1,472,348 research outputs found
Mechanisms of Lung Injury in a Mouse Model of Bronchopulmonary Dysplasia
No full textBronchopulmonary dysplasia (BPD) is a chronic lung disease that affects preterm infants. Increased levels of inflammatory mediators in the amniotic fluid and in the lungs of preterm infants are associated with the development of BPD. It has been shown that infant transgenic mice that express interleukin (IL)-1β in the lung epithelium from approximately embryonal day 14 (pseudoglandular stage of lung development) develop a pulmonary injury that resembles BPD, supporting the idea that inflammation plays an important role in the pathogenesis of BPD. The mechanisms by which inflammation causes lung injury have not been identified.
The aim of this thesis was to define mechanisms by which perinatal inflammatory lung injury develops by using transgenic mice that express IL-1β in the lung epithelium in an inducible manner.
The β6 integrin subunit has previously been shown to be involved in the progression of pulmonary diseases in adult mice. To investigate the involvement of the β6 integrin subunit in IL-1β-induced lung disease in the neonate, lung development of IL-1β-expressing mice lacking the β6 integrin subunit were compared with that of IL-1β-expressing mice with wild-type β6 loci. Absence of the β6 integrin subunit alleviated the IL-1β-induced lung injury, as demonstrated by smaller alveoli, thinner alveolar walls, and a milder lung inflammation than IL-1β-expressing mice with wild-type β6 integrin loci. The results suggest that the β6 integrin subunit plays a role in the development of neonatal lung disease.
Increased levels of matrix metalloproteinase (MMP)-9 and an imbalance between proteases and antiproteases in the lungs of infants and animals developing BPD have led to the hypothesis that MMP-9 may be involved in the pathogenesis of the disease. No differences in lung histology were detected between mice with wild-type MMP-9 loci and mice with null MMP-9 loci, implying a non-essential role of MMP-9 during lung development. However, IL-1β caused a more severe alveolar hypoplasia in mice deficient in MMP-9 than in MMP-9 wild-type mice, suggesting that MMP-9 may have a protective role during inflammatory lung injury.
A short-term exposure of IL-1 has been shown to accelerate development of the surfactant system in fetal rabbits and lambs. Using transgenic mice where the expression of IL-1β is restricted to the distal lung epithelium, the effects on lung development and function of chronic prenatal IL-1β production were studied. Distal lung expression of IL-1β disrupted acinar bud formation prior to birth and decreased the expression of the important surfactant proteins SP-B and SP-C. The 100% mortality observed among the IL-1β-expressing mice was probably due to the inflammation-induced structural changes and to deficient surfactant function. The results suggest that an early and continuous inflammatory stimulus in the distal lung epithelium causes severe lung injury and disrupts surfactant production
Biomaterials for in vitro models in lung research
No full textIn this chapter we introduce biomaterials science to a nonexpert reader in order to provide new perspectives for the development of in vitro three-dimensional models that are relevant in lung research. Specifically, we provide a comprehensive description of key concepts in the fields of biomaterials science and lung research to explain how merging them can give rise to new models of lung biology and disease that prevent overuse of animal models while making it possible to do tests in human lung cells and tissue. Along with the different examples of lung models reviewed here, we answer questions that can help a researcher in the lung field to understand the studies: what biomaterial, why this biomaterial, and how it has been used. Moreover, we discuss important findings and breakthroughs that have been made in the lung field with the use of biomaterials, and we comment on the advantages and disadvantages of these approaches
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Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function
Full text linkBackground: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. Methods: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. Results: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 × 10-7). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 × 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. Conclusions: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.Version of Recor
Deletion of vitamin D receptor leads to premature emphysema/COPD by increased matrix metalloproteinases and lymphoid aggregates formation
Full text linkDeficiency of vitamin D is associated with accelerated decline in lung function. Vitamin D is a ligand for nuclear hormone vitamin D receptor (VDR), and upon binding it modulates various cellular functions. The level of VDR is reduced in lungs of patients with chronic obstructive pulmonary disease (COPD) which led us to hypothesize that deficiency of VDR leads to significant alterations in lung phenotype that are characteristics of COPD/emphysema associated with increased inflammatory response. We found that VDR knock-out (VDR(-/-)) mice had increased influx of inflammatory cells, phospho-acetylation of nuclear factor-kappaB (NF-κB) associated with increased proinflammatory mediators, and up-regulation of matrix metalloproteinases (MMPs) MMP-2, MMP-9, and MMP-12 in the lung. This was associated with emphysema and decline in lung function associated with lymphoid aggregates formation compared to WT mice. These findings suggest that deficiency of VDR in mouse lung can lead to an early onset of emphysema/COPD because of chronic inflammation, immune dysregulation, and lung destruction
Nrf2 deficiency influences susceptibility to steroid resistance via HDAC2 reduction
Full text linkAbnormal lung inflammation and oxidant burden are associated with a significant reduction in histone deacetylase 2 (HDAC2) abundance and steroid resistance. We hypothesized that Nrf2 regulates steroid sensitivity via HDAC2 in response to inflammation in mouse lung. Furthermore, HDAC2 deficiency leads to steroid resistance in attenuating lung inflammatory response, which may be due to oxidant/antioxidant imbalance. Loss of antioxidant transcription factor Nrf2 resulted in decreased HDAC2 level in lung, and increased inflammatory lung response which was not reversed by steroid. Thus, steroid resistance or inability of steroids to control lung inflammatory response is dependent on Nrf2-HDAC2 axis. These findings have implications in steroid resistance, particularly during the conditions of oxidative stress when the lungs are more susceptible to inflammatory response, which is seen in patients with chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, and inflammatory bowel disease
Missed opportunities for tuberculosis diagnosis.
Full text linkBACKGROUND: In high tuberculosis (TB) burden, resource-poor countries, sputum smear microscopy remains the mainstay of diagnosis. The low sensitivity of this test means that patients with smear-negative but culture-positive TB pass undetected through the health care system. Such clinical episodes are missed opportunities for diagnosis and interruption of transmission, which might be averted through the application of more sensitive diagnostic tests. OBJECTIVES: To estimate the proportion of incident TB cases that might have been detected earlier than the actual date of diagnosis if a test more sensitive than smear microscopy had been used at an earlier presentation episode. METHOD: Retrospective cohort study in urban Peru, investigating health care facility interactions for symptoms suggestive of TB prior to TB diagnosis through patient interviews and a review of clinical records. RESULTS: Of 212 participants enrolled, 58% had one or more clinical interactions prior to their diagnostic episode. Of those with a prior episode, the median number of episodes was three. The median delay to diagnosis from first presentation was 26 days. CONCLUSION: There are clear missed opportunities for earlier TB diagnosis, delaying treatment initiation and continued spread of Mycobacterium tuberculosis to the community. The implementation of sensitive diagnostic tests appropriate to resource-poor settings should be given high priority
Blueprint Of Services For Lung Cancer
Full text linkPrimary lung cancer is the commonest malignant disease in the developed world, and is the
most prevalent form of cancer among men over 65 years. It continues to rise in those aged
over 75 years. Mortality from lung cancer is increasing in women. The condition still has a
short clinical course and a poor prognosis. The literature is in agreement about the effectiveness
of preventing lung cancer incidence by targeting smoking behaviour, particularly in preventing
young people taking up smoking. There is further consensus about the lack of a population
screening method which can be recommended, and the desirability of detecting non-small cell
lung cancer early enough for surgical intervention. The effectiveness of treatment for advanced
disease is less marked, and it is of concern that many people who present with lung cancer are
unsuitable for surgical intervention. The role of palliative care is critical in this condition and
this care should be introduced early in the interaction between the patient and the services
The five-item Brief-Symptom Rating Scale as a suicide ideation screening instrument for psychiatric inpatients and community residents
Full text linkAbstract Background An efficient screening instrument which can be used in diverse settings to predict suicide in different populations is vital. The aim of this study was to use the five-item Brief Symptom Rating Scale (BSRS-5) as a screening instrument for the prediction of suicide ideation in psychiatric, community and general medical settings. Methods Five hundred and one psychiatric, 1,040 community and 969 general medical participants were recruited. The community participants completed a structured telephone interview, and the other two groups completed the self-report BSRS-5 questionnaire. Results The logistic regression analysis showed that the predictors of suicide ideation for the psychiatric group were depression, hostility and inferiority (p p = 0.016, p = 0.011), for the community group, inferiority, hostility and insomnia (p p p = 0.003), and for the general medical group, inferiority, hostility, depression and insomnia (p p = 0.001, p = 0.020, p = 0.008). The structural equation model showed the same symptom domains that predicted suicide ideation for all three groups. The receiver operating characteristic curve using the significant symptom domains from logistic regression showed that for the psychiatric group, the optimal cut-off point was 4/5 for the total of the significant dimensions (positive predictive value [PPV] = 78.01%, negative predictive value [NPV] = 79.05%), for the community group, 7/8 (PPV = 68.75%, NPV = 96.09%), and for the general medical group, 12/13 (PPV = 92.86%, NPV = 88.48%). Conclusion The BSRS-5 is an efficient tool for the screening of suicide ideation-prone psychiatric inpatients, general medical patients, and community residents. Understanding the discriminative symptom domains for different groups and the relationship between them can help health care professionals in their preventative programs and clinical treatment.</p
Five-year lung cancer mortality risk analysis and topography in Xuan Wei: a spatiotemporal correlation analysis
Full text linkAbstract Background In Xuan Wei, China, the lung cancer mortality rate is rising significantly more than that of the nation overall. However, it remains unclear 1) if improved diagnosis can just partially explain this observation and how other local risk factors may be correlated with the lung cancer mortality rate and 2) how the lung cancer mortality rates differ within Xuan Wei and how these spatiotemporal patterns are linked with local risk factors. To increase etiological knowledge, this study evaluated the spatial and temporal distributions of the health effects (the lung cancer mortality rates) from 2011 to 2015. Methods Four steps of spatial analysis were applied, as follows: 1) hotspot analysis to determine the geographical patterns of lung cancer mortality, 2) spatially-weighted sum to identify areas with higher health risks, 3) bivariate statistical analysis to assess the overall correlation between coal mines and lung cancer mortality, and 4) geographically-weighted regression to test for correlations among different towns within Xuan Wei. Results Women had higher lung cancer mortality rates than those in men, with an increasing trend in both sexes over time. The incidence rates in Laibin Town were the highest in Xuan Wei every year. Over the 5-year study period, the lung cancer mortality was increasingly concentrated in Laibin, Shuanglong, and Longchang, where the smoky coal mines are most concentrated. The population-level health risks from the coal mine in Xuan Wei were mapped and divided into five types of risk areas (Type I – Type IV). Correlation analysis revealed that there was no significant correlation between lung cancer mortality as a whole and coal mine distribution during the 5-year study period. However, the geographically-weighted regression revealed a stronger correlation in medium (Type III) and second-lowest (Type IV) health risks. Conclusions Xuan Wei lung cancer mortality has increased continuously since the third national retrospective surveys on the causes of death by the Ministry of Health of the People’s Republic of China (2004–2005), especially for local women and residents over 35 years of age. Geographically, lung cancer in Xuan Wei showed unique spatiotemporal clustering. The local lung cancer mortality was significantly correlated with the smoky coal mine geographically. Some specific towns (Laibin, Shuanglong, and Longchang) within Xuan Wei manifested high correlations between lung cancer mortality and coal mines. The effects of coal mines on lung cancer mortality rates also spread geographically outward from these areas. Public health concern regarding lung cancer in Xuan Wei should prioritize higher-risk towns surrounded by smoking coal mines. Intervention strategies for particular toxic coal types require further studies on their chemical characteristics and mechanisms of carcinogenesis. Additional studies are also warranted to systematically examine the local environmental health risks related to coal industries and combustion air pollution and eventually to conduct early screening of lung cancer for local people who are more exposed to smoky coal in high-risk areas
Metabolic Signatures of Lung Cancer in Biofluids: NMR-Based Metabonomics of Blood Plasma
Full text linkIn this work, the variations in the metabolic profile of blood plasma from lung cancer patients and healthy controls were investigated through NMR-based metabonomics, to assess the potential of this approach for lung cancer screening and diagnosis. PLS-DA modeling of CPMG spectra from plasma, subjected to Monte Carlo Cross Validation, allowed cancer patients to be discriminated from controls with sensitivity and specificity levels of about 90%. Relatively lower HDL and higher VLDL + LDL in the patients' plasma, together with increased lactate and pyruvate and decreased levels of glucose, citrate, formate, acetate, several amino acids (alanine, glutamine, histidine, tyrosine, valine), and methanol, could be detected. These changes were found to be present at initial disease stages and could be related to known cancer biochemical hallmarks, such as enhanced glycolysis, glutaminolysis, and gluconeogenesis, together with suppressed Krebs cycle and reduced lipid catabolism, thus supporting the hypothesis of a systemic metabolic signature for lung cancer. Despite the possible confounding influence of age, smoking habits, and other uncontrolled factors, these results indicate that NMR-based metabonomics of blood plasma can be useful as a screening tool to identify suspicious cases for subsequent, more specific radiological tests, thus contributing to improved disease management.ERDF - Competitive Factors Thematic Operational ProgrammeFCT/PTDC/ QUI/68017/2006FCOMP-01-0124-FEDER-007439SFRH/BD/ 63430/2009National UNESCO Committee - L'Oréal Medals of Honor for Women in Science 200Portuguese National NMR Network - RNRM
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