184,319 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
Role of antibodies and T cells in pigeon fanciers' lung
No full textAbstract: Introduction: Pigeon fanciers’ lung (PFL) is one of the most common forms of hypersensitivity pneumonitis (HP) in the UK. Generally it is considered that PFL is caused by immune complexes, however, this does not explain why some fanciers are asymptomatic despite the presence of high levels of anti-avian antigen antibodies in their serum. Pigeon intestinal mucin (PIM) is considered to be an important antigen in PFL. Thus this study was designed in order to understand the role of specific antibodies and T cells in the pathogenesis of PFL. Methods: Anti-avian IgG and IgG subclass responses among 50 symptomatic and 50 asymptomatic pigeon fanciers were determined by ELISA and the functional affinity of IgG1 and IgG2 against a range of pigeon antigens was determined by inhibition ELISA and microcalimetry. Mucin-specific T cell clones were also generated from pigeon fanciers and T cell phenotypes and cytokine profile of these cells were identified. Results: The median titres of IgG1 and IgG2 against all the pigeon antigens tested was always higher in asymptomatic than symptomatic fanciers and these differences were significant for anti-PS IgG1 (P=0.04), anti-PDF IgG2 (P=0.028), anti-PDO IgG2 (P=0.04) and anti-PIS IgG2 (P=0.03). The functional affinity of IgG1 and IgG2 against PDO was higher in symptomatic individuals as compared to asymptomatic fanciers (P=0.006 and P=0.002, respectively) whilst the functional affinity of anti-PDF IgG2 was also significantly higher in these patients (P?0.001). Symptomatic fanciers were also significantly more likely to have high ?H and thus had higher avidity antibodies against PDO (P=0.044). 12 T cell clones specific for t mucin also were generated from an asymptomatic fancier and 90-96% of clone 04, 22, 23 were CD4-CD8- double negative (DN). Conclusion: The data suggests that the magnitude of the serum antibody response cannot determine the development of the disease and as symptomatic fanciers had higher IgG antibody avidities and therefore immune complexes in individuals with PFL may have a stronger composition and bonds. In addition, this is the first demonstration of the use of ITC to measure antibody avidity in a clinical situation. This is a rapid and simple method of measuring antibody avidity and has a diagnostic potential in PFL. Finally t mucin-specific T cell clones with double negative phenotype may have a crucial role in immune regulation in asymptomatic fanciers and can be one of the reasons why these individuals do not have any symptoms in spite of having high antibody responses
Nrf2 deficiency influences susceptibility to steroid resistance via HDAC2 reduction
Get PDFAbnormal 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
The avian lung-associated immune system
Get PDFThe lung is a major target organ for numerous viral and bacterial diseases of poultry. To control this constant threat birds have developed a highly organized lung-associated immune system. In this review the basic features of this system are described and their functional properties discussed. Most prominent in the avian lung is the bronchus-associated lymphoid tissue (BALT) which is located at the junctions between the primary bronchus and the caudal secondary bronchi. BALT nodules are absent in newly hatched birds, but gradually developed into the mature structures found from 6–8 weeks onwards. They are organized into distinct B and T cell areas, frequently comprise germinal centres and are covered by a characteristic follicle-associated epithelium. The interstitial tissue of the parabronchial walls harbours large numbers of tissue macrophages and lymphocytes which are scattered throughout tissue. A striking feature of the avian lung is the low number of macrophages on the respiratory surface under non-inflammatory conditions. Stimulation of the lung by live bacteria but not by a variety of bacterial products elicits a significant efflux of activated macrophages and, depending on the pathogen, of heterophils. In addition to the cellular components humoral defence mechanisms are found on the lung surface including secretory IgA. The compartmentalisation of the immune system in the avian lung into BALT and non BALTregions should be taken into account in studies on the host-pathogen interaction since these structures may have distinct functional properties during an immune response
Deletion of vitamin D receptor leads to premature emphysema/COPD by increased matrix metalloproteinases and lymphoid aggregates formation
Get PDFDeficiency 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
Heterogeneous and tissue-specific regulation of effector T cell responses by IFN-gamma during Plasmodium berghei ANKA infection.
Get PDFIFN-γ and T cells are both required for the development of experimental cerebral malaria during Plasmodium berghei ANKA infection. Surprisingly, however, the role of IFN-γ in shaping the effector CD4(+) and CD8(+) T cell response during this infection has not been examined in detail. To address this, we have compared the effector T cell responses in wild-type and IFN-γ(-/-) mice during P. berghei ANKA infection. The expansion of splenic CD4(+) and CD8(+) T cells during P. berghei ANKA infection was unaffected by the absence of IFN-γ, but the contraction phase of the T cell response was significantly attenuated. Splenic T cell activation and effector function were essentially normal in IFN-γ(-/-) mice; however, the migration to, and accumulation of, effector CD4(+) and CD8(+) T cells in the lung, liver, and brain was altered in IFN-γ(-/-) mice. Interestingly, activation and accumulation of T cells in various nonlymphoid organs was differently affected by lack of IFN-γ, suggesting that IFN-γ influences T cell effector function to varying levels in different anatomical locations. Importantly, control of splenic T cell numbers during P. berghei ANKA infection depended on active IFN-γ-dependent environmental signals--leading to T cell apoptosis--rather than upon intrinsic alterations in T cell programming. To our knowledge, this is the first study to fully investigate the role of IFN-γ in modulating T cell function during P. berghei ANKA infection and reveals that IFN-γ is required for efficient contraction of the pool of activated T cells
CD25(+) Natural Regulatory T Cells Are Critical in Limiting Innate and Adaptive Immunity and Resolving Disease following Respiratory Syncytial Virus Infection
Get PDFRegulatory CD4(+) T cells have been shown to be important in limiting immune responses, but their role in respiratory viral infections has received little attention. Here we observed that following respiratory syncytial virus (RSV) infection, CD4(+) Foxp3(+) CD25(+) natural regulatory T-cell numbers increased in the bronchoalveolar lavage fluid, lung, mediastinal lymph nodes, and spleen. The depletion of CD25(+) natural regulatory T cells prior to RSV infection led to enhanced weight loss with delayed recovery that was surprisingly accompanied by increased numbers of activated natural killer cells in the lung and bronchoalveolar lavage fluid on day 8 postinfection. Increased numbers of neutrophils were also detected within the bronchoalveolar lavage fluid and correlated with elevated levels of myeloperoxidase as well as interleukin-6 (IL-6) and gamma interferon (IFN-gamma). CD25(+) natural regulatory T-cell depletion also led to enhanced numbers of proinflammatory T cells producing IFN-gamma and tumor necrosis factor alpha (TNF-alpha) in the lung. Despite these increases in inflammatory responses and disease severity, the viral load was unaltered. This work highlights a critical role for natural regulatory T cells in regulating the adaptive and innate immune responses during the later stages of lung viral infections
PDGF-Producing CD4+ Foxp3+ Regulatory T Lymphocytes Promote Lung Fibrosis.
No full textRATIONALE: There is evidence that CD4(+) effector T lymphocytes (T eff) participate in the development of lung fibrosis but the role of their CD4(+) regulatory T cell counterparts (T regs) remains to be determined. OBJECTIVES: To elucidate the contribution of T regs in a mouse model of lung fibrosis induced by silica particles. METHODS: Lung T regs and T eff purified from silica-treated Foxp3-GFP transgenic mice were co-cultured with naive lung fibroblasts or transferred in the lung of healthy mice. DEREG mice which express the diphtheria toxin receptor (DTR) under the control of the foxp3 gene were used to deplete T regs during fibrogenesis. MEASUREMENTS AND MAIN RESULTS: CD4(+) Foxp3(+) T regs were persistently recruited in the lungs in response to silica. T reg accumulation paralleled the establishment of pulmonary immunosuppression and fibrosis. T regs highly expressed the growth factor PDGF-B via a TGF-β autocrine signaling pathway, directly stimulated fibroblast proliferation in vitro and increased lung collagen deposition upon transfer in the lung of naive mice. The direct profibrotic effects of T regs were completely abolished by the inhibitor of the PDGF-B/TGF-β signaling pathway, imatinib mesylate. Neutralization of T reg-immunosuppressive activity resulted in enhanced accumulation of T eff and IL-4-driven pulmonary fibrogenesis, further demonstrating that T regs control T eff functions during inflammatory fibrosis. CONCLUSIONS: Our study indicates that T regs contribute to lung fibrosis by stimulating fibroblasts through the secretion of PDGF-B in non-inflammatory conditions and regulate detrimental T eff activities during inflammation-related fibrosis
Immunotherapy of lung cancer: An update
Get PDFIn Germany lung cancer is the leading cause of cancer-associated death in men. Surgery, chemotherapy and radiation may enhance survival of patients suffering from lung cancer but the enhancement is typically transient and mostly absent with advanced disease; eventually more than 90% of lung cancer patients will die of disease. New approaches to the treatment of lung cancer are urgently needed. Immunotherapy may represent one new approach with low toxicity and high specificity but implementation has been a challenge because of the poor antigenic characterization of these tumors and their ability to escape immune responses. Several different immunotherapeutic treatment strategies have been developed. This review examines the current state of development and recent advances with respect to non-specific immune stimulation, cellular immunotherapy ( specific and non-specific), therapeutic cancer vaccines and gene therapy for lung cancer. The focus is primarily placed on immunotherapeutic cancer treatments that are already in clinical trial or well progressed in preclinical studies. Although there seems to be a promising future for immunotherapy in lung cancer, presently there is not standard immunotherapy available for clinical routine
Lung Cancer in Pulmonary Fibrosis: Tales of Epithelial Cell Plasticity
Get PDFLung epithelial cells exhibit a high degree of plasticity. Alterations to lung epithelial cell function are critically involved in several chronic lung diseases such as pulmonary fibrosis. Pulmonary fibrosis is characterized by repetitive injury and subsequent impaired repair of epithelial cells, which leads to aberrant growth factor activation and fibroblast accumulation. Increased proliferation and hyper- and metaplasia of epithelial cells upon injury have also been observed in pulmonary fibrosis; this epithelial cell activation might represent the basis for lung cancer development. Indeed, several studies have provided histopathological evidence of an increased incidence of lung cancer in pulmonary fibrosis. The mechanisms involved in the development of cancer in pulmonary fibrosis, however, remain poorly understood. This review highlights recently uncovered molecular mechanisms shared between lung cancer and fibrosis, which extend the current evidence of a common trait of cancer and fibrosis, as provided by histopathological observations. Copyright (C) 2011 S. Karger AG, Base
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