2,501 research outputs found

    Endothelin-1 directs airway remodeling and hyper-reactivity in a murine asthma model

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    BACKGROUND: The current paradigm describing asthma pathogenesis recognizes the central role of abnormal epithelial function in the generation and maintenance of the disease. However, the mechanisms responsible for the initiation of airway remodeling, which contributes to decreased lung function, remain elusive. Therefore, we aimed to determine the role of altered pulmonary gene expression in disease inception and identify proremodeling mediators. METHODS: Using an adenoviral vector, we generated mice overexpressing smad2, a TGF-β and activin A signaling molecule, in the lung. Animals were exposed to intranasal ovalbumin (OVA) without systemic sensitization. RESULTS: Control mice exposed to inhaled OVA showed no evidence of pulmonary inflammation, indices of remodeling, or airway hyper-reactivity. In contrast, local smad2 overexpression provoked airway hyper-reactivity in OVA-treated mice, concomitant with increased airway smooth muscle mass and peribronchial collagen deposition. Pulmonary eosinophilic inflammation was not evident, and there was no change in serum IgE or IgG1 levels. The profound remodeling changes were not mediated by classical pro-inflammatory Th2 cytokines. However, uric acid and interleukin-1β levels in the lung were increased. Epithelial-derived endothelin-1 and fibroblast growth factor were also augmented in smad2-expressing mice. Blocking endothelin-1 prevented these phenotypic changes. CONCLUSIONS: Innate epithelial-derived mediators are sufficient to drive airway hyper-reactivity and remodeling in response to environmental insults in the absence of overt Th2-type inflammation in a model of noneosinophilic, noninflammed types of asthma. Targeting potential asthma therapies to epithelial cell function and modulation of locally released mediators may represent an effective avenue for therapeutic design

    Activated TLR Signaling in Atherosclerosis among Women with Lower Framingham Risk Score: The Multi-Ethnic Study of Atherosclerosis

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    Atherosclerosis is the leading cause of cardiovascular disease (CVD). Traditional risk factors can be used to identify individuals at high risk for developing CVD and are generally associated with the extent of atherosclerosis; however, substantial numbers of individuals at low or intermediate risk still develop atherosclerosis.A case-control study was performed using microarray gene expression profiling of peripheral blood from 119 healthy women in the Multi-Ethnic Study of Atherosclerosis cohort aged 50 or above. All participants had low (<10%) to intermediate (10% to 20%) predicted Framingham risk; cases (N = 48) had coronary artery calcium (CAC) score >100 and carotid intima-media thickness (IMT) >1.0 mm, whereas controls (N = 71) had CAC<10 and IMT <0.65 mm. We identified two major expression profiles significantly associated with significant atherosclerosis (odds ratio 4.85; P<0.001); among those with Framingham risk score <10%, the odds ratio was 5.30 (P<0.001). Ontology analysis of the gene signature reveals activation of a major innate immune pathway, toll-like receptors and IL-1R signaling, in individuals with significant atherosclerosis.Gene expression profiles of peripheral blood may be a useful tool to identify individuals with significant burden of atherosclerosis, even among those with low predicted risk by clinical factors. Furthermore, our data suggest an intimate connection between atherosclerosis and the innate immune system and inflammation via TLR signaling in lower risk individuals

    Prolegomenon to the Comparison of Stylistic Features of Hungarian and Croatian Manor Houses in Historicism

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    Bogate hrvatsko-mađarske kulturne i arhitektonske veze proizlaze iz više od osam stoljeća dugog suživota unutar istoga kraljevstva. U članku koji je rezultat istraživanja ladanjske arhitekture Mađarske i Hrvatske, autori donose pregled dvoraca obiju zemalja, ponajprije onih izgrađenih u doba historicizma. Dvorci su analizirani, strukturirani i predstavljeni prema glavnim stilskim tendencijama toga doba.Croatian-Hungarian cultural and architectural relations are the result of more than eight centuries long cohabitation in the same kingdom. In the paper, which is the result of a research on country house building in Hungary and in Croatia, the authors present an overview of manors built in both countries, focusing on those built in the age of historicism. The manors are analysed, sorted, and presented according to the main stylistic trends of that period

    Pulmonary epithelial cell-derived cytokine TGF-β1 Is a critical cofactor for enhanced innate lymphoid cell function

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    SummaryEpithelial cells orchestrate pulmonary homeostasis and pathogen defense and play a crucial role in the initiation of allergic immune responses. Maintaining the balance between homeostasis and inappropriate immune activation and associated pathology is particularly complex at mucosal sites that are exposed to billions of potentially antigenic particles daily. We demonstrated that epithelial cell-derived cytokine TGF-β had a central role in the generation of the pulmonary immune response. Mice that specifically lacked epithelial cell-derived TGF-β1 displayed a reduction in type 2 innate lymphoid cells (ILCs), resulting in suppression of interleukin-13 and hallmark features of the allergic response including airway hyperreactivity. ILCs in the airway lumen were primed to respond to TGF-β by expressing the receptor TGF-βRII and ILC chemoactivity was enhanced by TGF-β. These data demonstrate that resident epithelial cells instruct immune cells, highlighting the central role of the local environmental niche in defining the nature and magnitude of immune reactions

    Pulmonary Epithelial Cell-Derived Cytokine TGF-β1 Is a Critical Cofactor for Enhanced Innate Lymphoid Cell Function.

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    Epithelial cells orchestrate pulmonary homeostasis and pathogen defense and play a crucial role in the initiation of allergic immune responses. Maintaining the balance between homeostasis and inappropriate immune activation and associated pathology is particularly complex at mucosal sites that are exposed to billions of potentially antigenic particles daily. We demonstrated that epithelial cell-derived cytokine TGF-β had a central role in the generation of the pulmonary immune response. Mice that specifically lacked epithelial cell-derived TGF-β1 displayed a reduction in type 2 innate lymphoid cells (ILCs), resulting in suppression of interleukin-13 and hallmark features of the allergic response including airway hyperreactivity. ILCs in the airway lumen were primed to respond to TGF-β by expressing the receptor TGF-βRII and ILC chemoactivity was enhanced by TGF-β. These data demonstrate that resident epithelial cells instruct immune cells, highlighting the central role of the local environmental niche in defining the nature and magnitude of immune reactions

    High Cholesterol Awareness, Treatment, and Control Among Hispanic/Latinos: Results From the Hispanic Community Health Study/Study of Latinos

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    BackgroundWe assessed high cholesterol (HC) awareness, treatment, and control rates among US Hispanic/Latino adults and describe factors associated with HC awareness and management.Methods and ResultsBaseline data (collected 2008–2011) from a multisite probability sample of Hispanic/Latino adults in the Hispanic Community Health Study/Study of Latinos (18 to 74years old; N=16207) were analyzed. HC was defined as low-density lipoprotein-cholesterol ≥130mg/dL and/or total cholesterol ≥240mg/dL or use of cholesterol-lowering medication. Among Hispanic/Latino adults with HC, almost half (49.3%) were not aware of their condition and only 29.5% were receiving treatment. Men had a higher HC prevalence than women (44.0% versus 40.5%) but a lower rate of treatment (28.1% versus 30.6%). Younger adults were significantly less likely to be HC aware compared to those who were older. Those with hypertension, diabetes, and high socioeconomic position were more likely to be HC aware. US-born Hispanic/Latino were more likely to be HC unaware than foreign-born Hispanics/Latinos, but longer US residency was significantly associated with being HC aware, treated, and controlled. Cholesterol control was achieved among 64.3% of those who were HC treated. However, younger adults, women, those with lower income, those uninsured, and more recent immigrants were less likely to be HC controlled. Individuals of Puerto Rican or Dominican background were most likely to be HC aware and treated, whereas those of Mexican or Central American background were least likely to be HC treated. Individuals of Cuban and South American background had the lowest rates of HC control, whereas Puerto Ricans had the highest.ConclusionsUnderstanding gaps in HC awareness, treatment, and control among US Hispanic/Latino adults can help inform physicians and policymakers to improve disease management and patient education programs
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