated with increased expression of IL33 in BEC (P = 1.3 × 10−6) but not in BAL. Conclusions Our study illustrates cell-type-specific regulation of the expression of asthma-related genes documenting SNPs in TSLP, GSDMB, IL33, HLA-DQB1, C11orf30, DEXI, CDHR3, and ZBTB10 affect asthma risk through cis-regulation of its gene expression. Whenever possible, disease-relevant tissues should be used for transcription analysis. SNPs in TSLP may affect asthma risk through up-regulating TSLP mRNA expression or protein secretion. Further functional studies are warranted.

Asthma Is More Severe in Older Adults

Abstract: Background Severe asthma occurs more often in older adult patients. We hypothesized that the greater risk for severe asthma in older individuals is due to aging, and is independent of asthma duration. Methods This is a cross-sectional study of prospectively collected data from adult participants (N=1130; 454 with severe asthma) enrolled from 2002 – 2011 in the Severe Asthma Research Program. Results The association between age and the probability of severe asthma, which was performed by applying a Locally Weighted Scatterplot Smoother, revealed an inflection point at age 45 for risk of severe asthma. The probability of severe asthma increased with each year of life until 45 years and thereafter increased at a much slower rate. Asthma duration also increased the probability of severe asthma but had less effect than aging. After adjustment for most comorbidities of aging and for asthma duration using logistic regression, asthmatics older than 45 maintained the greater probability of severe asthma [OR: 2.73 (95 CI: 1.96; 3.81)]. After 45, the age-related risk of severe asthma continued to increase in men, but not in women. Conclusions Overall, the impact of age and asthma duration on risk for asthma severity in men and women is greatest over times of 18-45 years of age; age has a greater effect than asthma duration on risk of severe asthma.

Clinical Implications of Having Reduced Mid Forced Expiratory Flow Rates (FEF25-75), Independently of FEV1, in Adult Patients with Asthma.

Abstract: Introduction FEF25-75 is one of the standard results provided in spirometry reports; however, in adult asthmatics there is limited information on how this physiological measure relates to clinical or biological outcomes independently of the FEV1 or the FEV1/FVC ratio. Purpose To determine the association between Hankinson’s percent-predicted FEF25-75 (FEF25-75%) levels with changes in healthcare utilization, respiratory symptom frequency, and biomarkers of distal airway inflammation. Methods In participants enrolled in the Severe Asthma Research Program 1–2, we compared outcomes across FEF25-75% quartiles. Multivariable analyses were done to avoid confounding by demographic characteristics, FEV1, and the FEV1/FVC ratio. In a sensitivity analysis, we also compared outcomes across participants with FEF25-75% below the lower limit of normal (LLN) and FEV1/FVC above LLN. Results Subjects in the lowest FEF25-75% quartile had greater rates of healthcare utilization and higher exhaled nitric oxide and sputum eosinophils. In multivariable analysis, being in the lowest FEF25-75% quartile remained significantly associated with nocturnal symptoms (OR 3.0 [95%CI 1.3–6.9]), persistent symptoms (OR 3.3 [95%CI 1–11], ICU admission for asthma (3.7 [1.3–10.8]) and blood eosinophil % (0.18 [0.07, 0.29]). In the sensitivity analysis, those with FEF25-75%

Platelets from Asthmatic Individuals Show Less Reliance on Glycolysis.

Abstract: Asthma, a chronic inflammatory airway disease, is typified by high levels of TH2-cytokines and excessive generation of reactive nitrogen and oxygen species, which contribute to bronchial epithelial injury and airway remodeling. While immune function plays a major role in the pathogenesis of the disease, accumulating evidence suggests that altered cellular metabolism is a key determinant in the predisposition and disease progression of asthma. Further, several studies demonstrate altered mitochondrial function in asthmatic airways and suggest that these changes may be systemic. However, it is unknown whether systemic metabolic changes can be detected in circulating cells in asthmatic patients. Platelets are easily accessible blood cells that are known to propagate airway inflammation in asthma. Here we perform a bioenergetic screen of platelets from asthmatic and healthy individuals and demonstrate that asthmatic platelets show a decreased reliance on glycolytic processes and have increased tricarboxylic acid cycle activity. These data demonstrate a systemic alteration in asthma and are consistent with prior reports suggesting that oxidative phosphorylation is more efficient asthmatic individuals. The implications for this potential metabolic shift will be discussed in the context of increased oxidative stress and hypoxic adaptation of asthmatic patients. Further, these data suggest that platelets are potentially a good model for the monitoring of bioenergetic changes in asthma.

Arginine metabolic endotypes in pulmonary arterial hypertension.

Abstract: 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 15N2-arginine, 13C,2H4-citrulline, 15N2-ornithine, and 13C-urea in the postabsorptive state. The results showed that, compared with healthy...

Biology and flow cytometry of proangiogenic hematopoietic progenitors cells

Abstract: During development, hematopoiesis and neovascularization are closely linked to each other via a common bipotent stem cell called the hemangioblast that gives rise to both hematopoietic cells and endothelial cells. In postnatal life, this functional connection between the vasculature and hematopoiesis is maintained by a subset of hematopoietic progenitor cells endowed with the capacity to differentiate into potent proangiogenic cells. These proangiogenic hematopoietic progenitors comprise a specific subset of bone marrow (BM)-derived cells that homes to sites of neovascularization and possess potent paracrine angiogenic activity. There is emerging evidence that this subpopulation of hematopoietic progenitors plays a critical role in vascular health and disease. Their angiogenic activity is distinct from putative "endothelial progenitor cells" that become structural cells of the endothelium by differentiation into endothelial cells. Proangiogenic hematopoietic progenitor cell research requires multidisciplinary expertise in flow cytometry, hematology, and vascular biology. This review provides a comprehensive overview of proangiogenic hematopoietic progenitor cell biology and flow cytometric methods to detect these cells in the peripheral blood circulation and BM.

A Novel IL-25 Signaling Pathway through STAT5

Abstract: IL-25 is a member of the IL-17 family of cytokines that promotes Th2 cell-mediated inflammatory responses. IL-25 signals through a heterodimeric receptor (IL-25R) composed of IL-17RA and IL-17RB, which recruits the adaptor molecule Act1 for downstream signaling. Although the role of IL-25 in potentiating type 2 inflammation is well characterized by its ability to activate the epithelium as well as T cells, the components of its signaling cascade remain largely unknown. In this study, we found that IL-25 can directly activate STAT5 independently of Act1. Furthermore, conditional STAT5 deletion in T cells or epithelial cells led to a defective IL-25-initiated Th2 polarization as well as defective IL-25 enhancement of Th2 responses. Finally, we found that STAT5 is recruited to the IL-25R in a ligand-dependent manner through unique tyrosine residues on IL-17RB. Together, these findings reveal a novel Act1-independent IL-25 signaling pathway through STAT5 activation.

Phenotype of asthmatics with increased airway S -nitrosoglutathione reductase activity

Abstract: S-Nitrosoglutathione is an endogenous airway smooth muscle relaxant. Increased airway S-nitrosoglutathione breakdown occurs in some asthma patients. We asked whether patients with increased airway catabolism of this molecule had clinical features that distinguished them from other asthma patients. We measured S-nitrosoglutathione reductase expression and activity in bronchoscopy samples taken from 66 subjects in the Severe Asthma Research Program. We also analysed phenotype and genotype data taken from the program as a whole. Airway S-nitrosoglutathione reductase activity was increased in asthma patients (p=0.032). However, only a subpopulation was affected and this subpopulation was not defined by a "severe asthma" diagnosis. Subjects with increased activity were younger, had higher IgE and an earlier onset of symptoms. Consistent with a link between S-nitrosoglutathione biochemistry and atopy: 1) interleukin 13 increased S-nitrosoglutathione reductase expression and 2) subjects with an S-nitrosoglutathione reductase single nucleotide polymorphism previously associated with asthma had higher IgE than those without this single nucleotide polymorphism. Expression was higher in airway epithelium than in smooth muscle and was increased in regions of the asthmatic lung with decreased airflow. An early-onset, allergic phenotype characterises the asthma population with increased S-nitrosoglutathione reductase activity.

Relationship between Right Ventricular Longitudinal Strain, Invasive Hemodynamics, and Functional Assessment in Pulmonary Arterial Hypertension

Abstract: Background and Objectives: Right ventricular longitudinal strain (RVLS) is a new parameter of RV function. We evaluated the relationship of RVLS by speckle-tracking echocardiography with functional and invasive parameters in pulmonary arterial hypertension (PAH) patients. Subjects and Methods: Thirty four patients with World Health Organization group 1 PAH (29 females, mean age 45±13 years old). RVLS were analyzed with velocity vector imaging. Results: Patients with advanced symptoms {New York Heart Association (NYHA) functional class III/IV} had impaired RVLS in global RV (RVLSglobal, -17±5 vs. -12±3%, p<0.01) and RV free wall (RVLSFW, -19±5 vs. -14±4%, p<0.01 to NYHA class I/II). Baseline RVLSglobal and RVLSFW showed significant correlation with 6-minute walking distance (r=-0.54 and r=-0.57, p<0.01 respectively) and logarithmic transformation of brain natriuretic peptide concentration (r=0.65 and r=0.65, p<0.01, respectively). These revealed significant correlations with cardiac index (r=-0.50 and r=-0.47, p<0.01, respectively) and pulmonary vascular resistance (PVR, r=0.45 and r=0.45, p=0.01, respectively). During a median follow-up of 33 months, 25 patients (74%) had follow-up examinations. Mean pulmonary arterial pressure (mPAP, 54±13 to 46±16 mmHg, p=0.03) and PVR (11±5 to 6±2 wood units, p<0.01) were significantly decreased with pulmonary vasodilator treatment. RVLSglobal (-12±5 to -16±5%, p<0.01) and RVLSFW (-14±5 to -18±5%, p<0.01) were significantly improved. The decrease of mPAP was significantly correlated with improvement of RVLS global (r=0.45, p<0.01) and RVLSFW (r=0.43, p<0.01). The PVR change demonstrated significant correlation with improvement of RVLS global (r=0.40, p<0.01). Conclusion: RVLS correlates with functional and invasive hemodynamic parameters in PAH patients. Decrease of mPAP and PVR as a result of treatment was associated with improvement of RVLS. (Korean Circ J 2015;45(5):398-407)

TRAF4-SMURF2–Mediated DAZAP2 Degradation Is Critical for IL-25 Signaling and Allergic Airway Inflammation

Abstract: IL-25 promotes type 2 immunity by inducing the expression of Th2-associated cytokines. Although it is known that the IL-25R (IL-17RB) recruits the adaptor protein ACT1, the IL-25R signaling mechanism remains poorly understood. While screening for IL-25R components, we found that IL-25 responses were impaired in Traf4 (-/-) cells. Administering IL-25 to Traf4 (-/-) mice resulted in blunted airway eosinophilia and Th2 cytokine production. Notably, IL-25R recruitment of TRAF4 was required for the ACT1/IL-25R interaction. Mechanistically, TRAF4 recruited the E3-ligase SMURF2, to degrade the IL-25R-inhibitory molecule DAZAP2. Silencing Dazap2 increased ACT1/IL-25R interaction and IL-25 responsiveness. Moreover, a tyrosine within the IL-25R elicited DAZAP2 interference. This study indicates that TRAF4-SMURF2-mediated DAZAP2 degradation is a crucial initiating event for the IL-25 response.

Endothelial Chromosome 13 Deletion in Congenital Heart Disease–associated Pulmonary Arterial Hypertension Dysregulates SMAD9 Signaling

Abstract: Supported in part by the National Heart, Lung and Blood Institute of the National Institutes of Health under award numbers R01HL098199, R03HL110831, and RC37HL60917. Author Contributions: K.M.D. and M.A.A. designed the study; acquired, analyzed, and interpreted data; and wrote the manuscript. S.A.C. and S.C.E. acquired samples, established cells, and reviewed the clinical information. R.M.T. reviewed and interpreted the pathology. All authors contributed to writing the manuscript. This letter has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Author disclosures are available with the text of this letter at www.atsjournals.org.

Impaired right ventricular-pulmonary vascular function in myeloproliferative neoplasms.

Abstract: Background Increased bone marrow hemangioblast numbers, alterations in erythroid/myeloid lineages, increased reticulin, and greater circulating bone marrow progenitor cells are present in patients with pulmonary arterial hypertension (PAH). The data suggest that myeloid progenitors contribute to the pathogenesis of PAH, but there are little data on the prevalence of pulmonary vascular disease among the different forms of myeloid diseases. We hypothesized that there would be a higher prevalence of pulmonary vascular disease in myeloproliferative neoplasms that have high circulating progenitor cells, such as myelofibrosis and chronic myelogenous leukemia (CML), compared with those with low circulating progenitors, such as in aplastic anemia. Methods Patients with myelofibrosis, CML, and aplastic anemia who underwent echocardiographic evaluation of cardiac function in preparation for bone marrow transplantation at the Cleveland Clinic between 1997 and 2012 were identified and their electronic medical records were queried for demographic data, blood cell counts, and pulmonary function tests. All echocardiograms were uniformly analyzed in a blinded fashion by an advanced sonographer and cardiologist for measures of right and left ventricular function and estimation of pulmonary vascular disease. Results Gender and race distribution among disease groups was similar. Patients with myelofibrosis ( n = 19) and aplastic anemia ( n = 30) had increased right ventricle (RV) wall thickness compared with CML ( n = 82) patients (aplastic anemia, 0.7 ± 0.1; CML, 0.5 ± 0.1; and myelofibrosis, 0.7 ± 0.1; p = 0.02). Patients with myelofibrosis had higher levels of estimated RV systolic pressure compared with the other groups (aplastic anemia, 29.9 ± 1.5; CML, 26.2 ± 1.1; and myelofibrosis, 36.7 ± 3.7 mm Hg; p Conclusions The findings suggest an important role for myeloid progenitors in the maintenance of pulmonary-vascular health, in which abnormal myeloproliferative progenitors are associated with RV pathology.

Defective Resensitization in Human Airway Smooth Muscle Cells Evokes β-Adrenergic Receptor Dysfunction in Severe Asthma.

Abstract: β2-adrenergic receptor (β2AR) agonists (β2-agonist) are the most commonly used therapy for acute relief in asthma, but chronic use of these bronchodilators paradoxically exacerbates airway hyper-responsiveness. Activation of βARs by β-agonist leads to desensitization (inactivation) by phosphorylation through G-protein coupled receptor kinases (GRKs) which mediate β-arrestin binding and βAR internalization. Resensitization occurs by dephosphorylation of the endosomal βARs which recycle back to the plasma membrane as agonist-ready receptors. To determine whether the loss in β-agonist response in asthma is due to altered βAR desensitization and/or resensitization, we used primary human airway smooth muscle cells (HASMCs) isolated from the lungs of non-asthmatic and fatal-asthmatic subjects. Asthmatic HASMCs have diminished adenylyl cyclase activity and cAMP response to β-agonist as compared to non-asthmatic HASMCs. Confocal microscopy showed significant accumulation of phosphorylated β2ARs in asthmatic HASMCs. Systematic analysis of desensitization components including GRKs and β-arrestin showed no appreciable differences between asthmatic and non-asthmatic HASMCs. However, asthmatic HASMC showed significant increase in PI3Kγ activity and was associated with reduction in PP2A activity. Since reduction in PP2A activity could alter receptor resensitization, endosomal fractions were isolated to assess the agonist ready β2ARs as a measure of resensitization. Despite significant accumulation of β2ARs in the endosomes of asthmatic HASMCs, endosomal β2ARs cannot robustly activate adenylyl cyclase. Furthermore, endosomes from asthmatic HASMCs are associated with significant increase in PI3Kγ and reduced PP2A activity that inhibits β2AR resensitization. Our study shows that resensitization, a process considered to be a homeostasis maintaining passive process is inhibited in asthmatic HASMCs contributing to β2AR dysfunction which may underlie asthma pathophysiology and loss in asthma control.

Carboxyhemoglobin and Methemoglobin in Asthma

Abstract: 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.

Coenzyme Q in Asthma

Abstract: To the Editor: Asthma is a chronic inflammatory disease characterized by an increase of reactive oxygen and nitrogen species production in the airways (1–3). Oxidative stress has been proportionately linked to the severity of the disease (2, 3). The lung has effective, well-integrated antioxidant systems to combat oxidative and nitrative injury, including superoxide dismutase (SOD), a primary antioxidant enzyme. SOD activity is lower in patients with asthma than in control subjects and decreases further during acute asthma attacks (1, 2, 4–6). Loss of SOD activity is a result of changes in the reducing–oxidizing environment in asthma, which increases the susceptibility of SOD enzymes to oxidative inactivation (2). It has been suggested that corticosteroids have a beneficial effect on antioxidants (7). A previous report has shown that treatment with inhaled or oral corticosteroids does not affect serum SOD activity measures in patients with asthma (1). Oxidative stress causes damage to a variety of biomolecules, including lipid membranes, proteins, and DNA, all of which mechanistically contribute to injury of the asthmatic airways. Increased oxidant production in asthma has been attributed to the activation of leukocytes (7, 8), but accumulating evidence from murine models of asthma and human studies points to a mitochondrial source of oxidant production by airway epithelium and smooth muscle (9). Coenzyme Q10 (CoQ), an integral part of the mitochondrial electron transport chain, also serves as an important mitochondrial antioxidant by scavenging free radicals and inhibiting lipid and protein peroxidation (10). There is evidence that CoQ has beneficial properties as an antioxidant molecule with antiinflammatory properties (10). For example, CoQ increases antioxidant enzyme activities in the liver of diabetic rats (11) and in patients with coronary artery disease (12). CoQ supplementation prevents mitochondrial-mediated oxidative damage in rodent models of sepsis and reperfusion injury of the heart (13). CoQ decreases oxidative and nitrative inflammatory biomarkers in a rodent model of metabolic syndrome and improves endothelial dysfunction (9). A possible beneficial role of CoQ in asthma was found in a study in which CoQ supplementation was associated with corticosteroid dose reduction (14). Here, we hypothesized that CoQ supplementation will restore the reducing–oxidizing balance and antioxidant capacity of patients with asthma to normal levels. To test this, 10 control subjects and 10 patients with asthma were supplemented with oral CoQ (H2Q Advanced Bioavailability CoQ10, H2Q; Health Thru Nutrition, Westbury, NY) for 4 weeks. Informed consent was obtained, and subjects had baseline characterization (visit 1, baseline) (Table 1). Subsequently, CoQ (100 mg) was taken orally with a meal daily for 4 weeks and then evaluated at a second visit (visit 2, end of CoQ). Six weeks after the end of CoQ, subjects were evaluated at a third visit (visit 3, follow-up). At each visit, serum SOD activity, urine oxidation products of DNA damage, and the redox ratio of dihydrobiopterin (BH2) to biopterin were tested. During the study, all patients with asthma were maintained on their standard antiasthma therapy. Spirometry and fractional exhaled nitric oxide were measured according to published guidelines (6). SOD activity and CoQ levels were measured as described previously (6, 15). The urinary pterin metabolites (biopterin, 7,8-BH2, and neopterin) and urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) were determined by HPLC Online Tandem Mass Spectrometry (see the online supplement). Table 1. Clinical Baseline Characteristics of Study Population Control subjects and patients with asthma had similar amounts of endogenous CoQ at baseline. CoQ supplementation increased plasma CoQ levels in control subjects and patients with asthma (Figure 1A). The average increase in plasma CoQ was significantly higher in control subjects than in patients with asthma (Figure 1A). As previously reported (1, 2, 5), patients with asthma had lower SOD activity than control subjects at baseline (P = 0.02; Figure 1B). CoQ corrected SOD activity in asthma, leading to SOD activities similar to those of control subjects (P = 0.2). SOD activity increased significantly in patients with asthma with CoQ (Figure 1B). Urinary 8-OHdG was not significantly different between the groups and was not affected by CoQ supplementation (urinary 8-OHdG [ng/mg Cr], mean ± SE: patients with asthma: visit 1, 1.41 ± 0.18; visit 2, 1.69 ± 0.22; visit 3, 1.77 ± 0.19; control subjects: visit 1, 2.11 ± 0.42; visit 2, 1.71 ± 0.21; visit 3: 2.10 ± 0.31). However, patients with asthma had a lower ratio of the reduced to oxidized forms of biopterin (BH2/[biopterin + BH2]) than control subjects at baseline (P = 0.04), which increased significantly with CoQ (paired t test, P = 0.03) (Figure 1C). The effect of CoQ on reduced/oxidized biopterin ratio was sustained even after stopping CoQ. A potential beneficial effect of CoQ on airflow was made evident by a significant increase in FEV1/FVC ratio, which continued to increase even 6 weeks after stopping CoQ (Figure 1D) (P = 0.008). Figure 1. Coenzyme Q10 (CoQ) supplementation in asthma and healthy control subjects. (A) Supplementation of CoQ at 100 mg/d for 4 weeks increases plasma CoQ in patients with asthma and in control subjects. Levels are higher in control subjects than in patients ... Oxidative mechanisms participate in the pathogenesis of asthma, either by direct oxidative damage to basic cellular components or through the activation of redox-sensitive signaling pathways that control apoptosis and inflammation. Here, we show that CoQ supplementation (100 mg daily for 4 wk) in asthma is associated with recovery of normal levels of SOD activity and redox state, as well as improvement in airflow. The study has limitations. First, the numbers of subjects were small. Second, the study was designed using 100 mg CoQ/day, without a placebo control group, for 4 weeks. Larger and longer intervention studies that are randomized and placebo-controlled are needed to investigate the clinical benefits of CoQ or other strategies targeting mitochondrial redox mechanisms in asthma.

Early Effect of Tidal Volume on Lung Injury Biomarkers in Surgical Patients With Healthy Lungs

Abstract: Background The early biological impact of short-term mechanical ventilation on healthy lungs is unknown We aimed to characterize the immediate tidal volume (VT)-related changes on lung injury biomarkers in patients with healthy lungs and low risk of pulmonary complications

Asthma in the Elderly

Abstract: Asthma is more prevalent and more severe in older individuals. Here, we review the literature on asthma in the elderly, with special focus on the pathophysiologic and immunologic mechanisms, healthcare utilization, the role of menopause and obesity, and the impact of chronic asthma on biological aging. Aging of the lung is characterized by constant decline in lung function, which is accelerated by occupational or tobacco exposure and pollution that may contribute to new onset asthma or greater severity of asthma in the elderly. Gender and sex hormones are critical determinants of asthma severity, such that perimenopausal women have more severe asthma, but postmenopausal women are protected from asthma. Immunosenescence places older adults at risk for infections, which may lead to airway hyper-reactivity and asthma exacerbations. Furthermore, the chronic low-level inflammatory state of aging is associated with decreased function of regulatory T (Treg) cells, which are important to resolve inflammation. The rate of obesity increases with age, and obesity independently places individuals at higher risk for asthma. Recent provocative studies suggest that asthma is characterized by accelerated molecular aging as defined by shorter leukocyte telomere lengths. Overall, older asthmatics suffer from greater morbidity, mortality, and healthcare utilization. More studies of the older asthmatic are needed to understand mechanisms and identify times for intervention to improve asthma control and outcomes.