| German Guideline for Idiopathic Pulmonary Fibrosis - Update on Pharmacological Therapies 2017 |
Idiopathic pulmonary fibrosis (IPF) is a severe and often fatal disease with a median survival of 2 - 4 years after diagnosis. Since the publication of the German IPF guideline in 2013 new treatment trials have been published, necessitating an update of the pharmacological therapy of IPF. Different from the previous guideline, the GRADE system was discarded and replaced by the Oxford evidence classification system which allows a more differentiated judgement. The following pharmacological therapies were rated not suitable for the treatment of IPF patients (recommendation A; evidence 1-b): triple therapy with prednisolone, azathioprine and acetyl-cysteine; imatinib; ambrisentan; bosentan; macitentan. A less clear but still negative recommendation (B, 1-b) was attributed to the treatment of IPF with the phosphodiesterase-5-inhibitor sildenafil and acetyl-cysteine monotherapy. In contrast to the international guideline antacid therapy as a general treatment for IPF was rated negative, based on conflicting results of recent analyses (recommendation C; evidence 4). An unanimous positive recommendation was granted for the antifibrotic drugs nintedanib and pirfenidone for the treatment of IPF (A, 1-a). For some open questions in the management of IPF patients for which firm evidence is lacking the guideline also offers recommendations based on expert consensus.
- Behr, J.
- Gunther, A.
- Bonella, F.
- Geissler, K.
- Koschel, D.
- Kreuter, M.
- Prasse, A.
- Schonfeld, N.
- Sitter, H.
- Muller-Quernheim, J.
- Costabel, U.
|
10.1055/s-0043-123035 |
Pneumologie |
CF |
LMU |
CPC-M |
Original |
2018 |
| Nasal potential difference in suspected cystic fibrosis patients with 5T polymorphism |
BACKGROUND: 5T polymorphism is a CFTR mutation with unclear clinical consequences: the phenotype varies from healthy individuals to Cystic Fibrosis (CF). The aim of this study was to evaluate if nasal potential difference (NPD) and sweat testing correlate with symptoms and CF diagnosis in 5T patients. METHODS: 86 patients with 5T who had undergone NPD measurement, were included (6 homozygous (5T/5T), 41 with a PI-CF causing mutation in trans (5T/PI-CF), 11 with a PS-CF causing mutation in trans (5T/PS-CF) and 28 without a known mutation in trans (5T/?). Data including age, phenotype, sweat chloride and follow up were collected. RESULTS: 33% of the 5T/5T patients had abnormal NPD results, compared to 70% in 5T/PI-CF; 33% in 5T/PS-CF and 29% in 5T/?. The percentage of high or borderline sweat chloride was highest in 5T/PI-CF, and 5T/?, compared to 5T/5T and 5T/PS-CF (91, 96, 80, and 63%, respectively). TGm (number of TG repeats in intron 8) analysis was performed in 21 5T/PI-CF patients. TG11 was associated with lower sweat chloride, lower percentage of abnormal NPD and less progression of symptoms compared to TG12 and TG13. CONCLUSION: There is much variation in clinical status among 5T patients. All patients in this study with 5T/PS CF, all patients with both normal NPD and sweat test, and most patients with TG11 were stable or improving over time. Therefore, NPD measurement and TGm status aid to assess if a patient is at high risk for developing CF or CFTR-related disease and if specific follow up in a CF center is required.
- Aalbers, B. L.
- Yaakov, Y.
- Derichs, N.
- Simmonds, N. J.
- De Wachter, E.
- Melotti, P.
- De Boeck, K.
- Leal, T.
- Tummler, B.
- Wilschanski, M.
- Bronsveld, I.
Keywords
- CFTR function
- CFTR-related disorder
- Cystic fibrosis
- Ivs8-5t
- Nasal potential difference
- Sweat chloride
|
10.1016/j.jcf.2019.07.001 |
J Cyst Fibros |
CF |
BIH, MHH |
Assoziierter Partner, BREATH |
Original |
2019 |
| Pulmonary vascular volume, impaired left ventricular filling and dyspnea: The MESA Lung Study |
BACKGROUND: Evaluation of impaired left ventricular (LV) filling has focused on intrinsic causes of LV dysfunction; however, pulmonary vascular changes may contribute to reduced LV filling and dyspnea. We hypothesized that lower total pulmonary vascular volume (TPVV) on computed tomography (CT) would be associated with dyspnea and decrements in LV end-diastolic volume, particularly among ever-smokers. METHODS: The Multi-Ethnic Study of Atherosclerosis recruited adults without clinical cardiovascular disease in 2000-02. In 2010-12, TPVV was ascertained as the volume of arteries and veins in the lungs detectable on non-contrast chest CT (vessels >/=1 mm diameter). Cardiac measures were assessed by magnetic resonance imaging (MRI). Dyspnea was self-reported. RESULTS: Of 2303 participants, 53% had ever smoked cigarettes. Among ever-smokers, a lower TPVV was associated with a lower LV end-diastolic volume (6.9 mL per SD TPVV), stroke volume, and cardiac output and with dyspnea (all P-values <0.001). Findings were similar among those without lung disease and those with 0-10 pack-years but were mostly non-significant among never-smokers. TPVV was associated smaller left atrial volume but not with LV ejection fraction or MRI measures of impaired LV relaxation. In a second sample of ever-smokers, a lower pulmonary microvascular blood volume on contrast-enhanced MRI was also associated with a lower LV end-diastolic volume (P-value = 0.008). CONCLUSION: Reductions in pulmonary vascular volume were associated with lower LV filling and dyspnea among ever-smokers, including those without lung disease, suggesting that smoking-related pulmonary vascular changes may contribute to symptoms and impair cardiac filling and function without evidence of impaired LV relaxation.
- Aaron, C. P.; Hoffman, E. A.; Lima, J. A. C.; Kawut, S. M.; Bertoni, A. G.; Vogel-Claussen, J.; Habibi, M.; Hueper, K.; Jacobs, D. R., Jr.; Kalhan, R.; Michos, E. D.; Post, W. S.; Prince, M. R.; Smith, B. M.; Ambale-Venkatesh, B.; Liu, C. Y.; Zemrak, F.; Watson, K. E.; Budoff, M.; Bluemke, D. A.; Barr, R. G.
|
10.1371/journal.pone.0176180 |
PLoS One |
PLI |
MHH |
BREATH |
Original |
2017 |
| Raw Cow's Milk Reduces Allergic Symptoms in a Murine Model for Food Allergy-A Potential Role For Epigenetic Modifications |
Epidemiological studies identified raw cow's milk consumption as an important environmental exposure that prevents allergic diseases. In the present study, we investigated whether raw cow's milk has the capacity to induce tolerance to an unrelated, non-milk, food allergen. Histone acetylation of T cell genes was investigated to assess potential epigenetic regulation. Female C3H/HeOuJ mice were sensitized and challenged to ovalbumin. Prior to sensitization, the mice were treated with raw milk, processed milk, or phosphate-buffered saline for eight days. Allergic symptoms were assessed after challenge and histone modifications in T cell-related genes of splenocyte-derived CD4(+) T cells and the mesenteric lymph nodes were analyzed after milk exposure and after challenge. Unlike processed milk, raw milk decreased allergic symptoms. After raw milk exposure, histone acetylation of Th1-, Th2-, and regulatory T cell-related genes of splenocyte-derived CD4(+) T cells was higher than after processed milk exposure. After allergy induction, this general immune stimulation was resolved and histone acetylation of Th2 genes was lower when compared to processed milk. Raw milk reduces allergic symptoms to an unrelated, non-milk, food allergen in a murine model for food allergy. The activation of T cell-related genes could be responsible for the observed tolerance induction, which suggested that epigenetic modifications contribute to the allergy-protective effect of raw milk.
- Abbring, S.
- Wolf, J.
- Ayechu-Muruzabal, V.
- Diks, M. A. P.
- Alhamwe, B. A.
- Alhamdan, F.
- Harb, H.
- Renz, H.
- Garn, H.
- Garssen, J.
- Potaczek, D. P.
- van Esch, Bcam
Keywords
- Acetylation
- Animals
- Cells, Cultured
- *Chromatin Assembly and Disassembly
- Cytokines/immunology/metabolism
- Disease Models, Animal
- *Epigenesis, Genetic
- Female
- Food Hypersensitivity/*diet therapy/genetics/immunology/metabolism
- Histones/*metabolism
- *Immune Tolerance
- *Lymphocyte Activation
- Mice, Inbred C3H
- Milk/*immunology
- Ovalbumin
- T-Lymphocyte Subsets/immunology/*metabolism
- T-Lymphocytes, Regulatory/immunology/metabolism
- Th1 Cells/immunology/metabolism
- Th2 Cells/immunology/metabolism
- *epigenetics
- *farming effect
- *food allergy
- *histone acetylation
- *milk processing
- *raw milk
- other authors report no potential conflicts of interest.
|
10.3390/nu11081721 |
Nutrients |
AA |
UMR |
UGMLC |
Original |
2019 |
| Histone Acetylation of Immune Regulatory Genes in Human Placenta in Association with Maternal Intake of Olive Oil and Fish Consumption |
Maternal diet modifies epigenetic programming in offspring, a potentially critical factor in the immune dysregulation of modern societies. We previously found that prenatal fish oil supplementation affects neonatal T-cell histone acetylation of genes implicated in adaptive immunity including PRKCZ, IL13, and TBX21. In this study, we measured H3 and H4 histone acetylation levels by chromatin immunoprecipitation in 173 term placentas collected in the prospective birth cohort, ALADDIN, in which information on lifestyle and diet is thoroughly recorded. In anthroposophic families, regular olive oil usage during pregnancy was associated with increased H3 acetylation at FOXP3 (p = 0.004), IL10RA (p = 0.008), and IL7R (p = 0.007) promoters, which remained significant after adjustment by offspring gender. Furthermore, maternal fish consumption was associated with increased H4 acetylation at the CD14 gene in placentas of female offspring (p = 0.009). In conclusion, prenatal olive oil intake can affect placental histone acetylation in immune regulatory genes, confirming previously observed pro-acetylation effects of olive oil polyphenols. The association with fish consumption may implicate omega-3 polyunsaturated fatty acids present in fish oil. Altered histone acetylation in placentas from mothers who regularly include fish or olive oil in their diets could influence immune priming in the newborn.
- Acevedo, N.
- Frumento, P.
- Harb, H.
- Alashkar Alhamwe, B.
- Johansson, C.
- Eick, L.
- Alm, J.
- Renz, H.
- Scheynius, A.
- Potaczek, D. P.
Keywords
- Acetylation
- Female
- Fish Oils/administration & dosage/metabolism/*pharmacology
- Fish Products
- Histones/*metabolism
- Humans
- Immunity, Innate/genetics
- Interleukin-13/genetics/metabolism
- Lipopolysaccharide Receptors/genetics/metabolism
- *Maternal Nutritional Physiological Phenomena
- Olive Oil/administration & dosage/*pharmacology
- Placenta/drug effects/*metabolism
- Pregnancy
- Protein Kinase C/genetics/metabolism
- *Protein Processing, Post-Translational
- Receptors, Interleukin/genetics/metabolism
- T-Box Domain Proteins/genetics/metabolism
- *aladdin
- *h3
- *h4
- *fish
- *histone acetylation
- *immune genes
- *maternal diet
- *olive oil
- *placenta
- *pregnancy
|
10.3390/ijms20051060 |
Int J Mol Sci |
General Lung and Other |
UMR |
UGMLC |
Original |
2019 |
| First-line immune checkpoint blockade for advanced non-small-cell lung cancer: Travelling at the speed of light |
The development of PD-1, PD-L1 and CTLA-4 immune checkpoint inhibitors (CPI) has revolutionised the treatment of advanced non-small cell lung cancer (NSCLC). The potential of immunotherapy (IO) to induce durable responses for a subset of patients represents a therapeutic milestone. After the approval of front-line single agent pembrolizumab, IO-based combinations are rapidly entering clinical practice resulting in a fast change of treatment algorithms for advanced NSCLC. We hereby summarize the recent first-line phase 3 trials evaluating PD-(L)1 blockade plus chemotherapy (ChT) and PD-1 plus CTLA-4 CPI for advanced NSCLC and provide potential treatment recommendations.
- Ackermann, C. J.
- Reck, M.
- Paz-Ares, L.
- Barlesi, F.
- Califano, R.
Keywords
- *Advanced
- *ctla-4
- *Checkpoint inhibitors
- *Chemotherapy
- *First-line
- *Immuno-Oncology
- *Immunotherapy
- *nsclc
- *Non-Small-Cell Lung Cancer
- *pd-1
- *pd-l1
|
10.1016/j.lungcan.2019.06.007 |
Lung Cancer |
LC |
Ghd |
ARCN |
Original |
2019 |
| Bioreactor-based mass production of human iPSC-derived macrophages enables immunotherapies against bacterial airway infections |
The increasing number of severe infections with multi-drug-resistant pathogens worldwide highlights the need for alternative treatment options. Given the pivotal role of phagocytes and especially alveolar macrophages in pulmonary immunity, we introduce a new, cell-based treatment strategy to target bacterial airway infections. Here we show that the mass production of therapeutic phagocytes from induced pluripotent stem cells (iPSC) in industry-compatible, stirred-tank bioreactors is feasible. Bioreactor-derived iPSC-macrophages (iPSC-Mac) represent a highly pure population of CD45(+)CD11b(+)CD14(+)CD163(+) cells, and share important phenotypic, functional and transcriptional hallmarks with professional phagocytes, however with a distinct transcriptome signature similar to primitive macrophages. Most importantly, bioreactor-derived iPSC-Mac rescue mice from Pseudomonas aeruginosa-mediated acute infections of the lower respiratory tract within 4-8 h post intra-pulmonary transplantation and reduce bacterial load. Generation of specific immune-cells from iPSC-sources in scalable stirred-tank bioreactors can extend the field of immunotherapy towards bacterial infections, and may allow for further innovative cell-based treatment strategies.
- Ackermann, M.
- Kempf, H.
- Hetzel, M.
- Hesse, C.
- Hashtchin, A. R.
- Brinkert, K.
- Schott, J. W.
- Haake, K.
- Kuhnel, M. P.
- Glage, S.
- Figueiredo, C.
- Jonigk, D.
- Sewald, K.
- Schambach, A.
- Wronski, S.
- Moritz, T.
- Martin, U.
- Zweigerdt, R.
- Munder, A.
- Lachmann, N.
|
10.1038/s41467-018-07570-7 |
Nat Commun |
ALI |
ITEM, MHH |
BREATH |
Original |
2018 |
| Morphomolecular motifs of pulmonary neoangiogenesis in interstitial lung diseases |
The pathogenetic role of angiogenesis in interstitial lung diseases (ILDs) is controversial. This study represents the first investigation of the spatial complexity and molecular motifs of microvascular architecture in important subsets of human ILD. The aim of our study was to identify specific variants of neoangiogenesis in three common pulmonary injury patterns in human ILD.We performed comprehensive and compartment-specific analysis of 24 human lung explants with usual intersitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP) and alveolar fibroelastosis (AFE) using histopathology, microvascular corrosion casting, micro-comupted tomography based volumetry and gene expression analysis using Nanostring as well as immunohistochemistry to assess remodelling-associated angiogenesis.Morphometrical assessment of vessel diameters and intervascular distances showed significant differences in neoangiogenesis in characteristically remodelled areas of UIP, NSIP and AFE lungs. Likewise, gene expression analysis revealed distinct and specific angiogenic profiles in UIP, NSIP and AFE lungs.Whereas UIP lungs showed a higher density of upstream vascularity and lower density in perifocal blood vessels, NSIP and AFE lungs revealed densely packed alveolar septal blood vessels. Vascular remodelling in NSIP and AFE is characterised by a prominent intussusceptive neoangiogenesis, in contrast to UIP, in which sprouting of new vessels into the fibrotic areas is characteristic. The molecular analyses of the gene expression provide a foundation for understanding these fundamental differences between AFE and UIP and give insight into the cellular functions involved.
- Ackermann, M.
- Stark, H.
- Neubert, L.
- Schubert, S.
- Borchert, P.
- Linz, F.
- Wagner, W. L.
- Stiller, W.
- Wielputz, M.
- Hoefer, A.
- Haverich, A.
- Mentzer, S. J.
- Shah, H. R.
- Welte, T.
- Kuehnel, M.
- Jonigk, D.
|
10.1183/13993003.00933-2019 |
Eur Respir J |
DPLD |
MHH, RKU |
BREATH, TLRC |
Original |
2019 |
| Plexiform Vasculopathy in Chronic Thromboembolic Pulmonary Hypertension |
- Ackermann, M.; Gaumann, A.; Mentzer, S. J.; Hinrichs, J. B.; Warnecke, G.; Hoeper, M. M.; Braubach, P.; Kuehnel, M.; Maegel, L.; Jonigk, D.
Keywords
- Angiography
- Chronic Disease
- Female
- Humans
- Hypertension, Pulmonary/*diagnostic imaging/etiology/pathology/surgery
- Lung Transplantation
- Microscopy, Electron, Scanning
- Middle Aged
- Pulmonary Artery/diagnostic imaging/ultrastructure
- Pulmonary Embolism/complications/*diagnostic imaging/pathology/surgery
- Vascular Remodeling
|
10.1164/rccm.201703-0591IM |
Am J Respir Crit Care Med |
PH |
MHH |
BREATH |
Original |
2017 |
| Ex vivo Generation of Genetically Modified Macrophages from Human Induced Pluripotent Stem Cells |
BACKGROUND: Pluripotent stem cells, including induced pluripotent stem cells (iPSCs), have the capacity to differentiate towards all three germ layers and have been highlighted as an attractive cell source for the field of regenerative medicine. Thus, stable expression of therapeutic transgenes in iPSCs, as well as thereof derived progeny of hematopoietic lineage, may lay the foundation for innovative cell replacement therapies. METHODS: We have utilized human iPSC lines genetically modified by lentiviral vector technology or targeted integration of reporter genes to evaluate transgene expression during hematopoietic specification and differentiation towards macrophages. RESULTS: Use of lentiviral vectors equipped with an ubiquitous chromatin opening element (CBX3-UCOE) as well as zinc finger nuclease-mediated targeting of an expression cassette into the human adeno-associated virus integration site 1 (AAVS1) safe harbor resulted in stable transgene expression in iPSCs. When iPSCs were differentiated along the myeloid pathway into macrophages, both strategies yielded sustained transgene expression during the hematopoietic specification process including mature CD14+ and CD11b+ macrophages. CONCLUSION: Combination of human iPSC technology with either lentiviral vector technology or designer nuclease-based genome editing allows for the generation of transgenic iPSC-derived macrophages with stable transgene expression which may be useful for novel cell and gene replacement therapies.
- Ackermann, M.; Kuhn, A.; Kunkiel, J.; Merkert, S.; Martin, U.; Moritz, T.; Lachmann, N.
Keywords
- Cbx3-ucoe
- Gene therapy
- Genome editing
- Hematopoiesis
- Lentivirus
- Macrophages
- iPSC
|
10.1159/000477129 |
Transfus Med Hemother |
ELD |
MHH |
BREATH |
Original |
2017 |
| Preschool wheezing diagnosis and management-Survey of physicians' and caregivers' perspective |
- Adamiec, A.
- Ambrozej, D.
- Ryczaj, K.
- Ruszczynski, M.
- Elenius, V.
- Cavkaytar, O.
- Hedlin, G.
- Konradsen, J. R.
- Maggina, P.
- Makrinioti, H.
- Papadopoulos, N.
- Schaub, B.
- Schwarze, J.
- Skevaki, C.
- Smits, H. H.
- Jartti, T.
- Feleszko, W.
- Eaaci Task Force on Clinical Practice Recommendations on Preschool Wheeze
|
10.1111/pai.13142 |
Pediatr Allergy Immunol |
AA |
LMU, UMR |
CPC-M, UGMLC |
Original |
2019 |
| Synthetic glycan-based TLR4 agonists targeting caspase-4/11 for the development of adjuvants and immunotherapeutics |
Gram-negative bacterial lipopolysaccharide (LPS)-induced Toll-like receptor 4 (TLR4) mediated pro-inflammatory signaling plays a key role in immunoprotection against infectious challenges and boosts adaptive immunity, whereas the activation of the cytosolic LPS receptor caspase-4/11 leads to cell death by pyroptosis and is deeply implicated in the development of sepsis. Despite tremendous advances in the understanding of the LPS-TLR4 interaction, predictably regulated TLR4 activation has not yet been achieved. The structural basis for the induction of caspase-4/11 protease activity by LPS is currently unknown. The modulation of innate and adaptive immune responses through the controlled induction of TLR4 signaling without triggering caspase-4/11 activity would open novel perspectives in the development of safe vaccine adjuvants and immunotherapeutics. We report the discovery of highly potent glycan-based immunostimulants with picomolar affinity for TLR4 which interact with caspase-4/11 and promote caspase-4/11 oligomerization while abolishing caspase-11 protease activity. The rigidity and twisted molecular shape of the alpha,alpha-(1<-->1')-linked disaccharide core of synthetic LPS mimicking anionic glycolipids accounted for both species-independent and adjustable TLR4-mediated NF-kappaB signaling and the modulation of caspase-4/11 activation. By the use of crystal structure based design and advanced synthetic chemistry we created a set of versatile probes for studying the structural basis of caspase-4/11 activation and established a chemical strategy for controllable TLR4 mediated cytokine release which is dissociable from the induction of caspase-11 protease activity.
- Adanitsch, F.
- Shi, J.
- Shao, F.
- Beyaert, R.
- Heine, H.
- Zamyatina, A.
|
10.1039/c7sc05323a |
Chem Sci |
ALI |
FZB |
ARCN |
Original |
2018 |
| BRAF Inhibition in a Lung Transplant Recipient With Metastatic Melanoma |
- Afshar, K.; David, S.; Fuehner, T.; Gottlieb, J.; Gutzmer, R.
Keywords
- Female
- Humans
- Immunosuppressive Agents/*administration & dosage/pharmacology
- Indoles/administration & dosage/pharmacology
- *Lung Transplantation
- Melanoma/*drug therapy/pathology
- Middle Aged
- Neoplasm Metastasis
- Proto-Oncogene Proteins B-raf/*antagonists & inhibitors
- Sulfonamides/administration & dosage/pharmacology
|
10.1001/jamadermatol.2015.2910 |
JAMA Dermatol |
ELD, LC |
MHH |
BREATH |
Original |
2016 |
| Mutant KRAS promotes malignant pleural effusion formation |
Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity. However, the mechanisms responsible for the development of MPE are still obscure. Here we show that mutant KRAS is important for MPE induction in mice. Pleural disseminated, mutant KRAS bearing tumour cells upregulate and systemically release chemokine ligand 2 (CCL2) into the bloodstream to mobilize myeloid cells from the host bone marrow to the pleural space via the spleen. These cells promote MPE formation, as indicated by splenectomy and splenocyte restoration experiments. In addition, KRAS mutations are frequently detected in human MPE and cell lines isolated thereof, but are often lost during automated analyses, as indicated by manual versus automated examination of Sanger sequencing traces. Finally, the novel KRAS inhibitor deltarasin and a monoclonal antibody directed against CCL2 are equally effective against an experimental mouse model of MPE, a result that holds promise for future efficient therapies against the human condition.
- Agalioti, T.
- Giannou, A. D.
- Krontira, A. C.
- Kanellakis, N. I.
- Kati, D.
- Vreka, M.
- Pepe, M.
- Spella, M.
- Lilis, I.
- Zazara, D. E.
- Nikolouli, E.
- Spiropoulou, N.
- Papadakis, A.
- Papadia, K.
- Voulgaridis, A.
- Harokopos, V.
- Stamou, P.
- Meiners, S.
- Eickelberg, O.
- Snyder, L. A.
- Antimisiaris, S. G.
- Kardamakis, D.
- Psallidas, I.
- Marazioti, A.
- Stathopoulos, G. T.
Keywords
- Adenocarcinoma/drug therapy/*genetics/pathology
- Animals
- Antineoplastic Agents/*pharmacology/therapeutic use
- Benzimidazoles/pharmacology/therapeutic use
- Cell Line, Tumor
- Chemokine CCL2/antagonists & inhibitors/metabolism/secretion
- Chickens
- Chorioallantoic Membrane
- Female
- HEK293 Cells
- Humans
- Lung Neoplasms/drug therapy/*genetics/pathology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Myeloid Cells/*pathology
- Pleural Cavity/cytology/pathology
- Pleural Effusion, Malignant/drug therapy/*genetics/pathology
- Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors/*genetics/metabolism
- RNA, Small Interfering/metabolism
- Spleen/cytology/pathology
- Up-Regulation
- Xenograft Model Antitumor Assays
|
10.1038/ncomms15205 |
Nat Commun |
LC |
HMGU |
CPC-M |
Original |
2017 |
| alpha-Linoleic acid enhances the capacity of alpha-1 antitrypsin to inhibit lipopolysaccharide induced IL-1beta in human blood neutrophils |
Alpha1-antitrypsin (A1AT, SERPINA1), a major circulating inhibitor of neutrophil elastase (NE) and proteinase-3 (PR3), has been proposed to reduce the processing and release of IL-1beta. Since the anti-inflammatory properties of A1AT are influenced by the presence of polyunsaturated fatty acids, we compared effects of fatty acid-free (A1AT-0) and alpha-linoleic acid bound (A1AT-LA) forms of A1AT on lipopolysaccharide (LPS)-induced synthesis of IL-1beta precursor and the release of IL-1beta from human blood neutrophils. The presence of A1AT-LA or A1AT-0 significantly reduced LPS induced release of mature IL-1beta. However, only A1AT-LA reduced both steady state mRNA levels of IL-1beta and the secretion of mature IL-1beta. In LPS-stimulated neutrophils, mRNA levels of TLR2/4, NFKBIA, P2RX7, NLRP3, and CASP1 decreased significantly in the presence of A1AT-LA but not A1AT-0. A1AT-0 and A1AT-LA did not inhibit the direct enzymatic activity of caspase-1, but we observed complexes of either form of A1AT with NE and PR3. Consistent with the effect on TLR and IL-1beta gene expression, only A1AT-LA inhibited LPS-induced gene expression of NE and PR3. Increased gene expression of PPAR-gamma was observed in A1AT-LA treated neutrophils without of LPS stimulation, and the selective PPAR-gamma antagonist (GW9662) prevented the reduction in IL-1beta by A1AT-LA. We conclude from our data, that the ability of A1AT to reduce TLR and IL-1beta gene expression depends on its association with LA. Moreover, the anti-inflammatory properties of A1AT-LA are likely to be mediated by the activation of PPAR-gamma.
- Aggarwal, N.
- Korenbaum, E.
- Mahadeva, R.
- Immenschuh, S.
- Grau, V.
- Dinarello, C. A.
- Welte, T.
- Janciauskiene, S.
Keywords
- Lps
- Serpina1
- alpha1 antitrypsin
- fatty acids
- human neutrophils
- inflammasome
- alpha-linoleic acid
|
10.2119/molmed.2016.00119 |
Mol Med |
ELD |
JLU, MHH |
BREATH, UGMLC |
Original |
2016 |
| Alpha-1 Antitrypsin Regulates Transcriptional Levels of Serine Proteases in Blood Mononuclear Cells |
- Aggarwal, N.; Koepke, J.; Matamala, N.; Martinez-Delgado, B.; Martinez, M. T.; Golpon, H.; Stolk, J.; Janciauskiene, S.; Koczulla, R.
|
10.1164/rccm.201510-2062LE |
Am J Respir Crit Care Med |
LC |
MHH |
BREATH |
Original |
2016 |
| Improved efficacy of allergen-specific immunotherapy by JAK inhibition in a murine model of allergic asthma |
BACKGROUND: Allergen-specific immunotherapy (AIT) is the only curative treatment for type-1 allergies, but sometimes shows limited therapeutic response as well as local and systemic side effects. Limited control of local inflammation and patient symptoms hampers its widespread use in severe allergic asthma. OBJECTIVE: Our aim was to evaluate whether AIT is more effective in suppression of local inflammation if performed under the umbrella of short-term non-specific immunomodulation using a small molecule inhibitor of JAK pathways. METHODS: In C57BL/6J mice, a model of ovalbumin (OVA)-induced allergic airway inflammation and allergen-specific immunotherapy was combined with the administration of Tofacitinib (TOFA, a FDA-approved JAK inhibitor) from 48 hours prior to 48 hours after therapeutic OVA-injection. The effect of TOFA on human FOXP3+CD4+ T cells was studied in vitro. RESULTS: AIT combined with short-term TOFA administration was significantly more effective in suppressing total cell and eosinophil infiltration into the lung, local cytokine production including IL-1beta and CXCL1 and showed a trend for the reduction of IL-4, IL-13, TNF-alpha and IL-6 compared to AIT alone. Furthermore, TOFA co-administration significantly reduced systemic IL-6, IL-1beta and OVA-specific IgE levels and induced IgG1 to the same extent as AIT alone. Additionally, TOFA enhanced the induction of human FOXP3+CD4+ T cells. CONCLUSIONS: This proof of concept study shows that JAK inhibition did not inhibit tolerance induction, but improved experimental AIT at the level of local inflammation. The improved control of local inflammation might extend the use of AIT in more severe conditions such as polyallergy, asthma and high-risk patients suffering from mastocytosis or anaphylaxis.
- Aguilar-Pimentel, A.
- Graessel, A.
- Alessandrini, F.
- Fuchs, H.
- Gailus-Durner, V.
- Hrabe de Angelis, M.
- Russkamp, D.
- Chaker, A.
- Ollert, M.
- Blank, S.
- Gutermuth, J.
- Schmidt-Weber, C. B.
Keywords
- Allergens/*administration & dosage
- Animals
- Asthma/*therapy
- Bronchoalveolar Lavage Fluid
- Cell Differentiation/drug effects
- Cytokines/secretion
- *Desensitization, Immunologic
- *Disease Models, Animal
- Humans
- Janus Kinases/*antagonists & inhibitors
- Mice
- Mice, Inbred C57BL
- Ovalbumin/*administration & dosage
- Piperidines/pharmacology
- Pyrimidines/pharmacology
- Pyrroles/pharmacology
|
10.1371/journal.pone.0178563 |
PLoS One |
AA |
HMGU |
CPC-M |
Original |
2017 |
| PROGRESS - prospective observational study on hospitalized community acquired pneumonia |
BACKGROUND: Community acquired pneumonia (CAP) is a high incidence disease resulting in about 260,000 hospital admissions per year in Germany, more than myocardial infarction or stroke. Worldwide, CAP is the most frequent infectious disease with high lethality ranging from 1.2 % in those 20-29 years old to over 10 % in patients older than 70 years, even in industrial nations. CAP poses numerous medical challenges, which the PROGRESS (Pneumonia Research Network on Genetic Resistance and Susceptibility for the Evolution of Severe Sepsis) network aims to tackle: Operationalization of disease severity throughout the course of disease, outcome prediction for hospitalized patients and prediction of transitions from uncomplicated CAP to severe CAP, and finally, to CAP with sepsis and organ failure as a life-threatening condition. It is a major aim of PROGRESS to understand and predict patient heterogeneity regarding outcome in the hospital and to develop novel treatment concepts. METHODS: PROGRESS was designed as a clinical, observational, multi-center study of patients with CAP requiring hospitalization. More than 1600 patients selected for low burden of co-morbidities have been enrolled, aiming at a total of 3000. Course of disease, along with therapy, was closely monitored by daily assessments and long-term follow-up. Daily blood samples allow in depth molecular-genetic characterization of patients. We established a well-organized workflow for sample logistics and a comprehensive data management system to collect and manage data from more than 50 study centers in Germany and Austria. Samples are stored in a central biobank and clinical data are stored in a central data base which also integrates all data from molecular assessments. DISCUSSION: With the PROGRESS study, we established a comprehensive data base of high quality clinical and molecular data allowing investigation of pressing research questions regarding CAP. In-depth molecular characterization will contribute to the discovery of disease mechanisms and establishment of diagnostic and predictive biomarkers. A strength of PROGRESS is the focus on younger patients with low burden of co-morbidities, allowing a more direct look at host biology with less confounding. As a resulting limitation, insights from PROGRESS will require validation in representative patient cohorts to assess clinical utility. TRIAL REGISTRATION: The PROGRESS study was retrospectively registered on May 24(th), 2016 with ClinicalTrials.gov: NCT02782013.
- Ahnert, P.; Creutz, P.; Scholz, M.; Schutte, H.; Engel, C.; Hossain, H.; Chakraborty, T.; Bauer, M.; Kiehntopf, M.; Volker, U.; Hammerschmidt, S.; Loeffler, M.; Suttorp, N.; Progress study group
Keywords
- Biobank
- Biomarkers
- Data base
- Disease progression
- Innate immunity
- Pneumonia
- Prospective observational study
- Sepsis
|
10.1186/s12890-016-0255-8 |
BMC Pulm Med |
PLB |
JLU, PROGRESS |
UGMLC |
Original |
2016 |
| MAP1LC3B overexpression protects against Hermansky-Pudlak syndrome type-1-induced defective autophagy in vitro |
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder, and some patients with HPS develop pulmonary fibrosis, known as HPS-associated interstitial pneumonia (HPSIP). We have previously reported that HPSIP is associated with severe surfactant accumulation, lysosomal stress, and alveolar epithelial cell type II (AECII) apoptosis. Here, we hypothesized that defective autophagy might result in excessive lysosomal stress in HPSIP. Key autophagy proteins, including LC3B lipidation and p62, were increased in HPS1/2 mice lungs. Electron microscopy demonstrated a preferable binding of LC3B to the interior of lamellar bodies in the AECII of HPS1/2 mice, whereas in wild-type mice it was present on the limiting membrane in addition to the interior of the lamellar bodies. Similar observations were noted in human HPS1 lung sections. In vitro knockdown of HPS1 revealed increased LC3B lipidation and p62 accumulation, associated with an increase in proapoptotic caspases. Overexpression of LC3B decreased the HPS1 knockdown-induced p62 accumulation, whereas rapamycin treatment did not show the same effect. We conclude that loss of HPS1 protein results in impaired autophagy that is restored by exogenous LC3B and that defective autophagy might therefore play a critical role in the development and progression of HPSIP.
- Ahuja, S.
- Knudsen, L.
- Chillappagari, S.
- Henneke, I.
- Ruppert, C.
- Korfei, M.
- Gochuico, B. R.
- Bellusci, S.
- Seeger, W.
- Ochs, M.
- Guenther, A.
- Mahavadi, P.
Keywords
- Alveolar Epithelial Cells/*physiology
- Animals
- Apoptosis Regulatory Proteins/metabolism
- *Autophagy
- Cell Line, Tumor
- Female
- Hermanski-Pudlak Syndrome/*metabolism/pathology
- Humans
- Lung/metabolism/pathology
- Male
- Membrane Proteins/genetics
- Mice, Inbred C57BL
- Microtubule-Associated Proteins/genetics/*metabolism
- Hermansky-Pudlak syndrome
- Hermansky-Pudlak syndrome-associated interstitial pneumonia
- alveolar epithelial cells
- apoptosis
- autophagy
- lung fibrosis
|
10.1152/ajplung.00213.2015 |
Am J Physiol Lung Cell Mol Physiol |
CF |
JLU, MHH |
BREATH, UGMLC |
Original |
2016 |
| Molecular similarities and differences from human pulmonary fibrosis and corresponding mouse model: MALDI imaging mass spectrometry in comparative medicine |
Animal models can reproduce some model-specific aspects of human diseases, but some animal models translate poorly or fail to translate to the corresponding human disease. Here, we develop a strategy to systematically compare human and mouse tissues, and conduct a proof-of-concept experiment to identify molecular similarities and differences using patients with idiopathic pulmonary fibrosis and a bleomycin-induced fibrosis mouse model. Our novel approach employs high-throughput tissue microarrays (TMAs) of humans and mice, high-resolution matrix-assisted laser desorption/ionization-Fourier transform-ion cyclotron resonance-mass spectrometry imaging (MALDI-FT-ICR-MSI) to spatially resolve mass spectra at the level of specific metabolites, and hierarchical clustering and pathway enrichment analysis to identify functionally similar/different molecular patterns and pathways in pathological lesions of humans and mice. We identified a large number of common molecules (n=1366) and fewer exclusive molecules in humans (n=83) and mice (n=54). Among the common molecules, the 'ascorbate and aldarate metabolism' pathway had the highest similarity in human and mouse lesions. This proof-of-concept study demonstrates that our novel strategy employing a reliable and easy-to-perform experimental design accurately identifies pathways and factors that can be directly compared between animal models and human diseases.Laboratory Investigation advance online publication, 16 October 2017; doi:10.1038/labinvest.2017.110.
- Aichler, M.; Kunzke, T.; Buck, A.; Sun, N.; Ackermann, M.; Jonigk, D.; Gaumann, A.; Walch, A.
|
10.1038/labinvest.2017.110 |
Lab Invest |
DPLD |
MHH |
BREATH |
Original |
2017 |
| Some Synonymous and Nonsynonymous gyrA Mutations in Mycobacterium tuberculosis Lead to Systematic False-Positive Fluoroquinolone Resistance Results with the Hain GenoType MTBDRsl Assays |
In this study, using the Hain GenoType MTBDRsl assays (versions 1 and 2), we found that some nonsynonymous and synonymous mutations in gyrA in Mycobacterium tuberculosis result in systematic false-resistance results to fluoroquinolones by preventing the binding of wild-type probes. Moreover, such mutations can prevent the binding of mutant probes designed for the identification of specific resistance mutations. Although these mutations are likely rare globally, they occur in approximately 7% of multidrug-resistant tuberculosis strains in some settings.
- Ajileye, A.
- Alvarez, N.
- Merker, M.
- Walker, T. M.
- Akter, S.
- Brown, K.
- Moradigaravand, D.
- Schon, T.
- Andres, S.
- Schleusener, V.
- Omar, S. V.
- Coll, F.
- Huang, H.
- Diel, R.
- Ismail, N.
- Parkhill, J.
- de Jong, B. C.
- Peto, T. E.
- Crook, D. W.
- Niemann, S.
- Robledo, J.
- Smith, E. G.
- Peacock, S. J.
- Koser, C. U.
Keywords
- Antitubercular Agents/*pharmacology
- Biological Assay
- DNA Gyrase/*genetics/metabolism
- Drug Resistance, Multiple, Bacterial/*genetics
- False Positive Reactions
- Fluoroquinolones/*pharmacology
- Gene Expression
- Humans
- *Mutation
- Mycobacterium tuberculosis/classification/drug effects/*genetics/isolation &
- purification
- Oligonucleotide Probes/chemistry/metabolism
- Phylogeny
- Tuberculosis, Multidrug-Resistant/drug therapy/microbiology
- *Hain GenoType MTBDRsl
- *Mycobacterium tuberculosis
- *fluoroquinolones
|
10.1128/AAC.02169-16 |
Antimicrob Agents Chemother |
General Lung and Other |
UKSH (Kiel) |
Assoziierter Partner, ARCN |
Original |
2017 |
| Motivations for (non)participation in population-based health studies among the elderly - comparison of participants and nonparticipants of a prospective study on influenza vaccination |
BACKGROUND: Participation in epidemiological studies has strongly declined in recent years. We examined the reasons for (non)participation in population-based health studies among participants and nonparticipants of a prospective study on influenza vaccination among the elderly. METHODS: Males and females between 65 and 80 years of age (N = 5582) were randomly selected from the residents' registration office in Hannover, Germany, and were invited to participate in a study featuring vaccination with a seasonal adjuvanted influenza vaccine (Fluad, Novartis) including five follow-up visits (day 0, 1/3, 7, 21, 70 with respect to vaccination). A 24-item nonresponder questionnaire, including 10 items on reasons for participating in a hypothetical health study, was mailed to 1500 randomly selected nonparticipants. The same 10 items were included in the end-of-study questionnaire administered to the participants in the vaccination study (n = 200). Logistic regression analysis with backward elimination was used to identify the reasons most strongly associated with nonparticipation. RESULTS: Five hundred thirty-one (35%) nonparticipants and 200 participants (100%) returned the respective questionnaires. Nonparticipation was associated with a lower interest in obtaining personal health information (OR = 3.32) and a preference for less invasive (OR = 3.01) and less time-demanding (OR = 2.19) studies. Responses to other items, e.g. regarding altruistic motives, monetary compensation, general interest of the study, or study approval through ethics committee and data security authority, did not differ between participants and nonparticipants. CONCLUSIONS: Participation rates in health studies among elderly individuals could potentially be improved by reducing interventions and time demand, for instance by implementing methods of self-sampling and remote data collection. TRIAL REGISTRATION: No. 1100359 (ClinicalTrials.gov, date of registration: 09.02.2015).
- Akmatov, M. K.; Jentsch, L.; Riese, P.; May, M.; Ahmed, M. W.; Werner, D.; Rosel, A.; Prokein, J.; Bernemann, I.; Klopp, N.; Prochnow, B.; Illig, T.; Schindler, C.; Guzman, C. A.; Pessler, F.
Keywords
- Elderly
- Germany
- Motivations
- Nonparticipants
- Participation
- Population-based study
- Reasons
|
10.1186/s12874-017-0302-z |
BMC Med Res Methodol |
PLB |
MHH |
BREATH |
Original |
2017 |
| Determination of nasal and oropharyngeal microbiomes in a multicenter population-based study - findings from Pretest 1 of the German National Cohort |
We examined acceptability, preference and feasibility of collecting nasal and oropharyngeal swabs, followed by microbiome analysis, in a population-based study with 524 participants. Anterior nasal and oropharyngeal swabs were collected by certified personnel. In addition, participants self-collected nasal swabs at home four weeks later. Four swab types were compared regarding (1) participants' satisfaction and acceptance and (2) detection of microbial community structures based on deep sequencing of the 16 S rRNA gene V1-V2 variable regions. All swabbing methods were highly accepted. Microbial community structure analysis revealed 846 phylotypes, 46 of which were unique to oropharynx and 164 unique to nares. The calcium alginate tipped swab was found unsuitable for microbiome determinations. Among the remaining three swab types, there were no differences in oropharyngeal microbiomes detected and only marginal differences in nasal microbiomes. Microbial community structures did not differ between staff-collected and self-collected nasal swabs. These results suggest (1) that nasal and oropharyngeal swabbing are highly feasible methods for human population-based studies that include the characterization of microbial community structures in these important ecological niches, and (2) that self-collection of nasal swabs at home can be used to reduce cost and resources needed, particularly when serial measurements are to be taken.
- Akmatov, M. K.; Koch, N.; Vital, M.; Ahrens, W.; Flesch-Janys, D.; Fricke, J.; Gatzemeier, A.; Greiser, H.; Gunther, K.; Illig, T.; Kaaks, R.; Krone, B.; Kuhn, A.; Linseisen, J.; Meisinger, C.; Michels, K.; Moebus, S.; Nieters, A.; Obi, N.; Schultze, A.; Six-Merker, J.; Pieper, D. H.; Pessler, F.
|
10.1038/s41598-017-01212-6 |
Sci Rep |
PLB |
MHH |
BREATH |
Original |
2017 |
| Establishment of a cohort for deep phenotyping of the immune response to influenza vaccination among elderly individuals recruited from the general population |
Elderly individuals have the highest burden of disease from influenza infection but also the lowest immune response to influenza vaccination. A better understanding of the host response to influenza vaccination in the elderly is therefore urgently needed. We conducted a biphasic prospective, population-based study from Dec. 2014 to May 2015 (pilot study) and Sept. 2015 to May 2016 (main study). Individuals 65-80 y of age were randomly selected from the residents' registration office in Hannover, Germany, for the pilot (n = 34) and main study (n = 200). The pilot study tested recruitment for study arms featuring 2, 4, or 5 visits/blood draws. The 5-visit (day 0, 1/3, 7, 21, 70 with respect to vaccination) study arm was selected for the main study. Both studies featured vaccination with Fluad (Novartis, Italy), a detailed medical history, a physical exam, recording of adverse events, completion of a questionnaire on common infections and an end-of-study questionnaire, and blood samples. Response rates in the pilot and main studies were 3.7% and 4.0%, respectively. Willingness to participate did not differ among the study arms (Fisher's exact test, p = 0.44). In both studies, there were no losses to follow-up. Compliance with study visits, blood sampling and completion of the questionnaires was very high (100%, >97%, 100%, respectively), as were participants' acceptance of and satisfaction with both phases of the study. The low response rates indicate the need for optimized recruitment strategies if the study population is to be representative of the general population. Nonetheless, the complex prospective study design proved to be highly feasible.
- Akmatov, M. K.; Riese, P.; May, M.; Jentsch, L.; Ahmed, M. W.; Werner, D.; Rosel, A.; Tyler, M.; Pessler, K.; Prokein, J.; Bernemann, I.; Klopp, N.; Prochnow, B.; Trittel, S.; Tallam, A.; Illig, T.; Schindler, C.; Guzman, C. A.; Pessler, F.
Keywords
- Germany
- elderly
- feasibility
- influenza vaccination
- nonresponse bias
- pilot study
- population-based study
- response rate
- vaccinomics
|
10.1080/21645515.2017.1299300 |
Hum Vaccin Immunother |
ALI |
MHH |
BREATH |
Original |
2017 |
| Pre-clinical imaging for establishment and comparison of orthotopic non-small cell lung carcinoma: in search for models reflecting clinical scenarios |
OBJECTIVE:: Clinically relevant animal models of non-small cell lung carcinoma (NSCLC) are required for the validation of novel treatments. We compared two different orthotopic transplantation techniques as well as imaging modalities to identify suitable mouse models mimicking clinical scenarios. METHODS:: We used three genomically diverse NSCLC cell lines [National Cancer Institute (NCI)-H1703 adenosquamous cell carcinoma, NCI-H23 adenocarcinoma and A549 adenocarcinoma) for implanting tumour cells either as spheroids or cell suspension into lung parenchyma. Bioluminescence imaging (BLI) and contrast-enhanced cone beam CT (CBCT) were performed twice weekly to monitor tumour growth. Tumour histological data and microenvironmental parameters were determined. RESULTS:: Tumour development after spheroid-based transplantation differs probably due to the integrity of spheroids, as H1703 developed single localised nodules, whereas H23 showed diffuse metastatic spread starting early after transplantation. A549 transplantation as cell suspension with the help of a stereotactic system was associated with initial single localised tumour growth and eventual metastatic spread. Imaging techniques were successfully applied to monitor longitudinal tumour growth: BLI revealed highly sensitive qualitative data, whereas CBCT was associated with less sensitive quantitative data. Histology revealed significant model-dependent heterogeneity in proliferation, hypoxia, perfusion and necrosis. CONCLUSION:: Our developed orthotopic NSCLC tumours have similarity with biological growth behaviour comparable to that seen in the clinic and could therefore be used as attractive models to study tumour biology and evaluate new therapeutic strategies. The use of human cancer cell lines facilitates testing of different genomic tumour profiles that may affect treatment outcomes. ADVANCES IN KNOWLEDGE:: The combination of different imaging modalities to identify tumour growth with subsequent use in treatment planning and orthotopic transplantation techniques to develop initially single lesions to ultimate metastases pave the way towards representative pre-clinical NSCLC models for experimental testing of novel therapeutic options in future studies.
- Aktar, R.
- Dietrich, A.
- Tillner, F.
- Kotb, S.
- Lock, S.
- Willers, H.
- Baumann, M.
- Krause, M.
- Butof, R.
|
10.1259/bjr.20180539 |
Br J Radiol |
PLI |
DKFZ |
TLRC |
Original |
2018 |
