Lung cancer is one of the leading causes of cancer related death worldwide with more than a million deaths per year. The poor prognosis is due to its high aggressiveness and its early metastasis. ...Although the exact mechanisms are still unknown, the process of epithelial to mesenchymal transition (EMT) seems to be involved in these neoplastic processes. We already demonstrated that serum levels of CCL18, a primate specific chemokine, are highly elevated in patients with lung cancer and correlate with their survival time of patients with adenocarcinoma of the lung. Therefore, we hypothesized that CCL18 may be directly involved in pathological processes of lung cancer, e.g. EMT. We investigated the effect of CCL18 on A549, an adenocarcinoma cell line of the lung, on EMT and other cell functions like proliferation, chemotaxis, invasion, chemoresistance and proliferation. Exposure of A549 lung cancer cells to CCL18 in various concentrations decreases the epithelial marker E-cadherin, whereas FSP-1, a marker of the mesenchymal phenotype increases. Accordingly, CCL18 induced the transcriptional EMT regulator SNAIL1 in a dose dependent fashion. In contrast, an increasing CCL18 concentration was associated with a decline of cell proliferation rate. In addition, CCL18 induced chemotaxis of these cells and increased their chemoresistance. Therefore, CCL18 may be an interesting therapeutic target for NSCLC.
Pulmonary sarcoidosis presents substantial management challenges, with limited evidence on effective therapies and phenotypes. In the absence of definitive evidence, expert consensus can supply ...clinically useful guidance in medicine. An international panel of 26 experts participated in a Delphi process to identify consensus on pharmacological management in sarcoidosis with the development of preliminary recommendations.The modified Delphi process used three rounds. The first round focused on qualitative data collection with open-ended questions to ensure comprehensive inclusion of expert concepts. Rounds 2 and 3 applied quantitative assessments using an 11-point Likert scale to identify consensus.Key consensus points included glucocorticoids as initial therapy for most patients, with non-biologics (immunomodulators), usually methotrexate, considered in severe or extrapulmonary disease requiring prolonged treatment, or as a steroid-sparing intervention in cases with high risk of steroid toxicity. Biologic therapies might be considered as additive therapy if non-biologics are insufficiently effective or are not tolerated with initial biologic therapy, usually with a tumour necrosis factor-α inhibitor, typically infliximab.The Delphi methodology provided a platform to gain potentially valuable insight and interim guidance while awaiting evidenced-based contributions.
ABSTRACT
The practise of modern medicine is unthinkable without biological markers, and their adoption is now established in various clinical settings. Pulmonary fibrosis occurs in a heterogeneous ...group of diseases. IPF is the most frequent fibrotic lung disease and has a poor prognosis. Despite the heterogeneity in underlying diseases multiple common mechanism resulting in pulmonary fibrosis are documented. In this context, several biomarkers for pulmonary fibrosis have been described. Some substances are produced by alveolar epithelial cells such as surfactant proteins A and D, the glycoprotein Krebs von den Lungen 6 Antigen, while others are derived from macrophages such as CCL18. Most recently, increased fibrocyte counts were proposed as a marker of acute exacerbation in IPF. None of these markers is established in clinical practise so far. Studies regarding the clinical value of biomarkers in pulmonary fibrosis are hampered by the fact that fibrotic lung diseases are uncommon and variable in course. However, some markers are clearly promising, and as a spin‐off the analysis of some of these in samples from recently finished pharmacological multicentric studies might give urgently needed information regarding their clinical value.
Chronic beryllium disease (CBD), a granulomatous disease with similarities to sarcoidosis, arises only in individuals exposed to beryllium. Inhaled beryllium can elicit a T-cell-dominated alveolitis ...leading nonnecrotizing granulomata. CBD can be distinguished from sarcoidosis by demonstrating beryllium sensitization in a lymphocyte proliferation test.
Beryllium exposure usually occurs in an occupational setting. Because of the diagnosis of CBD in a patient without evident beryllium exposure, we performed a beryllium-lymphocyte proliferation test (BeLPT) among his work colleagues.
This field study investigated a cohort of work colleagues without obvious beryllium exposure. Twenty-one of 30 individuals were assessed in our outpatient clinic for beryllium sensitization. Therefore, BeLPT was performed with freshly collected peripheral blood mononuclear cells. Data were extracted from clinical charts, including geographical data. Beryllium content in dust samples collected at the workplace was measured by graphite-furnace atomic absorption spectroscopy and was compared with samples from different areas of Germany.
For the initial patient, the diagnosis of sarcoidosis was reclassified as CBD based on two positive BeLPT results. Assessment of his workplace did not identify a source of beryllium. However, BeLPTs performed on his workmates demonstrated beryllium sensitization in 5 of 21 individuals, suggesting a local beryllium source. Concrete dust obtained from the building yard, the workplace of the index patient, contained high amounts of beryllium (1138 ± 162 μg/kg), whereas dust from other localities (control samples) showed much lower beryllium content (range, 147 ± 18-452 ± 206 μg/kg). Notably, the control dust collected from different places all over Germany exhibit different beryllium concentrations.
We describe a cluster of beryllium-sensitized workers from an industry not related to beryllium caused by environmental exposure to beryllium-containing concrete dust, which exhibited markedly elevated beryllium content. Importantly, analyses of dust samples collected from different localities showed that they contain markedly different amounts of beryllium. Thus, besides workplace-related exposure, environmental factors also are capable of eliciting a beryllium sensitization.
Evidence suggests that tumor necrosis factor (TNF)-alpha plays an important role in the pathophysiology of sarcoidosis.
To assess the efficacy of infliximab in sarcoidosis.
A phase 2, multicenter, ...randomized, double-blind, placebo-controlled study was conducted in 138 patients with chronic pulmonary sarcoidosis. Patients were randomized to receive intravenous infusions of infliximab (3 or 5 mg/kg) or placebo at Weeks 0, 2, 6, 12, 18, and 24 and were followed through Week 52.
The primary endpoint was the change from baseline to Week 24 in percent of predicted FVC. Major secondary efficacy parameters included Saint George's Respiratory Questionnaire, 6-min walk distance, Borg's CR10 dyspnea score, and the proportion of Lupus Pernio Physician's Global Assessment responders for patients with facial skin involvement. Patients in the combined infliximab groups (3 and 5 mg/kg) had a mean increase of 2.5% from baseline to Week 24 in the percent of predicted FVC, compared with no change in placebo-treated patients (p = 0.038). No significant differences between the treatment groups were observed for any of the major secondary endpoints at Week 24. Results of post hoc exploratory analyses suggested that patients with more severe disease tended to benefit more from infliximab treatment.
Infliximab therapy resulted in a statistically significant improvement in % predicted FVC at Week 24. The clinical importance of this finding is not clear. The results of this Phase 2 clinical study support further evaluation of anti-TNF-alpha therapy in severe, chronic, symptomatic sarcoidosis.
Abstract Activated macrophages have been characterized as M1 and M2 according to their inflammatory response pattern. Here we analyzed the M2 marker expression and intracellular signal transduction ...in the course of cytokine-driven differentiation. We found elevated spontaneous production of the chemokines CCL17, CCL18 and CCL22 and increased expression of CD206 by alveolar macrophages from patients with lung fibrosis. Stimulation of normal human AM with Th2 cytokines IL-4 and/or IL-10 in vitro revealed IL-4 as the most powerful inducer of M2-phenotype in AM and monocytes. Importantly, IL-10 enhanced IL-4-induced expression of CCL18 and IL-1RA in a synergistic fashion. IL-4/IL-10 stimulation induces a strong activation of STAT3 in AM from fibrosis patients. These results suggest an important role for M2 polarized AM in the pathogenesis of pulmonary fibrosis and indicate that both IL-4 and IL-10 account for human AM phenotype shift to M2, as seen in patients with fibrotic interstitial lung diseases.
Cough is one of the most common symptoms in general and pulmonary medicine with profound negative impact on health-related quality of life (HRQL). The Leicester Cough Questionnaire (LCQ) is a ...validated HRQL questionnaire, yet a validated German version of the LCQ is not available and it has never been tested in a cohort with sarcoidosis.
To translate the LCQ into German and determine its psychometric properties.
The LCQ was translated in a forward-backward approach. Structured interviews in sarcoidosis patients were performed. Subsequently, sarcoidosis patients were asked to answer the German LCQ and comparative questionnaires. Distribution properties, item difficulty, concurrent validity, Rasch model fit and internal consistency of the German LCQ were determined.
200 patients with sarcoidosis were included. We provide evidence for reliability, unidimensionality and internal consistency. However, only a moderate correlation with general and respiratory-specific HRQL questionnaires, no Rasch model fit could be shown. Skewed responses caused by floor effects were detected.
We demonstrate that the German LCQ is valid and reliable and its psychometric properties fulfil the standards required for its use in clinical settings as well as in interventional trials.
Recently, models of macrophage activation have been revised. Macrophages stimulated with Th2 cytokines have been classified as alternatively activated.
This article examines the expression and ...regulation of CC chemokine ligand 18 (CCL18), a marker of alternative activation, by human alveolar macrophages (AMs).
AM were obtained from bronchoalveolar lavage (BAL) fluid of patients with idiopathic pulmonary fibrosis, sarcoidosis, or hypersensitivity pneumonitis (n = 69) and healthy volunteers (n = 22). Expression of CCL18 was determined by quantitative reverse transcriptase-polymerase chain reaction, in situ hybridization, flow cytometry, and immunohistochemistry, respectively.
Spontaneous CCL18 production by BAL-derived cells was markedly increased in patients with pulmonary fibrosis and correlated negatively with pulmonary function test parameters. CCL18 gene expression and protein production were up-regulated in normal AMs after Th2 cytokine stimulation and/or coculture with human lung fibroblasts. Native collagen significantly up-regulated CCL18 expression in normal AMs activated with Th2 cytokines via a mechanism mediated by beta2-integrin/ scavenger receptor(s). Culture supernatants of AMs from patients with idiopathic pulmonary fibrosis increased collagen production by normal lung fibroblasts partly mediated via CCL18.
Our findings suggest that AMs from patients with pulmonary fibrosis disclose a phenotype of alternative activation and might be a part of a positive feedback loop with lung fibroblasts perpetuating fibrotic processes.
Acute exacerbations of idiopathic pulmonary fibrosis Collard, Harold R; Moore, Bethany B; Flaherty, Kevin R ...
American journal of respiratory and critical care medicine,
10/2007, Letnik:
176, Številka:
7
Journal Article
Recenzirano
Odprti dostop
The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may ...experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed.
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