Search

The associations of pulmonary function with cardiovascular disease (CVD) independent of diabetes mellitus (DM) and metabolic syndrome have not been examined in a populationbased setting. We examined prevalence and incidence CVD in relation to lower pulmonary function in the Strong Heart Study second examination (1993 to 1995) in 352 CVD and 2,873 non-CVD adults free of overt lung disease (mean age 60 years). Lung function was assessed by standard spirometry. Participants with metabolic syndrome or DM with or without CVD had lower pulmonary function than participants without these conditions after adjustment for hypertension, age, gender, abdominal obesity, smoking, physical activity index, and study field center. CVD participants with DM had significantly lower forced vital capacity than participants with CVD alone. Significant associations were observed between reduced pulmonary function, preclinical CVD, and prevalent CVD after adjustment for multiple CVD risk factors. During follow-up (median 13.3 years), pulmonary function did not predict CVD incidence, it predicted CVD mortality. Among 3,225 participants, 412 (298 without baseline CVD) died from CVD by the end of 2008. In models adjusted for multiple CVD risk factors, DM, metabolic syndrome, and baseline CVD, compared with highest quartile of lung function, lower lung function predicted CVD mortality (relative risk up to 1.5, 95% confidence interval 1.1 to 2.0, p <0.05). In conclusion, a population with a high prevalence of DM and metabolic syndrome and lower lung function was independently associated with prevalent clinical and preclinical CVD, and its impairment predicted CVD mortality. Additional research is needed to identify mechanisms linking metabolic abnormalities, low lung function, and CVD. [ABSTRACT FROM AUTHOR]

Objective: Important differences between men and women with asthma have been demonstrated, with women describing more symptoms and worse asthma-related quality of life (QOL) despite having similar or better pulmonary function. While current guidelines focus heavily on assessing asthma control, they lack information about whether sex-specific approaches to asthma assessment should be considered. We sought to determine if sex differences in asthma control or symptom profiles exist in the well-characterized population of participants in the American Lung Association Asthma Clinical Research Centers (ALA-ACRC) trials. Methods: We reviewed baseline data from four trials published by the ALA-ACRC to evaluate individual item responses to three standardized asthma questionnaires: the Juniper Asthma Control Questionnaire (ACQ), the multi-attribute Asthma Symptom Utility Index (ASUI), and Juniper Mini Asthma Quality of Life Questionnaire (mini-AQLQ). Results: In the poorly-controlled population, women reported similar overall asthma control (mean ACQ 1.9 vs. 1.8; p = 0.54), but were more likely to report specific symptoms such as nocturnal awakenings, activity limitations, and shortness of breath on individual item responses. Women reported worse asthma-related QOL on the mini-AQLQ (mean 4.5 vs. 4.9; p < 0.001) and more asthma-related symptoms with a lower mean score on the ASUI (0.73 vs. 0.77; p ≤ 0.0001) and were more likely to report feeling bothered by particular symptoms such as coughing, or environmental triggers. Conclusions: In participants with poorly-controlled asthma, women had outwardly similar asthma control, but had unique symptom profiles on detailed item analyses which were evident on evaluation of three standardized asthma questionnaires. [ABSTRACT FROM AUTHOR]

Summary: Community-acquired methicillin-resistant Staphylococcus aureus is increasingly recognized as an important pathogen causing skin and soft tissue infections. We report a case of severe necrotizing pneumonia caused by community-acquired methicillin-resistant S. aureus in a peripartum woman. This case illustrates that community-acquired methicillin-resistant S. aureus must be considered as a potential pathogen in severe community-acquired pneumonia. [Copyright &y& Elsevier]

Background Emerging studies suggest that enhanced glycolysis accompanies inflammatory responses. Virtually nothing is known about the relevance of glycolysis in patients with allergic asthma. Objectives We sought to determine whether glycolysis is altered in patients with allergic asthma and to address its importance in the pathogenesis of allergic asthma. Methods We examined alterations in glycolysis in sputum samples from asthmatic patients and primary human nasal cells and used murine models of allergic asthma, as well as primary mouse tracheal epithelial cells, to evaluate the relevance of glycolysis. Results In a murine model of allergic asthma, glycolysis was induced in the lungs in an IL-1–dependent manner. Furthermore, administration of IL-1β into the airways stimulated lactate production and expression of glycolytic enzymes, with notable expression of lactate dehydrogenase A occurring in the airway epithelium. Indeed, exposure of mouse tracheal epithelial cells to IL-1β or IL-1α resulted in increased glycolytic flux, glucose use, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL-1β– or IL-1α–mediated proinflammatory responses and the stimulatory effects of IL-1β on house dust mite (HDM)–induced release of thymic stromal lymphopoietin and GM-CSF from tracheal epithelial cells. Inhibitor of κB kinase ε was downstream of HDM or IL-1β and required for HDM-induced glycolysis and pathogenesis of allergic airways disease. Small interfering RNA ablation of lactate dehydrogenase A attenuated HDM-induced increases in lactate levels and attenuated HDM-induced disease. Primary nasal epithelial cells from asthmatic patients intrinsically produced more lactate compared with cells from healthy subjects. Lactate content was significantly higher in sputum supernatants from asthmatic patients, notably those with greater than 61% neutrophils. A positive correlation was observed between sputum lactate and IL-1β levels, and lactate content correlated negatively with lung function. Conclusions Collectively, these findings demonstrate that IL-1β/inhibitory κB kinase ε signaling plays an important role in HDM-induced glycolysis and pathogenesis of allergic airways disease. [ABSTRACT FROM AUTHOR]

Background The IL-1 family member IL-33 plays a critical role in type 2 innate immune responses to allergens and is an important mediator of allergic asthma. The mechanisms by which allergens provoke epithelial IL-33 secretion are still poorly understood. Objective Based on previous findings indicating involvement of the NADPH oxidase dual oxidase 1 (DUOX1) in epithelial wound responses, we explored the potential involvement of DUOX1 in allergen-induced IL-33 secretion and potential alterations in airways of asthmatic patients. Methods Cultured human or murine airway epithelial cells or mice were subjected to acute challenge with Alternaria alternata or house dust mite, and secretion of IL-33 and activation of subsequent type 2 responses were determined. The role of DUOX1 was explored by using small interfering RNA approaches and DUOX1-deficient mice. Cultured nasal epithelial cells from healthy subjects or asthmatic patients were evaluated for DUOX1 expression and allergen-induced responses. Results In vitro or in vivo allergen challenge resulted in rapid airway epithelial IL-33 secretion, which depended critically on DUOX1-mediated activation of epithelial epidermal growth factor receptor and the protease calpain-2 through a redox-dependent mechanism involving cysteine oxidation within epidermal growth factor receptor and the tyrosine kinase Src. Primary nasal epithelial cells from patients with allergic asthma were found to express increased DUOX1 and IL-33 levels and demonstrated enhanced IL-33 secretion in response to allergen challenge compared with values seen in nasal epithelial cells from nonasthmatic subjects. Conclusion Our findings implicate epithelial DUOX1 as a pivotal mediator of IL-33–dependent activation of innate airway type 2 immune responses to common airborne allergens and indicate that enhanced DUOX1 expression and IL-33 secretion might present important contributing features of allergic asthma. [ABSTRACT FROM AUTHOR]

Background Evidence for association between asthma and the unfolded protein response is emerging. Endoplasmic reticulum resident protein 57 (ERp57) is an endoplasmic reticulum–localized redox chaperone involved in folding and secretion of glycoproteins. We have previously demonstrated that ERp57 is upregulated in allergen-challenged human and murine lung epithelial cells. However, the role of ERp57 in asthma pathophysiology is unknown. Objectives Here we sought to examine the contribution of airway epithelium–specific ERp57 in the pathogenesis of allergic asthma. Methods We examined the expression of ERp57 in human asthmatic airway epithelium and used murine models of allergic asthma to evaluate the relevance of epithelium-specific ERp57. Results Lung biopsy specimens from asthmatic and nonasthmatic patients revealed a predominant increase in ERp57 levels in epithelium of asthmatic patients. Deletion of ERp57 resulted in a significant decrease in inflammatory cell counts and airways resistance in a murine model of allergic asthma. Furthermore, we observed that disulfide bridges in eotaxin, epidermal growth factor, and periostin were also decreased in the lungs of house dust mite–challenged ERp57-deleted mice. Fibrotic markers, such as collagen and α smooth muscle actin, were also significantly decreased in the lungs of ERp57-deleted mice. Furthermore, adaptive immune responses were dispensable for house dust mite–induced endoplasmic reticulum stress and airways fibrosis. Conclusions Here we show that ERp57 levels are increased in the airway epithelium of asthmatic patients and in mice with allergic airways disease. The ERp57 level increase is associated with redox modification of proinflammatory, apoptotic, and fibrotic mediators and contributes to airways hyperresponsiveness. The strategies to inhibit ERp57 specifically within the airways epithelium might provide an opportunity to alleviate the allergic asthma phenotype. [ABSTRACT FROM AUTHOR]

Background Chronic sinonasal disease is common in asthmatic patients and associated with poor asthma control; however, there are no long-term trials addressing whether chronic treatment of sinonasal disease improves asthma control. Objective We sought to determine whether treatment of chronic sinonasal disease with nasal corticosteroids improves asthma control, as measured by the Childhood Asthma Control Test and Asthma Control Test in children and adults, respectively. Methods A 24-week multicenter, randomized, placebo-controlled, double-blind trial of placebo versus nasal mometasone in adults and children with inadequately controlled asthma was performed. Treatments were randomly assigned, with concealment of allocation. Results Two hundred thirty-seven adults and 151 children were randomized to nasal mometasone versus placebo, and 319 participants completed the study. There was no difference in the Childhood Asthma Control Test score (difference in change with mometasone − change with placebo [ΔM − ΔP], −0.38; 95% CI, −2.19 to 1.44; P = .68; age 6-11 years) or the Asthma Control Test score (ΔM − ΔP, 0.51; 95% CI, −0.46 to 1.48; P = .30; age ≥12 years) in those assigned to mometasone versus placebo. In children and adolescents (age 6-17 years) there was no difference in asthma or sinus symptoms but a decrease in episodes of poorly controlled asthma defined by a decrease in peak flow. In adults there was a small difference in asthma symptoms measured by using the Asthma Symptom Utility Index (ΔM − ΔP, 0.06; 95% CI, 0.01 to 0.11; P < .01) and in nasal symptoms (sinus symptom score ΔM − ΔP, −3.82; 95% CI, −7.19 to −0.45; P = .03) but no difference in asthma quality of life, lung function, or episodes of poorly controlled asthma in adults assigned to mometasone versus placebo. Conclusions Treatment of chronic sinonasal disease with nasal corticosteroids for 24 weeks does not improve asthma control. Treatment of sinonasal disease in asthmatic patients should be determined by the need to treat sinonasal disease rather than to improve asthma control. [ABSTRACT FROM AUTHOR]

Background: Asthma in obese subjects is poorly understood, and these patients are often refractory to standard therapy. Objectives: We sought to gain insights into the pathogenesis and treatment of asthma in obese subjects by determining how obesity and bariatric surgery affect asthma control, airway hyperresponsiveness (AHR), and markers of asthmatic inflammation. Methods: We performed a prospective study of (1) asthmatic and nonasthmatic patients undergoing bariatric surgery compared at baseline and (2) asthmatic patients followed for 12 months after bariatric surgery. Results: We studied 23 asthmatic and 21 nonasthmatic patients undergoing bariatric surgery. At baseline, asthmatic patients had lower FEV1 and forced vital capacity and lower numbers of lymphocytes in bronchoalveolar lavage fluid. After surgery, asthmatic participants experienced significant improvements in asthma control (asthma control score, 1.55 to 0.74; P < .0001) and asthma quality of life (4.87 to 5.87, P < .0001). Airways responsiveness to methacholine improved significantly (methacholine PC20, 3.9 to 7.28, P = .03). There was a statistically significant interaction between IgE status and change in airways responsiveness (P for interaction = .01). The proportion of lymphocytes in bronchoalveolar lavage fluid and the production of cytokines from activated peripheral blood CD4+ T cells increased significantly. Conclusions: Bariatric surgery improves AHR in obese asthmatic patients with normal serum IgE levels. Weight loss has dichotomous effects on airway physiology and T-cell function typically involved in the pathogenesis of asthma, suggesting that obesity produces a unique phenotype of asthma that will require a distinct therapeutic approach. [ABSTRACT FROM AUTHOR]

Obesity is a major risk factor for asthma. Obese asthmatics exhibit poor symptom control, frequent exacerbation, and increased levels of reactive oxygen species (ROS). The consumption of a western diet, high in fat and carbohydrates, can both induce obesity and increase ROS. Oxidation of critical cysteine resides, due to high ROS, may hinder post-translational modifications required for proper protein function. Previous studies reported that increased cysteine oxidation, due to consumption of a high-fat diet (HFD), coincided with decreased protein S-acylation. Protein S-acylation is regulated by acyltransferases (zDHHCs) and thioesterases (PPT/APTs). To date, there have been no reports of the S-acylated protein profile in the lung and how it may be modified by comorbid disease. We hypothesize that identifying the pulmonary ‘palmitoylome’ will provide critical information and insight into pathogenesis of lung disease, including the pathophysiology of asthma. The lung ‘palmitoylome’ was profiled by LC-MS analysis of S-acylated proteins isolated from murine whole lung tissue. Additionally, to measure alterations of pulmonary S-acylation in obesity and asthma, we used whole lung tissue of lean and obese, or house dust mite (HDM) allergic, C57BL/6 mice. To assess whether gene expression of zDHHC or PPT/APT enzymes was altered in obesity or asthma, RT-PCR was performed from lung tissue cDNA from the aforementioned mice. Furthermore, a microarray was conducted from human nasal epithelial cells isolated from obese asthmatic and non-asthmatic patients. We identified several S-acylated proteins in murine lung tissue. Differences in protein S-acylation as a result of feeding a HFD, as well as HDM-induced asthma, were observed. Although, gene expression of zDHHC enzymes was not altered in lung tissue, PPT/APT genes were significantly altered in lean vs. obese and healthy vs. allergic lung tissue. PPT and zDHHC gene expression was differentially expressed in the nasal epithelial cells from obese control vs. obese asthmatic patients. In conclusion, both obesity and asthma exhibit an altered protein S-acylation profile in murine lung tissue and in primary nasal epithelial cells from human subjects, which may contribute to pulmonary pathophysiology. [ABSTRACT FROM AUTHOR]