Search

Mitochondrial dysfunction and metabolic reprogramming have been extensively studied in many disorders ranging from cardiovascular to neurodegenerative disease. Obesity has previously been associated with mitochondrial fragmentation, dysregulated glycolysis, and oxidative phosphorylation, as well as increased reactive oxygen species production. Current treatments focus on reducing cellular stress to restore homeostasis through the use of antioxidants or alterations of mitochondrial dynamics. This review focuses on the role of mitochondrial dysfunction in obesity particularly for those suffering from asthma and examines mitochondrial transfer from mesenchymal stem cells to restore function as a potential therapy. Mitochondrial targeted therapy to restore healthy metabolism may provide a unique approach to alleviate dysregulation in individuals with this unique endotype. [ABSTRACT FROM AUTHOR]

Mucus provides a protective barrier that is crucial for host defense in the lungs. However, excessive or abnormal mucus can have pathophysiological consequences in many pulmonary diseases, including asthma. Patients with asthma are treated with agents that relax airway smooth muscle and reduce airway inflammation, but responses are often inadequate. In part, this is due to the inability of existing therapeutic agents to directly target mucus. Accordingly, there is a critical need to better understand how mucus hypersecretion and airway plugging are affected by the epithelial cells that synthesize, secrete, and transport mucus components. This review highlights recent advances in the biology of mucin glycoproteins with a specific focus on MUC5AC and MUC5B, the chief macromolecular components of airway mucus. An improved mechanistic understanding of key steps in mucin production and secretion will help reveal novel potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Asthma is one of the most common chronic conditions in developed countries. We examined whether physical activity (PA) is related to asthma control and body mass index (BMI) in asthma patients. Cross-sectional data collected on PA (ActiGraph GT3X-BT), asthma control (the Asthma Control Questionnaire; ACQ), and BMI were examined in 206 adults (mean[sd] age 47.2[13.8] years; 49.5% had an obese BMI) with clinically diagnosed asthma. Relationships between PA and continuous BMI and asthma control were assessed using linear regression. Differences in PA across obesity (non-obese: <30 Kg/m2/obese: ≥30 Kg/m2) and asthma control categories (controlled: ≤0.75/uncontrolled: >0.75 ACQ score) were also examined. Median (p25, p75) steps counts and peak cadence were 6035 (4248, 8461) steps/day and 123 (115, 133) steps in a minute, respectively. There were nearly 2000 fewer steps/day among those with uncontrolled asthma versus controlled and among those with obese BMI versus nonobese, respectively (both p < 0.05). In regression models adjusted for relevant covariates each 1-unit increase in ACQ score was associated with −686 [95%CI −997, −13] (p ≤ 0.05) average steps/day. The statistical significance of these findings was attenuated (p ≥ 0.05) when BMI was added to the model. However, the point estimate was not reduced (-766 [95%CI −1060, 34]. Overall step counts were low in this population despite peak cadence values suggesting that most participants could perform moderate intensity activity. Increasing step counts should be considered an important lifestyle intervention goal in obese and non-obese asthma patients with low PA levels. [ABSTRACT FROM AUTHOR]

Our PAS team used prophylactic REBOA in all patients between December 2016 to June 2017 without observing complications associated with PAS [[2]]. Sir, We have reviewed with great interest the work of Whittington [[1]], about the vascular complications observed during REBOA use in a cohort of patients with placenta accreta spectrum (PAS). We have two suggestion for the authors, for reduce potential REBOA morbidity: What do they think about individualizing the use of REBOA in patients with PAS, reserving it only for the management of patients with complex injuries?. [Extracted from the article]

Objective: Rare disease Background: Hypereosinophilic syndrome (HES) is defined as hypereosinophilia with eosinophil mediated organ damage or dysfunction, provided that other causes of organ damage have been excluded. Case Report: An 83-year-old female presented with worsening dyspnea for 3 weeks. She was initially diagnosed with bronchitis and prescribed oral antibiotics along with prednisone taper. However, her dyspnea continued to worsen requiring hospitalization. Physical examination was significant for signs of volume overload. Laboratory investigations were notable for leukocytosis with eosinophilia, elevated BNP (brain natriuretic peptide) and troponin. Electrocardiogram (ECG) showed normal sinus rhythm with non-specific ST-T wave changes. Computed tomography (CT) scan of the chest showed pulmonary edema, bilateral peripheral ground glass opacities, and pleural effusions. Transthoracic echocardiogram (TTE) revealed an ejection fraction (EF) of 45%. She was diagnosed with NSTEMI (non-ST-elevation myocardial infarction) with new onset heart failure; appropriate management was initiated. Left heart catheterization did not show any significant obstructive lesions. Presence of peripheral ground glass opacities on the CT chest scan and eosinophilia raised suspicion for HES. Thorough HES workup was done, all tests came back negative except for elevated serum IgE level. Cardiac biopsy returned positive for eosinophilic myocarditis. Bone marrow biopsy showed 20% eosinophils. Positron emission tomography (PET) scan did not show any hypermetabolic lesions to suggest malignancy. The patient was managed for idiopathic HES with high dose steroids resulting in significant clinical improvement. Conclusions: About 40% of patient with HES manifest cardiac involvement, and one quarter of patients with HES have pulmonary involvement with variable radiologic findings. Steroids remain the mainstay treatment for idiopathic HES. [ABSTRACT FROM AUTHOR]

Objective: This literature review aims to compare obese-asthmatic adults and children, and to characterize differences and similarities between the two subgroups from epidemiological, demographical, phenotypical, and physiological perspectives. Methods: Literature search was conducted using Pubmed database with "obesity," "asthma," "epidemiology," "cluster analysis," "demography," "mechanics," and "FeNO" as search terms. Methods: Articles investigating epidemiological, demographic, phenotypical variation, and mechanical aspects of breathing specifically in obese asthmatics were identified. The studies were then divided according to age: children (<18 years of age) and adults (>18 years of age). Results: Increase in asthma incidence and prevalence is observed in both obese-asthmatic children and adults. Asthma prevalence is greater in adult females regardless of ethnic background, and in men of African American and Hispanic ethnicities. Degree of weight gain and early onset of menarche appears to directly affect asthma severity in adolescent girls and females. Airway hyperresponsiveness and fractional exhaled nitric oxide do not have any positive correlation with high BMI in obese-asthmatic children and adults. Obesity also alters lung mechanics in asthmatics, but the impact is different for children and adults likely due to differential effect of obesity on central and peripheral airway. Conclusion: Existing literature suggests both similarities and differences in obese-asthmatic children and adults. The most pertinent differences are related to gender, ethnicity, and lung functions. [ABSTRACT FROM AUTHOR]

Obesity is a comorbidity that adversely affects asthma severity and control by mechanisms that are not fully understood. This review will discuss evidence supporting a role for nitric oxide (NO) as a potential mechanistic link between obesity and late-onset asthma (>12 years). Several studies have shown that there is an inverse association between increasing body mass index (BMI) and reduced exhaled NO. Newer evidence suggests that a potential explanation for this paradoxical relationship is related to nitric oxide synthase (NOS) uncoupling, which occurs due to an imbalance between L-arginine (NOS substrate) and its endogenous inhibitor, asymmetric di-methyl arginine (ADMA). The review will propose a theoretical framework to understand the relevance of this pathway and how it may differ between early and late-onset obese asthmatics. Finally, the paper will discuss potential new therapeutic approaches, based on these paradigms, for improving the respiratory health of obese subjects with asthma. [ABSTRACT FROM AUTHOR]

Introduction. Obesity-mediated changes in plasma adipokines have been associated with increased systemic inflammation and oxidative stress. However, it is unknown whether obesity induces similar changes in airway levels of these adipokines and whether these changes are associated with increased airway biomarkers of inflammation and oxidative stress. Methods. Lean and obese asthmatics and controls underwent bronchoscopy with bronchoalveolar lavage (BAL), spirometry, and provided fasting plasma leptin and adiponectin. Biomarkers of oxidation and inflammation in the BAL included exhaled nitric oxide (NO), 8-isoprostanes, pH, and nitrogen oxide products (NOx). Results. Out of a total of 48 subjects, 44%% had asthma and 56%% were healthy controls. Among subjects with asthma, 66%% were obese, 10%% overweight, and 24%% lean; in the controls these proportions were 63%%, 11%%, and 26%%, respectively. After adjusting for age, sex, smoking history, ethnicity, and prebronchodilator forced exhalation in 1 second (FEV1), obesity was associated with higher BAL and plasma leptin levels in asthmatics and controls. Increasing BMI was associated with increased BAL leptin and was marginally and inversely associated with BAL adiponectin. Significant associations between BAL and plasma levels were only observed for leptin. No significant associations were observed between BAL and plasma adipokines with the airway biomarkers of oxidation and inflammation. Conclusion. Increasing BMI is associated with changes in the concentrations of airway adipokines in asthmatics and healthy controls; however, these associations are not related with biomarkers of airway oxidation or inflammation. [ABSTRACT FROM AUTHOR]

Background: Asthma is characterized by the loss of a deep breath (DB)-induced bronchodilation and bronchoprotection. Obesity causes lung restriction and increases airway resistance, which may further worsen the capacity of a DB to induce bronchodilation; however, whether increasing BMI impairs the bronchodilatory response to a DB in asthmatics is unknown. Methods: The population consisted of 99 subjects, 87 with moderate to severe persistent asthma and 12 obese control subjects. Using transfer impedance we derived airway resistance (Raw). Participants breathed for 1 minute and took a slow DB followed by passive exhalation to functional residual capacity (FRC) and tidal breathing for another minute. Results: After a DB, obese asthmatics had the largest percent increase in Raw (median 9.8% interquartile range [IQR] 3.1–15.1), compared with overweight (6.5% IQR −1.3, 12.1) and lean (0.7% IQR −3, 7.9) asthmatics and obese controls (2.5% IQR –.6, 11) (p for trend = 0.008). The association between the percent increase in Raw after a DB and BMI as a continuous variable was significant ( p = 0.02). Conclusions: In obese, moderate to severe and poorly controlled asthmatics, a DB results in increased Raw. This phenomenon was not observed in leaner asthmatics of similar severity or in obese control subjects. [ABSTRACT FROM AUTHOR]

The article presents a study which correlates the efficacy of short-acting β-agonists (SABAs) and the action of air pollutants which affects children with asthma. It notes that the study was conducted through examination of components in air pollutants including nitrogen dioxide (NO2), ozone (O3) and air particulates. It suggests that exposure to NO2 and O3 reduces the potency of SABAs in initiating bronchiodilation.

Rationale. Previous studies have demonstrated associations of high ozone levels with increased epidemiologic as well as lung function measures of asthma activity. Objectives. In an observational study during the summer months, we hypothesized that higher ambient ozone levels are associated with more frequent symptoms, higher airway and systemic inflammation, as well as worse lung function in asthmatics as compared with non-asthmatic individuals. Methods. Thirty-eight asthmatics and thirteen healthy control subjects residing in metropolitan Atlanta were enrolled during peak ozone season. Medical histories, quality-of-life questionnaires, spirometry, serum immunoglobulin (IgE), peripheral eosinophil counts, and exhaled nitric oxide (NO) were obtained during study visits. Personal ozone exposures over the 2 days before presentation were estimated based on location and activity surveys. Main results. Upper airway symptoms were more frequent in asthmatics. Higher levels of ozone were associated with worse airflow obstruction, lower quality of life scores, greater eosinophilia, and higher exhaled NO levels in asthmatics. Finally, both asthmatics and non-asthmatics with allergies showed associations between air quality and airway inflammation. Conclusions: In adults with asthma but not controls studied during peak ozone season, increasing ozone exposure predicted lower lung function and increased biomarkers of respiratory and systemic inflammation. These associations were enhanced in atopic participants, both with and without asthma. Importantly, the study findings were noted while atmospheric ozone levels were predominantly within the current and revised national air quality standards. [ABSTRACT FROM AUTHOR]

The article reports on the prevalence of asthma and obesity. Reportedly, both health problems increase the risk of severe respiratory problems. Studies regarding prevalence and incidence of asthma and weight loss are discussed to explain association to greater pulmonary problems. Mechanical factors, inflammation and conditions such as adipokines and comorbidities as well as the responses to medication and genetic mechanisms are also discussed.

Obese mice that lack leptin receptor ( db − /db −) have been shown to have innate bronchial hyperresponsiveness (BHR). It has been proposed that the obesity-mediated BHR may involve a combination of increased leptin and reduced systemic adiponectin levels. The aim of this study was to determine if obesity modifies the airway concentration of leptin and adiponectin and whether treatment with a synthetic peroxisome proliferator-activated receptor gamma (PPARγ) ligand can reduce airway leptin and increase airway adiponectin. In this study, obese, leptin receptor-deficient ( db − /db −), or lean ( db + /db −) mice were treated with rosiglitazone (3 mg/kg/day) or vehicle by gavage daily for 1 week. Bronchioalveolar lavage (BAL) was subsequently performed to determine levels of leptin, adiponectin, and inflammatory cytokines. Treatment with rosiglitazone increased BAL adiponectin levels in lean ( p = 0.04) and to a lesser extent in obese mice ( p = 0.07). Rosiglitazone treatment lowered leptin levels in lean mice, but increased leptin levels in BAL fluid of obese mice ( p < 0.01). The BAL levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) were lower in the lean rosiglitazone-treated group compared with the obese vehicle-treated group and lower in the obese rosiglitazone-treated group compared with the obese vehicle-treated group. These results demonstrate that obesity is associated with alterations in adipokine and cytokine levels in the airways that can be modulated by treatment with roziglitazone. [ABSTRACT FROM AUTHOR]

Summary: Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease that causes a large health and economic burden both in the US and around the world. Most of the risk factors for COPD are well known. These include smoking, occupational exposures to toxins and irritants, ambient air pollution, airway hyper-responsiveness, asthma, and genetic factors. Major medical organizations have agreed on a common definition of COPD, although newer measures, such as functional status or exercise capability, have emerged as important in determining the prognosis of COPD patients. In most of the world, COPD prevalence and mortality continue to increase. [Copyright &y& Elsevier]

This article presents information on a study which analyzes the prevalence and mortality from selected comorbidities in patients with and without a diagnosis of COPD using the National Hospital Discharge Survey. COPD is the fourth-most-common cause of death in adults in the United States and is projected to be the third-most-common cause of death in both men and women by the year 2020. COPD is also a leading cause of hospitalizations in adults in the United States, particularly in older populations. Even though the prevalence of COPD has increased in the last 20 years, it is infrequently mentioned as a contributing or underlying cause of death even in patients with severe disease.

Introduction: Omega-3 fatty acid levels are associated with decreased risk for sudden death; however, the protective cardiovascular mechanisms of omega-3 are poorly understood. This study addresses the heart rate variability (HRV) changes in a cohort of elderly subjects randomized to receive either a daily high dose of marine-derived omega-3 fatty acids (fish oil) or a lower daily dose of a plant-derived omega-3 fatty acid (α-linolenic acid) in soy oil. Methods: A total of 58 elderly nursing home residents were randomized to receive 2 g/d of fish oil capsules vs 2 g/d of soy oil capsules, and were subsequently followed up every other day for a period of 6 months with 6-min measurements of HRV while resting supine. An initial control period of 2 months without supplementation was allowed to establish an HRV baseline for each participant. Results: The average time- and frequency-domain parameters of HRV increased significantly during the supplementation period in both the fish oil and soy oil groups. In the regression model after adjusting for age and mean heart rate, supplementation with fish oil was associated with a significant increase in the high- and low-frequency components, and SD of normal RR intervals (SDNN), whereas only SDNN increased significantly in the soy oil group. Conclusions: Supplementation with 2 g/d of fish oil was well tolerated and was associated with a significant increase in HRV. Supplementation with 2 g/d of soy oil was associated with a lesser but significant increase in HRV. [ABSTRACT FROM AUTHOR]

A review of the articles "VX-659-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles" by J.C. Davies and "VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles" by D. Keating in this journal is presented.

Asthma and obesity are common coexisting conditions with increasing prevalence and substantial morbidity. This study examines the inter-relationship between illness and treatment beliefs in asthma and obesity and how they influence self-management behaviors. Overweight and obese adults ≥ 18 years with asthma were recruited from primary care and pulmonary practices in New York, NY and Denver, CO (n = 219). Path analysis was used to examine the relationship between asthma, weight and exercise-related illness and medication beliefs and SMB. Necessity beliefs about asthma medications and diet were associated with better medication adherence and healthier dietary behaviors (β = 0.276, p = < 0.001, β = 0.148, p = 0.018 respectively) whereas concerns about these self-care activities were associated with poorer adherence and worse dietary behaviors (β = − 0.282, p < 0.001, β = − 0.188, p = 0.003 respectively). We found no statistically significant association of exercise behaviors with any other weight or asthma illness or treatment beliefs. Our study demonstrates that necessity and concerns about treatment are associated with adherence in asthma and obesity. The lack of association of exercise behaviors with any asthma or weight related beliefs may reflect limited awareness of the impact of weight on asthma and warrants additional research. [ABSTRACT FROM AUTHOR]

The lung allocation score (LAS) is a tool used to prioritize patients for lung transplantation. For patients with interstitial lung diseases (ILDs), spirometry data are used for the LAS calculation. Spirometry values such as a FVC are subjected to race-specific equations that determine expected values. The effect of race-specific equations in LAS score remains unknown. Did the use of a race-based spirometry equation lead to longer waitlist times for Black patients? We performed a retrospective analysis of patients listed for lung transplantation from 2005 through 2020 using publicly available data from the United Network for Organ Sharing. We recalculated LAS scores for Black patients using White-specific equations with the available variables. The primary objective was to evaluate the effect of race-specific equations on LAS scores and time on the transplant waitlist. A total of 33,845 patients listed for lung transplantation were included in the analysis. White patients were listed at lower LAS scores, a higher proportion of White patients underwent transplantation, and White patients died on the waitlist at lower rates. When recalculating LAS scores using White-specific equations, Black patients with ILD had up to a 1.9-point higher score, which resulted in additional waitlist time. Race-specific equations led to longer wait times in Black patients listed for lung transplantation. The use of race-based equations widened already known disparities in pulmonary transplantation. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Albuterol is the first-line asthma medication used in diverse populations. Although DNA methylation (DNAm) is an epigenetic mechanism involved in asthma and bronchodilator drug response (BDR), no study has assessed whether albuterol could induce changes in the airway epithelial methylome. We aimed to characterize albuterol-induced DNAm changes in airway epithelial cells, and assess potential functional consequences and the influence of genetic variation and asthma-related clinical variables. Results: We followed a discovery and validation study design to characterize albuterol-induced DNAm changes in paired airway epithelial cultures stimulated in vitro with albuterol. In the discovery phase, an epigenome-wide association study using paired nasal epithelial cultures from Puerto Rican children (n = 97) identified 22 CpGs genome-wide associated with repeated-use albuterol treatment (p < 9 × 10–8). Albuterol predominantly induced a hypomethylation effect on CpGs captured by the EPIC array across the genome (probability of hypomethylation: 76%, p value = 3.3 × 10–5). DNAm changes on the CpGs cg23032799 (CREB3L1), cg00483640 (MYLK4-LINC01600), and cg05673431 (KSR1) were validated in nasal epithelia from 10 independent donors (false discovery rate [FDR] < 0.05). The effect on the CpG cg23032799 (CREB3L1) was cross-tissue validated in bronchial epithelial cells at nominal level (p = 0.030). DNAm changes in these three CpGs were shown to be influenced by three independent genetic variants (FDR < 0.05). In silico analyses showed these polymorphisms regulated gene expression of nearby genes in lungs and/or fibroblasts including KSR1 and LINC01600 (6.30 × 10–14 ≤ p ≤ 6.60 × 10–5). Additionally, hypomethylation at the CpGs cg10290200 (FLNC) and cg05673431 (KSR1) was associated with increased gene expression of the genes where they are located (FDR < 0.05). Furthermore, while the epigenetic effect of albuterol was independent of the asthma status, severity, and use of medication, BDR was nominally associated with the effect on the CpG cg23032799 (CREB3L1) (p = 0.004). Gene-set enrichment analyses revealed that epigenomic modifications of albuterol could participate in asthma-relevant processes (e.g., IL-2, TNF-α, and NF-κB signaling pathways). Finally, nine differentially methylated regions were associated with albuterol treatment, including CREB3L1, MYLK4, and KSR1 (adjusted p value < 0.05). Conclusions: This study revealed evidence of epigenetic modifications induced by albuterol in the mucociliary airway epithelium. The epigenomic response induced by albuterol might have potential clinical implications by affecting biological pathways relevant to asthma. [ABSTRACT FROM AUTHOR]

Obesity is a major comorbidity for the development and worsening of asthma. It is associated with increased disease incidence, reduced response to inhaled and systemic steroids, increased asthma exacerbations, and poor disease control. Over the past two decades, we have learned that there are clinical asthma phenotypes associated with obesity, which have unique immune, inflammatory, and metabolic disease mechanisms. The objectives of this review are to provide a brief overview of the associations and gaps between these chronic inflammatory diseases and the role that traditional therapies have on treating patients with obesity-related asthma, and to describe new clinical research of therapeutic developments targeting mechanisms that are more specific to this patient population. [ABSTRACT FROM AUTHOR]

The article provides an overview of the study presented in the journal which evaluated the association between traffic related exposures and changes in exhaled lung volumes in participants from the Atherosclerosis Risk in Communities (ARIC) cohort study in the U.S. Using traffic density and road proximity as proxy measures of exposure, researchers have shown that vehicular emissions are associated with chronic lung function changes in a large sample of adult subjects.

Obesity and associated changes to the gut microbiome worsen airway inflammation and hyperresponsiveness in asthma. Obesogenic host-microbial metabolomes have altered production of metabolites that may influence lung function and inflammatory responses in asthma. To understand the interplay of the gut microbiome, metabolism, and host inflammation in obesity-associated asthma, we used a multi-omics approach to profile the gut-lung axis in the setting of allergic airway disease and diet-induced obesity. We evaluated an immunomodulator, nitro-oleic acid (NO2-OA), as a host- and microbial-targeted treatment intervention for obesity-associated allergic asthma. Allergic airway disease was induced using house dust mite and cholera toxin adjuvant in C57BL6/J mice with diet-induced obesity to model obesity-associated asthma. Lung function was measured by flexiVent following a week of NO2-OA treatment and allergen challenge. 16S rRNA gene (from DNA, taxa presence) and 16S rRNA (from RNA, taxa activity) sequencing, metabolomics, and host gene expression were paired with a Treatment-Measured-Response model as a data integration framework for identifying latent/hidden relationships with linear regression among variables identified from high-dimensional meta-omics datasets. Targeting both the host and gut microbiota, NO2-OA attenuated airway inflammation, improved lung elastance, and modified the gut microbiome. Metaomics data integration and modeling determined that gut-associated inflammation, metabolites, and functionally active gut microbiota were linked to lung function outcomes. Using Treatment-Measured-Response modeling and meta-omics profiling of the gut-lung axis, we uncovered a previously hidden network of interactions between gut levels of amino acid metabolites involved in elastin and collagen synthesis, gut microbiota, NO2-OA, and lung elastance. Further targeted metabolomics analyses revealed that obese mice with allergic airway disease had higher levels of proline and hydroxyproline in the lungs. NO2- OA treatment reduced proline biosynthesis by downregulation of pyrroline-5-carboxylate reductase 1 (PYCR1) expression. These findings are relevant to human disease: adults with mild-moderate asthma and BMI ≥ 25 had higher plasma hydroxyproline levels. Our results suggest that changes to structural proteins in the lung airways and parenchyma may contribute to heightened lung elastance and serve as a potential therapeutic target for obese allergic asthma. [ABSTRACT FROM AUTHOR]

Background: Sleep difficulties are commonly reported by patients with asthma; however, the prevalence of insomnia and its association with disease burden and well-being is unknown. We aimed to determine the prevalence of insomnia, defined as combined sleep-specific complaints with associated daytime symptoms, among a large sample of adults with asthma, and to compare well-being, asthma control, and asthma-related health care utilization in individuals with asthma and insomnia and those without insomnia.Methods: Baseline data from adults with physician-confirmed asthma enrolled in the Severe Asthma Research Program III was used for analyses (N = 714). Participants completed the Insomnia Severity Index (ISI), Asthma Control Test, Asthma Quality of Life Questionnaire, and Hospital Anxiety and Depression Scale.Results: Insomnia (ISI ≥ 10) was identified in 263 participants (37%). Presence of insomnia was associated with higher levels of depression and anxiety symptoms and poorer quality of life. Those with insomnia had a 2.4-fold increased risk for having not well-controlled asthma and a 1.5-fold increased risk for asthma-related health care utilization in the past year compared with those without insomnia.Conclusions: Insomnia is highly prevalent in asthma and is associated with adverse outcomes. Further studies are needed to gain a better understanding of the interaction between insomnia and asthma control. [ABSTRACT FROM AUTHOR]

Background: Imbalance in L-arginine and nitric oxide (NO) metabolism has been implicated in the pathophysiology of asthma and obstructive sleep apnea (OSA), and both diseases impact the other's morbidity. We sought to determine whether L-arginine/NO metabolism differs between adults with asthma with or without comorbid OSA, and its association with asthma morbidity.Methods: This is a cross-sectional study of 322 adults with asthma recruited in Denver, CO and New York City, NY. Data were collected on OSA status, spirometry, and metrics of asthma control and morbidity. L-Arginine metabolites were quantified in patient serum. Bivariate analyses and multiple regression were performed to determine differences between L-arginine metabolism, OSA and association with asthma morbidity.Results: Among the 322 participants, 92 (28.5%) had OSA. The cohort was 81.6% female, 23.4% identified as Black and 30.6% as Latino. Patients with asthma and OSA had significantly higher serum concentrations of NO synthase inhibitor asymmetric dimethylarginine (ADMA) (p-value = 0.019), lower L-arginine to ornithine ratios (p-value = 0.003), and increased ornithine (p-value = 0.001) and proline levels (p-value < 0.001) compared to those without OSA. In adjusted models, OSA was associated with worse asthma control, adjusted mean difference in asthma control questionnaire of 0.36 (95% confidence interval [CI]: 0.06 to 0.65), and asthma quality of life questionnaire, adjusted mean difference: - 0.53 (95% CI: - 0.85 to - 0.21), after adjusting for relevant covariates including body mass index and L-arginine metabolites.Conclusions: Adults with asthma and OSA had increased ADMA, an inhibitor of nitric oxide synthase, and greater metabolism of L-arginine via the arginase pathway compared to those with asthma alone, indicating a possible shared pathophysiological mechanism of these diseases. [ABSTRACT FROM AUTHOR]

Background: Obesity in asthmatics has been associated with higher airway oxidative stress in which dysfunctional mitochondria are a potential contributing source of excess free radicals. Paraoxonase 2 (PON2) plays an important role in reducing mitochondrial-derived oxidative stress and could, therefore, have therapeutic potential in these patients. Objectives: We used primary human bronchial epithelial cells (HBECs) from asthmatics and healthy controls to evaluate: a) protein levels of Paraoxonase 2 and b) to test the potential protective effect of quercetin supplementation in cells under oxidative stress conditions. Results: Compared to lean controls, obese asthmatics had significantly lower PON2 airway epithelial levels (respectively, 1.08 vs. 0.47 relative units normalized by GAPDH) (p-value < 0.006). Treating HBECs in vitro for 24 hrs. with 25μM quercetin significantly increased PON2 protein levels: 15.5 treated cells vs. 9.8 untreated cells (relative units normalized by GAPDH) (p value = 0.004). Notably, compared to untreated cells, quercetin supplementation reduces mitochondrial superoxide and hydrogen peroxide production on HBECs cells exposed to different oxidative stress triggers such as 1–2 Naphthoquinone (1–2 NQ) and hydrogen peroxide, suggesting that PON2 might play a protective role ameliorating oxidative injury on human airway epithelium. Conclusion: Compared to lean controls, obese asthmatics have significantly reduced PON2 levels in airway epithelial cells. Treatment with quercetin in vitro increased PON2 protein levels and prevented oxidative stress from different types of stimuli. Hence, quercetin supplementation may be a potential therapeutic strategy to prevent obesity-mediated airway oxidative stress in obese asthmatics. [ABSTRACT FROM AUTHOR]

Background Eosinophilic inflammation is implicated in asthma. Eotaxin 1-3 regulate eosinophil trafficking into the airways along with other chemotactic factors. However, the epithelial and bronchoalveolar lavage (BAL) cell expression of these chemokines in relation to asthma severity and eosinophilic phenotypes has not been addressed. Objective To measure the expression of the three eotaxin isoforms in bronchoscopically obtained samples and compare them with clinically relevant parameters between normal subjects and patients with asthma. Methods Normal subjects and patients with asthma of varying severity recruited through the Severe Asthma Research Program underwent clinical assessment and bronchoscopy with airway brushing and BAL. Eotaxin 1-3 mRNA/protein were measured in epithelial and BAL cells and compared with asthma severity, control and eosinophilic inflammation. Results Eotaxin-2 and eotaxin-3 mRNA and eotaxin-2 protein were increased in airway epithelial brushings from patients with asthma and were highest in cases of severe asthma (p values 0.0155, 0.0033 and 0.0006, respectively), with eotaxin-2 protein increased with age at onset. BAL cells normally expressed high levels of eotaxin-2 mRNA/protein but BAL fluid levels of eotaxin-2 were lowest in severe asthma. Epithelial eotaxin-2 and eotaxin-3 mRNA/protein was associated with sputum eosinophilia, lower forced expiratory volume in 1 s and more asthma exacerbations. Airway epithelial cell eotaxin-2 protein differed by asthma severity only in those with late onset disease, and tended to be highest in those with late onset eosinophilic asthma. Conclusions Epithelial eotaxin-2 and 3 are increased in asthma and severe asthma. Their expression may contribute to luminal migration of eosinophils, especially in later onset disease, asthma control and severity. [ABSTRACT FROM AUTHOR]

Bile acid profiles are altered in obese individuals with asthma. Thus, we sought to better understand how obesity-related systemic changes contribute to lung pathophysiology. We also test the therapeutic potential of nitro-oleic acid (NO2-OA), a regulator of metabolic and inflammatory signaling pathways, to mitigate allergen and obesity-induced lung function decline in a murine model of asthma. Bile acids were measured in the plasma of healthy subjects and individuals with asthma and serum and lung tissue of mice with and without allergic airway disease (AAD). Lung function, indices of inflammation and hepatic bile acid enzyme expression were measured in obese mice with house dust mite-induced AAD treated with vehicle or NO2-OA. Serum levels of glycocholic acid and glycoursodeoxycholic acid clinically correlate with body mass index and airway hyperreactivity whereas murine levels of β-muricholic acid and tauro-β-muricholic acid were significantly increased and positively correlated with impaired lung function in obese mice with AAD. NO2-OA reduced murine bile acid levels by modulating hepatic expression of bile acid synthesis enzymes, with a concomitant reduction in small airway resistance and tissue elastance. Bile acids correlate to body mass index and lung function decline and the signaling actions of nitroalkenes can limit AAD by modulating bile acid metabolism, revealing a potential pharmacologic approach to improving the current standard of care. [ABSTRACT FROM AUTHOR]

Background: Although asthma has been suggested as a risk factor for cardiovascular disease (CVD), robust longitudinal evidence of this relationship is limited.Research Question: Using Framingham Offspring Cohort data, the goal of this study was to longitudinally examine the association between asthma and lifetime risk of CVD while controlling for cardiovascular risk factors included in the Framingham Risk Score.Study Design and Methods: Data were analyzed from a prospective population-based cohort of 3,612 individuals, ages 17 to 77 years, who participated in Framingham Offspring Study examinations from 1979 to 2014. Asthma was defined based on physician diagnosis during study interviews. Incident CVD included myocardial infarction, angina, coronary insufficiency, stroke, transient ischemic attack, and heart failure. Time-dependent Cox regression models were used to evaluate the relationship between asthma and CVD incidence.Results: Overall, 533 (15%) participants had a diagnosis of asthma and 897 (25%) developed CVD during the course of the study. Unadjusted analyses revealed that asthma was associated with increased CVD incidence (hazard ratio, 1.40; 95% CI, 1.17-1.68). Cox regression also showed an adjusted association between asthma and CVD incidence (hazard ratio, 1.28; 95% CI, 1.07-1.54) after controlling for established cardiovascular risk factors.Interpretation: This prospective analysis with > 35 years of follow-up shows that asthma is a risk factor for CVD after adjusting for potential confounders. When assessing risk of cardiovascular disease, asthma should be evaluated and managed as a risk factor contributing to morbidity and mortality. [ABSTRACT FROM AUTHOR]

Aims: Asthma, characterized by airway obstruction and hyper-responsiveness, is more severe and less responsive to treatment in obese subjects. While alterations in mitochondrial function and redox signaling have been implicated in asthma pathogenesis, it is unclear whether these mechanisms differ in lean versus obese asthmatics. In addition, we previously demonstrated that circulating platelets from asthmatic individuals have altered bioenergetics; however, it is unknown whether platelet mitochondrial changes reflect those observed in airway epithelial cells. Herein we hypothesized that lean and obese asthmatics show differential bioenergetics and redox signaling in airway cells and that these alterations could be measured in platelets from the same individual. Results: Using freshly isolated bronchial airway epithelial cells and platelets from lean and obese asthmatics and healthy individuals, we show that both cell types from obese asthmatics have significantly increased glycolysis, basal and maximal respiration, and oxidative stress compared with lean asthmatics and healthy controls. This increased respiration was associated with enhanced arginine metabolism by arginase, which has previously been shown to drive respiration. Inducible nitric oxide synthase (iNOS) was also upregulated in cells from all asthmatics. However, due to nitric oxide synthase uncoupling in obese asthmatics, overall nitric oxide (NO) bioavailability was decreased, preventing NO-dependent inhibition in obese asthmatic cells that was observed in lean asthmatics. Innovation and Conclusion: These data demonstrate bioenergetic differences between lean and obese asthmatics that are, in part, due to differences in NO signaling. They also suggest that the platelet may serve as a useful surrogate to understand redox, oxidative stress and bioenergetic changes in the asthmatic airway. [ABSTRACT FROM AUTHOR]

Background: Both obesity and the metabolic syndrome have been independently associated with increased asthma morbidity. However, it is unclear whether metabolic syndrome limits the beneficial effects of weight loss on asthma. Objectives: To evaluate whether bariatric weight loss is associated with improved asthma control, and whether this association varies by metabolic syndrome status. Methods: We determined the changes in asthma control, defined by the Asthma Control Test (ACT), before and after bariatric surgery among participants with asthma in the multi-center Longitudinal Assessment of Bariatric Surgery (LABS) study, stratifying our analysis by the presence or absence of metabolic syndrome. Results: Among 2,458 LABS participants, 555 participants had an asthma diagnosis and were included in our analysis. Of these, 78% (n = 433) met criteria for metabolic syndrome (MetSyn) at baseline. In patients without MetSyn, mean ACT increased from 20.4 at baseline to 22.1 by 12–24 months, ending at 21.3 at 60 months. In contrast, among those with MetSyn there was no significant improvement in ACT scores. The proportion of patients without MetSyn with adequate asthma control (ACT >19) increased from 58% at baseline to 78% and 82% at 12 and 60 months, respectively, whereas among those with MetSyn, it was 73.8% at baseline, 77.1% at 12 months, dropping to 47.1% at 60 months (p = 0.004 for interaction between metabolic syndrome and time). Having MetSyn also increased the likelihood of losing asthma control during follow-up (HR = 1.92, 95% confidence interval [CI] 1.24–2.97, p = 0.003). Conclusions: Metabolic syndrome may negatively modify the effect of bariatric surgery-induced weight loss on asthma control. [ABSTRACT FROM AUTHOR]

Because fine particulate matter (PM 2.5 ) differs in chemical composition, source apportionment is frequently used for identification of relative contributions of multiple sources to outdoor concentrations. Indoor air pollution and source apportionment is often overlooked, though people in northern climates may spend up to 90% of their time inside. We selected 21 homes for a 1-week indoor sampling session during summer (July to September 2011), repeated in winter (January to March 2012). Elemental analysis was performed using inductively-coupled plasma mass spectrometry (ICP-MS), and factor analysis was used to determine constituent grouping. Multivariate modeling was run on factor scores to corroborate interpretations of source factors based on a literature review. For each season, a 5-factor solution explained 86–88% of variability in constituent concentrations. Indoor sources (i.e. cooking, smoking) explained greater variability than did outdoor sources in these industrial communities. A smoking factor was identified in each season, predicted by number of cigarettes smoked. Cooking factors were also identified in each season, explained by frequency of stove cooking and stovetop frying. Significant contributions from outdoor sources including coal and motor vehicles were also identified. Higher coal and secondary-related elemental concentrations were detected during summer than winter. Our findings suggest that source contributions to indoor concentrations can be identified and should be examined in relation to health effects. [ABSTRACT FROM AUTHOR]

Background: Worldwide, asthma is a leading cause of morbidity, mortality and economic burden, with significant gender and racial disparities. However, little attention has been given to the independent role of age on lifetime asthma severity and hospitalization. We aimed to assess the effect of age, gender, race and ethnicity on indicators of asthma severity including asthma related hospitalization, mortality, hospital cost, and the rate of respiratory failure. Methods: We analyzed the 2011 and 2012 Healthcare Cost and Utilization Project- National Inpatient Sample (NIS). We validated and extended those results using the National Heart, Lung, and Blood Institute-Severe Asthma Research Program (SARP; 2002–2011) database. Severe asthma was prospectively defined using the stringent American Thoracic Society (ATS) definition. Results: Hospitalization for asthma was reported in 372,685 encounters in 2012 and 368,528 in 2011. The yearly aggregate cost exceeded $2 billion. There were distinct bimodal distributions for hospitalization age, with an initial peak at 5 years and a second at 50 years. Likewise, this bimodal age distribution of patients with severe asthma was identified using SARP. Males comprised the majority of individuals in the first peak, but women in the second. Aggregate hospital cost mirrored the bimodal peak distribution. The probability of respiratory failure increased with age until the age of 60, after which it continued to increase in men, but not in women. Conclusions: Severe asthma is primarily a disease of young boys and middle age women. Greater understanding of the biology of lung aging and influence of sex hormones will allow us to plan for targeted interventions during these times in order to reduce the personal and societal burdens of asthma. [ABSTRACT FROM AUTHOR]

A link between metabolic syndrome (MetS) and lung diseases has been observed in several cross-sectional and longitudinal studies. This syndrome has been identified as an independent risk factor for worsening respiratory symptoms, greater lung function impairment, pulmonary hypertension, and asthma. This review will discuss several potential mechanisms to explain these associations, including dietary factors and the effect of adiposity and fat-induced inflammation on the lungs, and the role of other comorbidities that frequently coexist with MetS, such as OSA and obesity. In contrast to the well-known association between asthma and obesity, the recognition that MetS affects the lung is relatively new. Although some controversy remains as to whether MetS is a unique disease entity, its individual components have independently been associated with changes in pulmonary function or lung disease. There is, however, uncertainty as to the relative contribution that each metabolic factor has in adversely affecting the respiratory system; also, it is unclear how much of the MetS-related lung effects occur independently of obesity. In spite of these epidemiological limitations, the proposed mechanistic pathways strongly suggest that this association is likely to be causal. Given the wide prevalence of MetS in the general population, it is imperative that we continue to further understand how this metabolic disorder impacts the lung and how to prevent its complications. [ABSTRACT FROM AUTHOR]

Background and Objectives: Exposure to particulate matter (PM2.5) has been associated with increased cardiovascular outcomes, mediated by a hypothesized biological mechanism of systemic inflammation and oxidation. Although PM10 has been linked to inflammatory markers in a nationally representative sample (NHANES) using data from earlier cycles (1989-1994); no study has considered these relationships for PM2.5 in more recent time periods. We examined the association of ambient PM2.5 exposure and inflammatory markers in adult NHANES participants for cycles 2001-2008.Methods: We linked each of the adult NHANES participant's address with meteorological and modeled air pollution data for each census tract in conterminous United States. The effects of short and long term PM2.5 on C-reactive protein, white blood cells, fibrinogen and homocysteine were analyzed using multiple linear regression, adjusting for cardiovascular risk factors, temperature and ozone. SAS SURVEYREG was used to account for the complex survey design of NHANES.Results: In the overall population, no significant positive associations were noted for either short or long term PM2.5 exposures for any of the biomarkers after controlling for confounders. However, stronger associations were found among obese, diabetics, hypertensive and smokers. For every 10μg/m(3) increase in PM2.5, there was an increase of (a) 36.9% (95% CI: 0.1%, 87.2%) in CRP at annual average PM2.5 (adjusting for short term exposure) among diabetics (b) 2.6% (95% CI: 0.1%, 5.1%) in homocysteine at lag 0 among smokers.Conclusions: In a nationally representative sample of individuals we noted no overall association between PM2.5 and biomarkers of cardiovascular risk. However, sensitive subgroups manifested increases in these markers to PM2.5 exposure. Further studies should concentrate on the impact of PM2.5 on these biomarkers in those with multiple cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

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%

Impacts of industrial emissions on outdoor air pollution in nearby communities are well-documented. Fewer studies, however, have explored impacts on indoor air quality in these communities. Because persons in northern climates spend a majority of their time indoors, understanding indoor exposures, and the role of outdoor air pollution in shaping such exposures, is a priority issue. Braddock and Clairton, Pennsylvania, industrial communities near Pittsburgh, are home to an active steel mill and coke works, respectively, and the population experiences elevated rates of childhood asthma. Twenty-one homes were selected for 1-week indoor sampling for fine particulate matter (PM 2.5 ) and black carbon (BC) during summer 2011 and winter 2012. Multivariate linear regression models were used to examine contributions from both outdoor concentrations and indoor sources. In the models, an outdoor infiltration component explained 10 to 39% of variability in indoor air pollution for PM 2.5 , and 33 to 42% for BC. For both PM 2.5 models and the summer BC model, smoking was a stronger predictor than outdoor pollution, as greater pollutant concentration increases were identified. For winter BC, the model was explained by outdoor pollution and an open windows modifier. In both seasons, indoor concentrations for both PM 2.5 and BC were consistently higher than residence-specific outdoor concentration estimates. Mean indoor PM 2.5 was higher, on average, during summer (25.8 ± 22.7 μg/m 3 ) than winter (18.9 ± 13.2 μg/m 3 ). Contrary to the study's hypothesis, outdoor concentrations accounted for only little to moderate variability (10 to 42%) in indoor concentrations; a much greater proportion of PM 2.5 was explained by cigarette smoking. Outdoor infiltration was a stronger predictor for BC compared to PM 2.5 , especially in winter. Our results suggest that, even in industrial communities of high outdoor pollution concentrations, indoor activities – particularly cigarette smoking – may play a larger role in shaping indoor exposures. [ABSTRACT FROM AUTHOR]

Background: Obese asthmatics tend to have poorly controlled asthma, and resistance to standard asthma controller medications. The purpose of this study was to determine the efficacy of pioglitazone, an anti-diabetic medication which can alter circulating adipokines and have direct effects on asthmatic inflammation, in the treatment of asthma in obesity.Methods: A two-center, 12-week, randomized, placebo-controlled, double-blinded trial. Treatments were randomly assigned with concealment of allocation. The primary outcome was difference in change in airway reactivity between participants assigned to pioglitazone versus placebo at 12 weeks.Results: Twenty-three participants were randomized to treatment, 19 completed the study. Median airway reactivity, measured by PC20 to methacholine was 1.99 (IQR 3.08) and 1.60 (5.91) mg/ml in placebo and pioglitazone group at baseline, and 2.37 (15.22) and 5.08 (7.42) mg/ml after 12 weeks, p = 0.38. There was no difference in exhaled nitric oxide, asthma control or lung function between treatment groups over the 12 week trial. Participants assigned to pioglitazone gained a significant amount more weight than those assigned to placebo (pioglitazone group mean weight 113.6, CI 94.5-132.7 kg at randomization and 115.9, CI 96.9-135.1 at 12 weeks; placebo mean weight 127.5, CI 108.4 - 146.6 kg at randomization and 124.5, CI 105.4 - 143.6 kg at 12 weeks; p = 0.04).Conclusions: This pilot study suggests limited efficacy for pioglitazone in the treatment of poorly controlled asthma in obesity, and also the potential for harm, given the weight gain in those assigned to active treatment, and the association between increased weight and worse outcomes in asthma.Trial Registration: Clinicaltrials.gov (NCT00634036). [ABSTRACT FROM AUTHOR]

Importance: Many preschool children develop recurrent, severe episodes of lower respiratory tract illness (LRTI). Although viral infections are often present, bacteria may also contribute to illness pathogenesis. Strategies that effectively attenuate such episodes are needed.Objective: To evaluate if early administration of azithromycin, started prior to the onset of severe LRTI symptoms, in preschool children with recurrent severe LRTIs can prevent the progression of these episodes.Design, Setting, and Participants: A randomized, double-blind, placebo-controlled, parallel-group trial conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute's AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by December 2014. Participants were 607 children aged 12 through 71 months with histories of recurrent, severe LRTIs and minimal day-to-day impairment.Intervention: Participants were randomly assigned to receive azithromycin (12 mg/kg/d for 5 days; n = 307) or matching placebo (n = 300), started early during each predefined RTI (child's signs or symptoms prior to development of LRTI), based on individualized action plans, over a 12- through 18-month period.Main Outcomes and Measures: The primary outcome measure was the number of RTIs not progressing to a severe LRTI, measured at the level of the RTI, that would in clinical practice trigger the prescription of oral corticosteroids. Presence of azithromycin-resistant organisms in oropharyngeal samples, along with adverse events, were among the secondary outcome measures.Results: A total of 937 treated RTIs (azithromycin group, 473; placebo group, 464) were experienced by 443 children (azithromycin group, 223; placebo group, 220), including 92 severe LRTIs (azithromycin group, 35; placebo group, 57). Azithromycin significantly reduced the risk of progressing to severe LRTI relative to placebo (hazard ratio, 0.64 [95% CI, 0.41-0.98], P = .04; absolute risk for first RTI: 0.05 for azithromycin, 0.08 for placebo; risk difference, 0.03 [95% CI, 0.00-0.06]). Induction of azithromycin-resistant organisms and adverse events were infrequently observed.Conclusions and Relevance: Among young children with histories of recurrent severe LRTIs, the use of azithromycin early during an apparent RTI compared with placebo reduced the likelihood of severe LRTI. More information is needed on the development of antibiotic-resistant pathogens with this strategy.Trial Registration: clinicaltrials.gov Identifier: NCT01272635. [ABSTRACT FROM AUTHOR]

Severe asthma (SA) is a challenge to control, as patients are not responsive to high doses of systemic corticosteroids (CS). In contrast, mild-moderate asthma (MMA) is responsive to low doses of inhaled CS, indicating that Th2 cells, which are dominant in MMA, do not solely orchestrate SA development. Here, we analyzed broncholalveolar lavage cells isolated from MMA and SA patients and determined that IFN-γ (Th1) immune responses are exacerbated in the airways of individuals with SA, with reduced Th2 and IL-17 responses. We developed a protocol that recapitulates the complex immune response of human SA, including the poor response to CS, in a murine model. Compared with WT animals, lfng-/- mice subjected to this SA model failed to mount airway hyperresponsiveness (AHR) without appreciable effect on airway inflammation. Conversely, AHR was not reduced in ll17ra-/- mice, although airway inflammation was lower. Computer-assisted pathway analysis tools linked IFN-γ to secretory leukocyte protease inhibitor (SLPI), which is expressed by airway epithelial cells, and IFN-γ inversely correlated with SLPI expression in SA patients and the mouse model. In mice subjected to our SA model, forced SLPI expression decreased AHR in the absence of CS, and it was further reduced when SLPI was combined with CS. Our study identifies a distinct immune response in SA characterized by a dysregulated IFN-γ/SLPI axis that affects lung function. [ABSTRACT FROM AUTHOR]

15-Hydroxyprostaglandin dehydrogenase (15PGDH) is the primary enzyme catalyzing the conversion of hydroxylated arachidonic acid species to their corresponding oxidized metabolites. The oxidation of hydroxylated fatty acids, such as the conversion of prostaglandin (PG) E2 to 15-ketoPGE2, by 15PGDHis viewed to inactivate signaling responses. In contrast, the typically electrophilic products can also induce anti-inflammatory and anti-proliferative responses. This study determined that hydroxylated docosahexaenoic acid metabolites (HDoHEs) are substrates for 15PGDH. Examination of 15PGDH substrate specificity was conducted in cell culture (A549 and primary human airway epithelia and alveolar macrophages) using chemical inhibition and shRNA knockdown of 15PGDH. Substrate specificity is broad and relies on the carbon position of the acyl chain hydroxyl group. 14-HDoHE was determined to be the optimal DHA substrate for 15PGDH, resulting in the formation of its electrophilic metabolite, 14-oxoDHA. Consistent with this, 14-HDoHE was detected in bronchoalveolar lavage cells of mild to moderate asthmatics, and the exogenous addition of 14-oxoDHA to primary alveolar macrophages inhibited LPS-induced proinflammatory cytokine mRNA expression. These data reveal that 15PGDH-derived DHA metabolites are biologically active and can contribute to the salutary signaling actions of Ω-3 fatty acids. [ABSTRACT FROM AUTHOR]

Importance: In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency.Objective: To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels.Design, Setting, and Participants: The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute's AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized.Interventions: Oral vitamin D3 (100,000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained.Main Outcomes and Measures: The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care).Results: Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28% [95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%-35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6-1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2-120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2-135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1-27.7 µg/d]).Conclusions and Relevance: Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma.Trial Registration: clinicaltrials.gov Identifier: NCT01248065. [ABSTRACT FROM AUTHOR]