397 results on '"Gazdhar, A"'
Search Results
2. Allies or enemies? The effect of regulatory T cells and related T lymphocytes on the profibrotic environment in bleomycin-injured lung mouse models
- Author
-
Seyran, Mutlu, Melanie, Scalise, Philip, Stumbles, Amiq, Gazdhar, and Fabian, Blank
- Published
- 2023
- Full Text
- View/download PDF
3. Mesenchyme-derived vertebrate lonesome kinase controls lung organogenesis by altering the matrisome
- Author
-
Brütsch, Salome M., Madzharova, Elizabeta, Pantasis, Sophia, Wüstemann, Till, Gurri, Selina, Steenbock, Heiko, Gazdhar, Amiq, Kuhn, Gisela, Angel, Peter, Bellusci, Saverio, Brinckmann, Jürgen, auf dem Keller, Ulrich, Werner, Sabine, and Bordoli, Mattia R.
- Published
- 2023
- Full Text
- View/download PDF
4. Biogenic polymer-based patches for congenital cardiac surgery: a feasibility study
- Author
-
Emma Richert, Andrea Nienhaus, Silje Ekroll Jahren, Amiq Gazdhar, Maximilian Grab, Jürgen Hörer, Thierry Carrel, Dominik Obrist, and Paul Philipp Heinisch
- Subjects
biomedical engineering ,patch ,congenital ,biogenic polymers ,innovation ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
ObjectiveCurrently used patch materials in congenital cardiac surgery do not grow, renew, or remodel. Patch calcification occurs more rapidly in pediatric patients eventually leading to reoperations. Bacterial cellulose (BC) as a biogenic polymer offers high tensile strength, biocompatibility, and hemocompatibility. Thus, we further investigated the biomechanical properties of BC for use as patch material.MethodsThe BC-producing bacteria Acetobacter xylinum were cultured in different environments to investigate optimal culturing conditions. For mechanical characterization, an established method of inflation for biaxial testing was used. The applied static pressure and deflection height of the BC patch were measured. Furthermore, a displacement and strain distribution analysis was performed and compared to a standard xenograft pericardial patch.ResultsThe examination of the culturing conditions revealed that the BC became homogenous and stable when cultivated at 29°C, 60% oxygen concentration, and culturing medium exchange every third day for a total culturing period of 12 days. The estimated elastic modulus of the BC patches ranged from 200 to 530 MPa compared to 230 MPa for the pericardial patch. The strain distributions, calculated from preloaded (2 mmHg) to 80 mmHg inflation, show BC patch strains ranging between 0.6% and 4%, which was comparable to the pericardial patch. However, the pressure at rupture and peak deflection height varied greatly, ranging from 67 to around 200 mmHg and 0.96 to 5.28 mm, respectively. The same patch thickness does not automatically result in the same material properties indicating that the manufacturing conditions have a significant impact on durabilityConclusionsBC patches can achieve comparable results to pericardial patches in terms of strain behavior as well as in the maximum applied pressure that can be withstood without rupture. Bacterial cellulose patches could be a promising material worth further research.
- Published
- 2023
- Full Text
- View/download PDF
5. MMP-24 Is a Novel Profibrotic Factor Produced by KRT5+/ TP63+ Lung Basal Cells
- Author
-
Geiser, T.K., primary, Fytianos, K., additional, Pfister, E., additional, Baty, F., additional, Kahn, P., additional, Brutsche, M.H., additional, Hostettler, K.E., additional, and Gazdhar, A., additional
- Published
- 2024
- Full Text
- View/download PDF
6. Basal-Like Cell-Conditioned Medium Exerts Anti-Fibrotic Effects In Vitro and In Vivo
- Author
-
Petra Khan, Kleanthis Fytianos, Sabrina Blumer, Julien Roux, Amiq Gazdhar, Spasenija Savic, Lars Knudsen, Danny Jonigk, Mark P. Kuehnel, Sofia Mykoniati, Michael Tamm, Thomas Geiser, and Katrin E. Hostettler
- Subjects
basal cells ,idiopathic pulmonary fibrosis ,conditioned medium ,PGE2 ,lung fibroblasts ,aberrant basaloid cells ,Biotechnology ,TP248.13-248.65 - Abstract
In idiopathic pulmonary fibrosis (IPF), basal-like cells are atypically present in the alveolar region, where they may affect adjacent stromal cells by paracrine mechanisms. We here aimed to confirm the presence of basal-like cells in peripheral IPF lung tissue in vivo, to culture and characterize the cells in vitro, and to investigate their paracrine effects on IPF fibroblasts in vitro and in bleomycin-injured rats in vivo. Basal-like cells are mainly localized in areas of pathological bronchiolization or honeycomb cysts in peripheral IPF lung tissue. Single-cell RNA sequencing (scRNA-seq) demonstrated an overall homogeneity, the expression of the basal cell markers cytokeratin KRT5 and KRT17, and close transcriptomic similarities to basal cells in the majority of cells cultured in vitro. Basal-like cells secreted significant levels of prostaglandin E2 (PGE2), and their conditioned medium (CM) inhibited alpha-smooth muscle actin (α-SMA) and collagen 1A1 (Col1A1) and upregulated matrix metalloproteinase-1 (MMP-1) and hepatocyte growth factor (HGF) by IPF fibroblasts in vitro. The instillation of CM in bleomycin-injured rat lungs resulted in reduced collagen content, improved lung architecture, and reduced α-SMA-positive cells. Our data suggested that basal-like cells may limit aberrant fibroblast activation and differentiation in IPF through paracrine mechanisms.
- Published
- 2022
- Full Text
- View/download PDF
7. Transcriptomic profiling reveals disease-specific characteristics of epithelial cells in idiopathic pulmonary fibrosis
- Author
-
Maximilian Boesch, Florent Baty, Martin H. Brutsche, Michael Tamm, Julien Roux, Lars Knudsen, Amiq Gazdhar, Thomas Geiser, Petra Khan, and Katrin E. Hostettler
- Subjects
Idiopathic pulmonary fibrosis ,Lung fibrosis ,Epithelial cell ,Mesenchymal stem cell ,RNA-sequencing ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Idiopathic pulmonary fibrosis (IPF) is an incurable disease characterized by progressive lung fibrosis ultimately resulting in respiratory failure and death. Recurrent micro-injuries to the alveolar epithelium and aberrant alveolar wound healing with impaired re-epithelialization define the initial steps of the pathogenic trajectory. Failure of timely alveolar epithelial repair triggers hyper-proliferation of mesenchymal cells accompanied by increased deposition of extracellular matrix into the lung interstitium. Methods We previously isolated fibrosis-specific mesenchymal stem cell (MSC)-like cells from lung tissue of patients with interstitial lung diseases. These cells produced factors bearing anti-fibrotic potential and changed their morphology from mesenchymal to epithelial upon culture in an epithelial cell (EC)-specific growth medium. Here, we set out to molecularly characterize these MSC-like cell-derived ECs using global gene expression profiling by RNA-sequencing. Moreover, we aimed at characterizing disease-specific differences by comparing the transcriptomes of ECs from IPF and non-IPF sources. Results Our results suggest that differentially expressed genes are enriched for factors related to fibrosis, hypoxia, bacterial colonization and metabolism, thus reflecting many of the hallmark characteristics of pulmonary fibrosis. IPF-ECs showed enrichment of both pro- and anti-fibrotic genes, consistent with the notion of adaptive, compensatory regulation. Conclusions Our findings support the hypothesis of a functional impairment of IPF-ECs, which could possibly explain the poor clinical outcome of IPF that roughly compares to those of advanced-stage cancers. Our study provides a valuable resource for downstream mechanistic investigation and the quest for novel therapeutic IPF targets.
- Published
- 2020
- Full Text
- View/download PDF
8. Method for analysis of electrospray for gene transfer and the impact on cell viability of A549 alveolar epithelial like cells.
- Author
-
David Hradetzky, Stephan Boehringer, Paulius Ruzgys, Saulius Satkauskas, Thomas Geiser, and Amiq Gazdhar
- Published
- 2018
- Full Text
- View/download PDF
9. Anti-Fibrotic Effect of SDF-1β Overexpression in Bleomycin-Injured Rat Lung
- Author
-
Kleanthis Fytianos, Ronja Schliep, Sofia Mykoniati, Petra Khan, Katrin E. Hostettler, Michael Tamm, Amiq Gazdhar, Lars Knudsen, and Thomas Geiser
- Subjects
interstitial lung disease ,IPF ,lung fibrosis ,SDF-1b ,myofibroblast apoptosis ,lung repair and regeneration ,Pharmacy and materia medica ,RS1-441 - Abstract
Rational: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease and is associated with high mortality due to a lack of effective treatment. Excessive deposition of the extracellular matrix by activated myofibroblasts in the alveolar space leads to scar formation that hinders gas exchange. Therefore, selectively removing activated myofibroblasts with the aim to repair and remodel fibrotic lungs is a promising approach. Stromal-derived growth factor (SDF-1) is known to stimulate cellular signals which attract stem cells to the site of injury for tissue repair and remodeling. Here, we investigate the effect of overexpression of SDF-1β on lung structure using the bleomycin-injured rat lung model. Methods: Intratracheal administration of bleomycin was performed in adult male rats (F344). Seven days later, in vivo electroporation-mediated gene transfer of either SDF-1β or the empty vector was performed. Animals were sacrificed seven days after gene transfer and histology, design-based stereology, flow cytometry, and collagen measurement were performed on the tissue collected. For in vitro experiments, lung fibroblasts obtained from IPF patients were used. Results: Seven days after SDF-1β gene transfer to bleomycin-injured rat lungs, reduced total collagen, reduced collagen fibrils, improved histology and induced apoptosis of myofibroblasts were observed. Furthermore, it was revealed that TNF-α mediates SDF-1β-induced apoptosis of myofibroblasts; moreover, SDF-1β overexpression increased alveolar epithelial cell numbers and proliferation in vivo and also induced their migration in vitro. Conclusions: Our study demonstrates a new antifibrotic mechanism of SDF-1β overexpression and suggests SDF-1β as a potential new approach for the treatment of lung fibrosis.
- Published
- 2022
- Full Text
- View/download PDF
10. Electrospray Mediated Localized and Targeted Chemotherapy in a Mouse Model of Lung Cancer
- Author
-
Paulius Ruzgys, Stephan Böhringer, Ayse Sila Dokumaci, Yvonne Hari, Christian M. Schürch, Frido Brühl, Stefan Schürch, Sönke Szidat, Carsten Riether, Saulius Šatkauskas, Thomas Geiser, David Hradetzky, and Amiq Gazdhar
- Subjects
localized and targeted therapy ,electrospray ,novel cancer treatment ,coulomb repulsion ,localized tumor treatment ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Background: An advanced stage, centrally localized invasive tumor is a major cause of sudden death in lung cancer patients. Currently, chemotherapy, radiotherapy, laser ablation, or surgical resection if possible are the available state-of-the-art treatments but none of these guarantee remedy or long-term relief and are often associated with fatal complications. Allowing localized chemotherapy, by direct and confined drug delivery only at the tumor site, could be a promising option for preoperative down staging or palliative therapy. Here we report the localized and targeted application of intra tumor delivery of chemotherapeutics using a novel device based on the principle of electrospray.Methods: C57BL/6J mice were injected with Lewis lung carcinoma cells subcutaneously. After 15 days, the animals were anesthetized and the tumors were exposed by skin incision. Tumors were electrosprayed with 100 µg cisplatin on days 0 and 2, and tumor volumes were measured daily. Animals were sacrificed on day 7 after the first electrospray and tumors were analyzed by immunohistochemistry.Results: In this proof-of-concept study, we report that the tumor volume was reduced by 81.2% (22.46 ± 12.14 mm3) after two electrospray mediated Cisplatin deliveries, while the control tumor growth, at the same time point, increased by 200% (514.30 ± 104.50 mm3). Moreover, tunnel and Caspase-3 positive cells were increased after Cisplatin electrospray compared to other experimental groups of animals.Conclusion: Targeted drug delivery by electrospray is efficient in the subcutaneous mouse model of lung cancer and offers a promising opportunity for further development toward its clinical application.
- Published
- 2021
- Full Text
- View/download PDF
11. Efficacy of Combined in-vivo Electroporation-Mediated Gene Transfer of VEGF, HGF, and IL-10 on Skin Flap Survival, Monitored by Label-Free Optical Imaging: A Feasibility Study
- Author
-
S. Morteza Seyed Jafari, Fabian Blank, Hallie E. Ramser, Alan E. Woessner, Maziar Shafighi, Thomas Geiser, Kyle P. Quinn, Robert E. Hunger, and Amiq Gazdhar
- Subjects
cell metabolism ,flap survival ,gene delivery ,HGF ,IL-10 ,in-vivo electroporation ,Surgery ,RD1-811 - Abstract
Preventing surgical flaps necrosis remains challenging. Laser Doppler imaging and ultrasound can monitor blood flow in flap regions, but they do not directly measure the cellular response to ischemia. The study aimed to investigate the efficacy of synergistic in-vivo electroporation-mediated gene transfer of interleukin 10 (IL-10) with either hepatocyte growth factor (HGF) or vascular endothelial growth factor (VEGF) on the survival of a modified McFarlane flap, and to evaluate the effect of the treatment on cell metabolism, using label-free fluorescence lifetime imaging. Fifteen male Wistar rats (290–320 g) were randomly divided in three groups: group-A (control group) underwent surgery and received no gene transfer. Group-B received electroporation mediated hIL-10 gene delivery 24 h before and VEGF gene delivery 24 h after surgery. Group-C received electroporation mediated hIL-10 gene delivery 24 h before and hHGF gene delivery 24 h after surgery. The animals were assessed clinically and histologically. In addition, label-free fluorescence lifetime imaging was performed on the flap. Synergistic electroporation mediated gene delivery significantly decreased flap necrosis (P = 0.0079) and increased mean vessel density (P = 0.0079) in treatment groups B and C compared to control group-A. NADH fluorescence lifetime analysis indicated an increase in oxidative phosphorylation in the epidermis of the group-B (P = 0.039) relative to controls. These findings suggested synergistic in-vivo electroporation-mediated gene transfer as a promising therapeutic approach to enhance viability and vascularity of skin flap. Furthermore, the study showed that combinational gene therapy promoted an increase in tissue perfusion and a relative increase in oxidative metabolism within the epithelium.
- Published
- 2021
- Full Text
- View/download PDF
12. Non-viral Gene Delivery Methods for Bone and Joints
- Author
-
Benjamin Gantenbein, Shirley Tang, Julien Guerrero, Natalia Higuita-Castro, Ana I. Salazar-Puerta, Andreas S. Croft, Amiq Gazdhar, and Devina Purmessur
- Subjects
non-viral gene delivery ,bone ,tendon ,cartilage ,intervertebral disk ,GDF5 ,Biotechnology ,TP248.13-248.65 - Abstract
Viral carrier transport efficiency of gene delivery is high, depending on the type of vector. However, viral delivery poses significant safety concerns such as inefficient/unpredictable reprogramming outcomes, genomic integration, as well as unwarranted immune responses and toxicity. Thus, non-viral gene delivery methods are more feasible for translation as these allow safer delivery of genes and can modulate gene expression transiently both in vivo, ex vivo, and in vitro. Based on current studies, the efficiency of these technologies appears to be more limited, but they are appealing for clinical translation. This review presents a summary of recent advancements in orthopedics, where primarily bone and joints from the musculoskeletal apparatus were targeted. In connective tissues, which are known to have a poor healing capacity, and have a relatively low cell-density, i.e., articular cartilage, bone, and the intervertebral disk (IVD) several approaches have recently been undertaken. We provide a brief overview of the existing technologies, using nano-spheres/engineered vesicles, lipofection, and in vivo electroporation. Here, delivery for microRNA (miRNA), and silencing RNA (siRNA) and DNA plasmids will be discussed. Recent studies will be summarized that aimed to improve regeneration of these tissues, involving the delivery of bone morphogenic proteins (BMPs), such as BMP2 for improvement of bone healing. For articular cartilage/osteochondral junction, non-viral methods concentrate on targeted delivery to chondrocytes or MSCs for tissue engineering-based approaches. For the IVD, growth factors such as GDF5 or GDF6 or developmental transcription factors such as Brachyury or FOXF1 seem to be of high clinical interest. However, the most efficient method of gene transfer is still elusive, as several preclinical studies have reported many different non-viral methods and clinical translation of these techniques still needs to be validated. Here we discuss the non-viral methods applied for bone and joint and propose methods that can be promising in clinical use.
- Published
- 2020
- Full Text
- View/download PDF
13. Culture of human alveolar epithelial type II cells by sprouting
- Author
-
Petra Khan, Kleanthis Fytianos, Luca Tamò, Michael Roth, Michael Tamm, Thomas Geiser, Amiq Gazdhar, and Katrin E Hostettler
- Subjects
Alveolar epithelium ,Cell culture ,Primary human cell ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Type II alveolar epithelial cells (AT2) play a pivotal role in maintaining the integrity and function of the alveoli. Only recently, the role of impaired epithelial repair mechanisms after injury in the pathogenesis of idiopathic pulmonary fibrosis has been demonstrated, and has shifted the AT2 cell in the focus of interest. Therefore, using primary human AT2 cells instead of cell lines for in vitro experiments has become desirable. Several groups have developed methods to isolate human AT2 cells applying tissue digestion and consecutive filtration in their protocols. Here we present a technique to isolate primary human AT2 cells by sprouting directly from peripheral human lung tissue. Methods Epithelial cell cultures were established from lung tissue obtained from patients undergoing diagnostic or therapeutic video-assisted thoracoscopic surgery or undergoing flexible bronchoscopy with transbronchial biopsy. Lung tissue was cut into small pieces and those were placed into cell culture flasks containing supplemented epithelial growth medium for cell sprouting. Cells were characterized by immunofluorescence stainings for E-cadherin, pan-cytokeratin, surfactant protein C (SP-C), and for lysotracker; fluorescent surfactant associated protein B (SP-B) uptake and secretion was assessed by live cell imaging; RNA levels of SP-A, SP-B, SP-C, and SP-D were determined by real-time PCR; Electron microscopy was used to search for the presence of lamellar bodies. Results Sprouting of cells started two to four days after the start of culture. Epithelial differentiation was confirmed by positive staining for E-cadherin and pan-cytokeratin. Further characterization demonstrated positivity for the AT2 cell marker SP-C and for lysotracker which selectively labels lamellar bodies in cultured AT2 cells. The up-take and release of SP-B, a mechanism described for AT2 cells only, was demonstrated by live cell imaging. Real-time RT-PCR showed mRNA expression of all four surfactant proteins with highest levels for SP-B. The presence of lamellar bodies was demonstrated by electron microscopy. Conclusions This study describes a novel method for isolating AT2 cells from human adult lung tissue by sprouting. The characterization of the cultured AT2 cells complies with current criteria for an alveolar type 2 cell phenotype. Compared to current protocols for the culture of AT2 cells, isolating the cells by sprouting is simple, avoids proteolytic tissue digestion, and has the advantage to be successful even from as few tissue as attained from a transbronchial forceps biopsy.
- Published
- 2018
- Full Text
- View/download PDF
14. Biogenic polymer-based patches for congenital cardiac surgery: a feasibility study
- Author
-
Richert, Emma, primary, Nienhaus, Andrea, additional, Ekroll Jahren, Silje, additional, Gazdhar, Amiq, additional, Grab, Maximilian, additional, Hörer, Jürgen, additional, Carrel, Thierry, additional, Obrist, Dominik, additional, and Heinisch, Paul Philipp, additional
- Published
- 2023
- Full Text
- View/download PDF
15. Gene Network Analysis of Interstitial Macrophages After Treatment with Induced Pluripotent Stem Cells Secretome (iPSC-cm) in the Bleomycin Injured Rat Lung
- Author
-
Tamò, Luca, Simillion, Cedric, Hibaoui, Youssef, Feki, Anis, Gugger, Mathias, Prasse, Antje, Jäger, Benedikt, Goldmann, Torsten, Geiser, Thomas, and Gazdhar, Amiq
- Published
- 2018
- Full Text
- View/download PDF
16. Application of electrochemotherapy in the management of primary and metastatic cutaneous malignant tumours: a systematic review and meta-analysis
- Author
-
Seyed Jafari, S. Morteza, Jabbary Lak, Fatemeh, Gazdhar, Amiq, Shafighi, Maziar, Borradori, Luca, and Hunger, Robert E.
- Published
- 2018
- Full Text
- View/download PDF
17. Efficacy of In Vivo Electroporation-Mediated IL-10 Gene Delivery on Survival of Skin Flaps
- Author
-
Seyed Jafari, S. Morteza, Shafighi, Maziar, Beltraminelli, Helmut, Weber, Benedikt, Schmid, Ralph. A., Geiser, Thomas, Gazdhar, Amiq, and Hunger, Robert E.
- Published
- 2018
- Full Text
- View/download PDF
18. Interactome Analysis of iPSC Secretome and Its Effect on Macrophages In Vitro
- Author
-
Luca Tamò, Kleanthis Fytianos, Fabienne Caldana, Cedric Simillion, Anis Feki, Izabela Nita, Manfred Heller, Thomas Geiser, and Amiq Gazdhar
- Subjects
lung fibrosis ,macrophages ,induced pluripotent stem cells ,stem cells secretome ,lung repair and regeneration ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Induced pluripotent stem cell secretome (iPSC-CM) mitigate organ injury and help in repair. Macrophages play a critical role in tissue repair and regeneration and can be directed to promote tissue repair by iPSC-CM, although the exact mechanisms are not known. In the current investigative study, we evaluated the possible mechanism by which iPSC-CM regulates the phenotype and secretory pattern of macrophages in vitro. Macrophages were obtained from human peripheral blood mononuclear cells and differentiated to various subpopulations and treated with either iPSC-CM or control media in vitro. Macrophage phenotype was assessed by flow cytometry, gene expression changes by qRT PCR and secretory pattern by multiplex protein analysis. The protein and gene interaction network revealed the involvement of Amyloid precursor protein (APP) and ELAV-like protein 1 (ELAVL-1) both present in the iPSC-CM to play an important role in regulating the macrophage phenotype and their secretory pattern. This exploratory study reveals, in part, the possible mechanism and identifies two potential targets by which iPSC-CM regulate macrophages and help in repair and regeneration.
- Published
- 2021
- Full Text
- View/download PDF
19. Mitochondrial DNA mutations and respiratory chain dysfunction in idiopathic and connective tissue disease-related lung fibrosis
- Author
-
Jaeger, Veronika K., Lebrecht, Dirk, Nicholson, Andrew G., Wells, Athol, Bhayani, Harshil, Gazdhar, Amiq, Tamm, Michael, Venhoff, Nils, Geiser, Thomas, and Walker, Ulrich A.
- Published
- 2019
- Full Text
- View/download PDF
20. Allies or enemies? The effect of regulatory T cells and related T lymphocytes on the profibrotic environment in bleomycin-injured lung mouse models
- Author
-
Seyran, Mutlu, primary, Melanie, Scalise, additional, Philip, Stumbles, additional, Amiq, Gazdhar, additional, and Fabian, Blank, additional
- Published
- 2022
- Full Text
- View/download PDF
21. Biogenic polymer-based patches for congenital cardiac surgery: a feasibility study
- Author
-
Richert, Emma, Nienhaus, Andrea, Jahren, Silje Ekroll, Gazdhar, Amiq, Grab, Maximilian, Hörer, Jürgen, Carrel, Thierry, Obrist, Dominik, and Heinisch, Paul Philipp
- Subjects
610 Medicine & health - Abstract
OBJECTIVE Currently used patch materials in congenital cardiac surgery do not grow, renew, or remodel. Patch calcification occurs more rapidly in pediatric patients eventually leading to reoperations. Bacterial cellulose (BC) as a biogenic polymer offers high tensile strength, biocompatibility, and hemocompatibility. Thus, we further investigated the biomechanical properties of BC for use as patch material. METHODS The BC-producing bacteria Acetobacter xylinum were cultured in different environments to investigate optimal culturing conditions. For mechanical characterization, an established method of inflation for biaxial testing was used. The applied static pressure and deflection height of the BC patch were measured. Furthermore, a displacement and strain distribution analysis was performed and compared to a standard xenograft pericardial patch. RESULTS The examination of the culturing conditions revealed that the BC became homogenous and stable when cultivated at 29°C, 60% oxygen concentration, and culturing medium exchange every third day for a total culturing period of 12 days. The estimated elastic modulus of the BC patches ranged from 200 to 530 MPa compared to 230 MPa for the pericardial patch. The strain distributions, calculated from preloaded (2 mmHg) to 80 mmHg inflation, show BC patch strains ranging between 0.6% and 4%, which was comparable to the pericardial patch. However, the pressure at rupture and peak deflection height varied greatly, ranging from 67 to around 200 mmHg and 0.96 to 5.28 mm, respectively. The same patch thickness does not automatically result in the same material properties indicating that the manufacturing conditions have a significant impact on durability. CONCLUSIONS BC patches can achieve comparable results to pericardial patches in terms of strain behavior as well as in the maximum applied pressure that can be withstood without rupture. Bacterial cellulose patches could be a promising material worth further research.
- Published
- 2023
22. Mesenchyme-derived vertebrate lonesome kinase controls lung organogenesis by altering the matrisome
- Author
-
Salome M. Brütsch, Elizabeta Madzharova, Sophia Pantasis, Till Wüstemann, Selina Gurri, Heiko Steenbock, Amiq Gazdhar, Gisela Kuhn, Peter Angel, Saverio Bellusci, Jürgen Brinckmann, Ulrich auf dem Keller, Sabine Werner, and Mattia R. Bordoli
- Subjects
Pharmacology ,Proteomics ,Cellular and Molecular Neuroscience ,Lung organogenesis ,Skull ,Pkdcc ,Molecular Medicine ,610 Medicine & health ,Cell Biology ,Collagen ,Molecular Biology - Abstract
Vertebrate lonesome kinase (VLK) is the only known secreted tyrosine kinase and responsible for the phosphorylation of a broad range of secretory pathway-resident and extracellular matrix proteins. However, its cell-type specific functions in vivo are still largely unknown. Therefore, we generated mice lacking the VLK gene (protein kinase domain containing, cytoplasmic (Pkdcc)) in mesenchymal cells. Most of the homozygous mice died shortly after birth, most likely as a consequence of their lung abnormalities and consequent respiratory failure. E18.5 embryonic lungs showed a reduction of alveolar type II cells, smaller bronchi, and an increased lung tissue density. Global mass spectrometry-based quantitative proteomics identified 97 proteins with significantly and at least 1.5-fold differential abundance between genotypes. Twenty-five of these had been assigned to the extracellular region and 15 to the mouse matrisome. Specifically, fibromodulin and matrilin-4, which are involved in extracellular matrix organization, were significantly more abundant in lungs from Pkdcc knockout embryos. These results support a role for mesenchyme-derived VLK in lung development through regulation of matrix dynamics and the resulting modulation of alveolar epithelial cell differentiation., Cellular and Molecular Life Sciences, 80 (4), ISSN:1420-682X, ISSN:1420-9071
- Published
- 2023
23. In Vivo Electroporation-Mediated, Intrahepatic Alpha1 Antitrypsin Gene Transfer Reduces Pulmonary Emphysema in Pallid Mice
- Author
-
Marco A. Sutter, Tiziana P. Cremona, Izabela Nita, Eleonora Cavarra, Giuseppe Lungarella, Eli C. Lewis, Johannes C. Schittny, Thomas Geiser, and Amiq Gazdhar
- Subjects
alpha1 antitrypsin ,nonviral gene delivery ,electroporation ,localized gene delivery ,emphysema ,liver gene transfer ,Pharmacy and materia medica ,RS1-441 - Abstract
Rationale: Mutation in the alpha1 antitrypsin (AAT) gene leads to low circulating levels of AAT, which is associated with several disease processes including pulmonary emphysema. The standard of care relies on substitution with plasma-purified AAT. We studied a novel approach to obtain sustained therapeutic levels of circulating AAT using nonviral in vivo electroporation-mediated gene transfer to the liver. Methods: In vivo intrahepatic electroporation-mediated human AAT gene transfer was performed in C57 Bl/6J mice carrying a genetic deficiency of murine AAT (pallid mice) and suffering from pulmonary emphysema. The animals were evaluated for lung function using flexiVent and detailed stereological assessments. Lung neutrophilic burden was assessed. Results: Pallid mice showed morphologically detectable pulmonary emphysema. Thirty days after in vivo electroporation-mediated gene transfer directly aimed at the liver, circulating human AAT was elevated and lung function was significantly improved compared to non-treated pallid mice. Stereological analysis revealed a reduction in pulmonary emphysema. Conclusion: Our data indicate that in vivo intrahepatic electroporation-mediated gene transfer of AAT is a safe and efficient procedure resulting in reduction of pulmonary emphysema in pallid mice.
- Published
- 2020
- Full Text
- View/download PDF
24. An approach towards bronchoscopic-based gene therapy using electrical field accelerated plasmid droplets.
- Author
-
David Hradetzky, Stephan Boehringer, Thomas Geiser, and Amiq Gazdhar
- Published
- 2012
- Full Text
- View/download PDF
25. Anti-Fibrotic Effect of SDF-1β Overexpression in Bleomycin-Injured Rat Lung
- Author
-
Fytianos, Kleanthis, primary, Schliep, Ronja, additional, Mykoniati, Sofia, additional, Khan, Petra, additional, Hostettler, Katrin E., additional, Tamm, Michael, additional, Gazdhar, Amiq, additional, Knudsen, Lars, additional, and Geiser, Thomas, additional
- Published
- 2022
- Full Text
- View/download PDF
26. Bone marrow stem cells modified with human interleukin 10 attenuate acute rejection in rat lung allotransplantation†
- Author
-
Pieróg, Jarosław, Tamo, Luca, Fakin, Richard, Kocher, Gregor, Gugger, Mathias, Grodzki, Tomasz, Geiser, Thomas, Gazdhar, Amiq, and Schmid, Ralph A
- Published
- 2018
- Full Text
- View/download PDF
27. Human Bronchial Epithelial Cells Induce CD141/CD123/DC-SIGN/FLT3 Monocytes That Promote Allogeneic Th17 Differentiation
- Author
-
Carolina Obregon, Amiq Gazdhar, Fabian Blank, Valerie Cesson, Alban Lovis, John David Aubert, Romain Lazor, Francois Spertini, Anne Wilson, Katrin Hostettler, and Laurent P. Nicod
- Subjects
bronchial epithelial cell-conditioned media ,monocytes ,monocyte-derived dendritic cell ,Th17 ,interleukin-17 ,IL-1β ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Little is known about monocyte differentiation in the lung mucosal environment and about how the epithelium shapes monocyte function. We studied the role of the soluble component of bronchial epithelial cells (BECs) obtained under basal culture conditions in innate and adaptive monocyte responses. Monocytes cultured in bronchial epithelial cell-conditioned media (BEC-CM) specifically upregulate CD141, CD123, and DC-SIGN surface levels and FLT3 expression, as well as the release of IL-1β, IL-6, and IL-10. BEC-conditioned monocytes stimulate naive T cells to produce IL-17 through IL-1β mechanism and also trigger IL-10 production by memory T cells. Furthermore, monocytes cultured in an inflammatory environment induced by the cytokines IL-6, IL-8, IL-1β, IL-15, TNF-α, and GM-CSF also upregulate CD123 and DC-SIGN expression. However, only inflammatory cytokines in the epithelial environment boost the expression of CD141. Interestingly, we identified a CD141/CD123/DC-SIGN triple positive population in the bronchoalveolar lavage fluid (BALF) from patients with different inflammatory conditions, demonstrating that this monocyte population exists in vivo. The frequency of this monocyte population was significantly increased in patients with sarcoidosis, suggesting a role in inflammatory mechanisms. Overall, these data highlight the specific role that the epithelium plays in shaping monocyte responses. Therefore, the unraveling of these mechanisms contributes to the understanding of the function that the epithelium may play in vivo.
- Published
- 2017
- Full Text
- View/download PDF
28. Multipotent mesenchymal stem cells in lung fibrosis.
- Author
-
Katrin E Hostettler, Amiq Gazdhar, Petra Khan, Spasenija Savic, Luca Tamo, Didier Lardinois, Michael Roth, Michael Tamm, and Thomas Geiser
- Subjects
Medicine ,Science - Abstract
Stem cells have been identified in the human lung; however, their role in lung disease is not clear. We aimed to isolate mesenchymal stem cells (MSC) from human lung tissue and to study their in vitro properties.MSC were cultured from lung tissue obtained from patients with fibrotic lung diseases (n = 17), from emphysema (n = 12), and normal lungs (n = 3). Immunofluorescence stainings were used to characterize MSC. The effect of MSC-conditioned media (MSC-CM) on fibroblast proliferation and on lung epithelial wound repair was studied.Expression of CD44, CD90, and CD105 characterized the cells as MSC. Moreover, the cells stained positive for the pluripotency markers Oct3/4 and Nanog. Positive co-stainings of chemokine receptor type 4 (CXCR4) with CD44, CD90 or CD105 indicated the cells are of bone marrow origin. MSC-CM significantly inhibited the proliferation of lung fibroblasts by 29% (p = 0.0001). Lung epithelial repair was markedly increased in the presence of MSC-CM (+ 32%). Significantly more MSC were obtained from fibrotic lungs than from emphysema or control lungs.Our study demonstrates enhanced numbers of MSC in fibrotic lung tissue as compared to emphysema and normal lung. The cells inhibit the proliferation of fibroblasts and enhance epithelial repair in vitro. Further in vivo studies are needed to elucidate their potential role in the treatment of lung fibrosis.
- Published
- 2017
- Full Text
- View/download PDF
29. Size-dependent accumulation of particles in lysosomes modulates dendritic cell function through impaired antigen degradation
- Author
-
Seydoux E, Rothen-Rutishauser B, Nita IM, Balog S, Gazdhar A, Stumbles PA, Petri-Fink A, Blank F, and von Garnier C
- Subjects
Medicine (General) ,R5-920 - Abstract
Emilie Seydoux,1,2 Barbara Rothen-Rutishauser,1,3 Izabela M Nita,1 Sandor Balog,3 Amiq Gazdhar,1 Philip A Stumbles,4,5 Alke Petri-Fink,3,6 Fabian Blank,1,* Christophe von Garnier1,*1Department of Respiratory Medicine, Inselspital, Bern University Hospital, Department of Clinical Research, University of Bern, 2Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland; 3Adolphe Merkle Institute, University of Fribourg, Fribourg, Switzerland; 4School of Veterinary and Life Sciences, Molecular and Biomedical Sciences, Murdoch University, Perth, WA, Australia; 5Telethon Kids Institute, Perth, WA, Australia; 6Department of Chemistry, University of Fribourg, Fribourg, Switzerland*These authors contributed equally to the manuscriptIntroduction: Nanosized particles may enable therapeutic modulation of immune responses by targeting dendritic cell (DC) networks in accessible organs such as the lung. To date, however, the effects of nanoparticles on DC function and downstream immune responses remain poorly understood. Methods: Bone marrow–derived DCs (BMDCs) were exposed in vitro to 20 or 1,000 nm polystyrene (PS) particles. Particle uptake kinetics, cell surface marker expression, soluble protein antigen uptake and degradation, as well as in vitro CD4+ T-cell proliferation and cytokine production were analyzed by flow cytometry. In addition, co-localization of particles within the lysosomal compartment, lysosomal permeability, and endoplasmic reticulum stress were analyzed. Results: The frequency of PS particle–positive CD11c+/CD11b+ BMDCs reached an early plateau after 20 minutes and was significantly higher for 20 nm than for 1,000 nm PS particles at all time-points analyzed. PS particles did not alter cell viability or modify expression of the surface markers CD11b, CD11c, MHC class II, CD40, and CD86. Although particle exposure did not modulate antigen uptake, 20 nm PS particles decreased the capacity of BMDCs to degrade soluble antigen, without affecting their ability to induce antigen-specific CD4+ T-cell proliferation. Co-localization studies between PS particles and lysosomes using laser scanning confocal microscopy detected a significantly higher frequency of co-localized 20 nm particles as compared with their 1,000 nm counterparts. Neither size of PS particle caused lysosomal leakage, expression of endoplasmic reticulum stress gene markers, or changes in cytokines profiles. Conclusion: These data indicate that although supposedly inert PS nanoparticles did not induce DC activation or alteration in CD4+ T-cell stimulating capacity, 20 nm (but not 1,000 nm) PS particles may reduce antigen degradation through interference in the lysosomal compartment. These findings emphasize the importance of performing in-depth analysis of DC function when developing novel approaches for immune modulation with nanoparticles. Keywords: polystyrene particles, nanoparticles, immune modulation, mouse dendritic cells, CD4+ T-cells
- Published
- 2014
30. Induced pluripotent stem cell derived alveolar lung organoids
- Author
-
Ozan, Vedat Burak, Tschirren, Anna-Barbara, Gazdhar, Amiq, and Geiser, Thomas
- Subjects
610 Medicine & health - Published
- 2022
31. Novel nasal virosome spray vaccine to protect against COVID-19
- Author
-
Tiziana Patrizia Cremona, Burak Vedat Ozan, Melanie Scalise, Melanie Scherer, Seyran Mutlu, Anna Barbara Tschirren, Farien Bhoelan, Denzel Bemelman, Philippe Plattet, Toon Stegmann, Thomas Geiser, Sylvain Fleury, and Amiq Gazdhar
- Published
- 2022
32. Novel nasal virosome spray vaccine to protect against COVID-19
- Author
-
Cremona, Tiziana Patrizia, primary, Ozan, Burak Vedat, additional, Scalise, Melanie, additional, Scherer, Melanie, additional, Mutlu, Seyran, additional, Tschirren, Anna Barbara, additional, Bhoelan, Farien, additional, Bemelman, Denzel, additional, Plattet, Philippe, additional, Stegmann, Toon, additional, Geiser, Thomas, additional, Fleury, Sylvain, additional, and Gazdhar, Amiq, additional
- Published
- 2022
- Full Text
- View/download PDF
33. Basal-Like Cell-Conditioned Medium Exerts Anti-Fibrotic Effects In Vitro and In Vivo
- Author
-
Khan, Petra, primary, Fytianos, Kleanthis, additional, Blumer, Sabrina, additional, Roux, Julien, additional, Gazdhar, Amiq, additional, Savic, Spasenija, additional, Knudsen, Lars, additional, Jonigk, Danny, additional, Kuehnel, Mark P., additional, Mykoniati, Sofia, additional, Tamm, Michael, additional, Geiser, Thomas, additional, and Hostettler, Katrin E., additional
- Published
- 2022
- Full Text
- View/download PDF
34. LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity
- Author
-
Bombaci, Giuseppe, primary, Sarangdhar, Mayuresh Anant, additional, Andina, Nicola, additional, Tardivel, Aubry, additional, Yu, Eric Chi-Wang, additional, Mackie, Gillian M, additional, Pugh, Matthew, additional, Ozan, Vedat Burak, additional, Banz, Yara, additional, Spinetti, Thibaud, additional, Hirzel, Cedric, additional, Youd, Esther, additional, Schefold, Joerg C, additional, Taylor, Graham, additional, Gazdhar, Amiq, additional, Bonadies, Nicolas, additional, Angelillo-Scherrer, Anne, additional, Schneider, Pascal, additional, Maslowski, Kendle M, additional, and Allam, Ramanjaneyulu, additional
- Published
- 2022
- Full Text
- View/download PDF
35. Basal-Like Cell-Conditioned Medium Exerts Anti-Fibrotic Effects In Vitro and In Vivo
- Author
-
Khan, Petra, Fytianos, Kleanthis, Blumer, Sabrina, Roux, Julien, Gazdhar, Amiq, Savic, Spasenija, Knudsen, Lars, Jonigk, Danny D., Kuehnel, Mark P., Mykoniati, Sofia, Tamm, Michael, Geiser, Thomas, and Hostettler, Katrin E.
- Subjects
610 Medicine & health ,respiratory system ,respiratory tract diseases - Abstract
Frontiers in Bioengineering and Biotechnology 10, 1-12 (2022). doi:10.3389/fbioe.2022.844119, Published by Frontiers Media, Lausanne
- Published
- 2022
36. Allies or enemies? The effect of regulatory T cells and related T lymphocytes on the profibrotic environment in bleomycin-injured lung mouse models
- Author
-
Mutlu Seyran, Scalise Melanie, Stumbles Philip, Gazdhar Amiq, and Blank Fabian
- Subjects
610 Medicine & health ,General Medicine ,610 Medizin und Gesundheit ,General Biochemistry, Genetics and Molecular Biology - Abstract
Idiopathic pulmonary fibrosis (IPF) is characterized by permanent scarring of lung tissue and declining lung function, and is an incurable disease with increase in prevalence over the past decade. The current consensus is that aberrant wound healing following repeated injuries to the pulmonary epithelium is the most probable cause of IPF, with various immune inflammatory pathways having been reported to impact disease pathogenesis. While the role of immune cells, specifically T lymphocytes and regulatory T cells (Treg), in IPF pathogenesis has been reported and discussed recently, the pathogenic or beneficial roles of these cells in inducing or preventing lung fibrosis is still debated. This lack of understanding could be due in part to the difficulty in obtaining diseased human lung tissue for research purposes. For this reason, many animal models have been developed over the years to attempt to mimic the main clinical hallmarks of IPF: among these, inducing lung injury in rodents with the anti-cancer agent bleomycin has now become the most commonly studied animal model of IPF. Pulmonary fibrosis is the major side effect when bleomycin is administered for cancer treatment in human patients, and a similar effect can be observed after intra-tracheal administration of bleomycin to rodents. Despite many pathophysiological pathways of lung fibrosis having been investigated in bleomycin-injured animal models, one central facet still remains controversial, namely the involvement of specific T lymphocyte subsets, and in particular Treg, in disease pathogenesis. This review aims to summarize the major findings and conclusions regarding the involvement of immune cells and their receptors in the pathogenesis of IPF, and to elaborate on important parallels between animal models and the human disease. A more detailed understanding of the role of Treg and other immune cell subsets in lung injury and fibrosis derived from animal models is a critical basis for translating this knowledge to the development of new immune-based therapies for the treatment of human IPF.
- Published
- 2022
- Full Text
- View/download PDF
37. Basal-Like Cell-Conditioned Medium Exerts Anti-Fibrotic Effects
- Author
-
Petra, Khan, Kleanthis, Fytianos, Sabrina, Blumer, Julien, Roux, Amiq, Gazdhar, Spasenija, Savic, Lars, Knudsen, Danny, Jonigk, Mark P, Kuehnel, Sofia, Mykoniati, Michael, Tamm, Thomas, Geiser, and Katrin E, Hostettler
- Abstract
In idiopathic pulmonary fibrosis (IPF), basal-like cells are atypically present in the alveolar region, where they may affect adjacent stromal cells by paracrine mechanisms. We here aimed to confirm the presence of basal-like cells in peripheral IPF lung tissue
- Published
- 2021
38. LRR-protein RNH1 dampens the inflammasome activation and is associated with COVID-19 severity
- Author
-
Bombaci, Giuseppe, Sarangdhar, Mayuresh Anant, Andina, Nicola, Tardivel, Aubry, Yu, Eric Chi-Wang, Mackie, Gillian M, Pugh, Matthew, Ozan, Vedat Burak, Banz, Yara, Spinetti, Thibaud, Hirzel, Cedric, Youd, Esther, Schefold, Joerg C, Taylor, Graham, Gazdhar, Amiq, Bonadies, Nicolas, Angelillo-Scherrer, Anne, Schneider, Pascal, Maslowski, Kendle M, and Allam, Ramanjaneyulu
- Subjects
Male ,Mice, Knockout ,Proteasome Endopeptidase Complex ,Inflammasomes ,Caspase 1 ,NF-kappa B ,Patient Acuity ,COVID-19 ,610 Medicine & health ,Leucine-Rich Repeat Proteins ,Mice, Inbred C57BL ,Mice ,NLR Family, Pyrin Domain-Containing 3 Protein ,570 Life sciences ,biology ,Animals ,Humans ,COVID-19/immunology ,COVID-19/pathology ,Carrier Proteins/metabolism ,Caspase 1/metabolism ,Inflammasomes/metabolism ,Leucine-Rich Repeat Proteins/metabolism ,NF-kappa B/metabolism ,NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ,Proteasome Endopeptidase Complex/metabolism ,Carrier Proteins - Abstract
Inflammasomes are cytosolic innate immune sensors of pathogen infection and cellular damage that induce caspase-1-mediated inflammation upon activation. Although inflammation is protective, uncontrolled excessive inflammation can cause inflammatory diseases and can be detrimental, such as in coronavirus disease (COVID-19). However, the underlying mechanisms that control inflammasome activation are incompletely understood. Here we report that the leucine-rich repeat (LRR) protein ribonuclease inhibitor (RNH1), which shares homology with LRRs of NLRP (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing) proteins, attenuates inflammasome activation. Deletion of RNH1 in macrophages increases interleukin (IL)-1β production and caspase-1 activation in response to inflammasome stimulation. Mechanistically, RNH1 decreases pro-IL-1β expression and induces proteasome-mediated caspase-1 degradation. Corroborating this, mouse models of monosodium urate (MSU)-induced peritonitis and lipopolysaccharide (LPS)-induced endotoxemia, which are dependent on caspase-1, respectively, show increased neutrophil infiltration and lethality in Rnh1 -/- mice compared with wild-type mice. Furthermore, RNH1 protein levels were negatively related with disease severity and inflammation in hospitalized COVID-19 patients. We propose that RNH1 is a new inflammasome regulator with relevance to COVID-19 severity.
- Published
- 2021
39. Mitochondrial DNA mutations and respiratory chain dysfunction in idiopathic and connective tissue disease-related lung fibrosis
- Author
-
Nils Venhoff, Amiq Gazdhar, Athol U. Wells, Thomas Geiser, Veronika K. Jaeger, Michael Tamm, Andrew G. Nicholson, Ulrich A. Walker, Harshil Bhayani, and Dirk Lebrecht
- Subjects
Adult ,Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Mitochondrial DNA ,Biopsy ,lcsh:Medicine ,610 Medicine & health ,Mitochondrion ,DNA, Mitochondrial ,Article ,Electron Transport ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Connective Tissue Diseases ,Lung cancer ,lcsh:Science ,Aged ,Aged, 80 and over ,Multidisciplinary ,Lung ,medicine.diagnostic_test ,business.industry ,lcsh:R ,Interstitial lung disease ,Middle Aged ,respiratory system ,medicine.disease ,Connective tissue disease ,3. Good health ,respiratory tract diseases ,030104 developmental biology ,Mitochondrial respiratory chain ,medicine.anatomical_structure ,Case-Control Studies ,Mutation ,Female ,lcsh:Q ,Lung Diseases, Interstitial ,Reactive Oxygen Species ,business ,030217 neurology & neurosurgery - Abstract
Reactive oxygen species (ROS) are implicated in the aetiology of interstitial lung disease (ILD). We investigated the role of large-scale somatically acquired mutations in mitochondrial DNA (mtDNA) and consecutive respiratory chain dysfunction as a trigger of ROS-formation and lung fibrosis. Mitochondria were analysed in lung biopsies from 30 patients with idiopathic or connective tissue disease (CTD)-related ILD and 13 controls. In 17 patients we had paired biopsies from upper and lower lobes. Control samples were taken from lung cancer resections without interstitial fibrosis. Malondialdehyde, a marker of ROS-formation, was elevated in ILD-biopsies (p = 0.044). The activity of the mitochondrial respiratory chain (cytochrome c-oxidase/succinate dehydrogenase [COX/SDH]-ratio) was depressed in ILD (median = 0.10,) compared with controls (0.12, p
- Published
- 2019
40. Modulation of the unfolded protein response pathway as an antiviral approach in airway epithelial cells
- Author
-
Izabela Nita, Marco P. Alves, Blandina I. Oliveira Esteves, Amiq Gazdhar, Melanie Brügger, Aline Schögler, Oliver Stephan Caliaro, and Thomas Geiser
- Subjects
0301 basic medicine ,Programmed cell death ,Cystic Fibrosis ,Rhinovirus ,030106 microbiology ,Cellular homeostasis ,Bronchi ,Respiratory Mucosa ,Virus Replication ,Antiviral Agents ,03 medical and health sciences ,chemistry.chemical_compound ,Virology ,540 Chemistry ,Humans ,Child ,610 Medicine & health ,Endoplasmic Reticulum Chaperone BiP ,Cells, Cultured ,Pharmacology ,630 Agriculture ,Endoplasmic reticulum ,Epithelial Cells ,Tunicamycin ,Endoplasmic Reticulum Stress ,030104 developmental biology ,Viral replication ,chemistry ,Case-Control Studies ,Unfolded Protein Response ,Cancer research ,Unfolded protein response ,Chronic inflammatory response ,570 Life sciences ,biology ,Respiratory virus ,Signal Transduction - Abstract
Introduction Rhinovirus (RV) infection is a major cause of cystic fibrosis (CF) lung morbidity with limited therapeutic options. Various diseases involving chronic inflammatory response and infection are associated with endoplasmic reticulum (ER) stress and subsequent activation of the unfolded protein response (UPR), an adaptive response to maintain cellular homeostasis. Recent evidence suggests impaired ER stress response in CF airway epithelial cells, this might be a reason for recurrent viral infection in CF. Therefore, assuming that ER stress inducing drugs have antiviral properties, we evaluated the activation of the UPR by selected ER stress inducers as an approach to control virus replication in the CF bronchial epithelium. Methods We assessed the levels of UPR markers, namely the glucose-regulated protein 78 (Grp78) and the C/EBP homologous protein (CHOP), in primary CF and control bronchial epithelial cells and in a CF and control bronchial epithelial cell line before and after infection with RV. The cells were also pretreated with ER stress-inducing drugs and RV replication and shedding was measured by quantitative RT-PCR and by a TCID50 assay, respectively. Cell death was assessed by a lactate dehydrogenate (LDH) activity test in supernatants. Results We observed a significantly impaired induction of Grp78 and CHOP in CF compare to control cells following RV infection. The ER stress response could be significantly induced in CF cells by pharmacological ER stress inducers Brefeldin A, Tunicamycin, and Thapsigargin. The chemical induction of the UPR pathway prior to RV infection of CF and control cells reduced viral replication and shedding by up to two orders of magnitude and protected cells from RV-induced cell death. Conclusion RV infection causes an impaired activation of the UPR in CF cells. Rescue of the ER stress response by chemical ER stress inducers reduced significantly RV replication in CF cells. Thus, pharmacological modulation of the UPR might represent a strategy to control respiratory virus replication in the CF bronchial epithelium.
- Published
- 2019
41. Alveolar Derecruitment and Collapse Induration as Crucial Mechanisms in Lung Injury and Fibrosis
- Author
-
Lutz, Dennis, Gazdhar, Amiq, Lopez-Rodriguez, Elena, Ruppert, Clemens, Mahavadi, Poornima, Günther, Andreas, Klepetko, Walter, Bates, Jason H., Smith, Bradford, Geiser, Thomas, Ochs, Matthias, and Knudsen, Lars
- Published
- 2015
- Full Text
- View/download PDF
42. Stem cell secretome attenuates acute rejection in rat lung allotransplant
- Author
-
Amiq Gazdhar, Ralph A. Schmid, Cedric Simillion, Kleanthis Fytianos, Gregor J. Kocher, Jarosław Pieróg, Manfred Heller, Mathias Gugger, Thomas Geiser, Tomasz Grodzki, Luca Tamò, Fabian Blank, and Adriano Taddeo
- Subjects
Graft Rejection ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Cell ,030204 cardiovascular system & hematology ,Mesenchymal Stem Cell Transplantation ,Group A ,Gastroenterology ,Group B ,03 medical and health sciences ,0302 clinical medicine ,Rats, Inbred BN ,Internal medicine ,medicine ,Animals ,Transplantation, Homologous ,Lung transplantation ,Rejection (Psychology) ,Lung ,Immunosuppression Therapy ,business.industry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Rats, Inbred F344 ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,030228 respiratory system ,Surgery ,Stem cell ,Cardiology and Cardiovascular Medicine ,business ,Immunosuppressive Agents ,Lung Transplantation - Abstract
OBJECTIVES Stem cells secrete significant amounts of bioactive factors in their secretome that can be immunosuppressive. We studied the effect of the secretome obtained from bone marrow-derived mesenchymal stem cells (BMSC-sec) in combination with cyclosporine A following acute rejection of lung allografts in the rat. METHODS Lung allotransplants were performed from male Brown Norway donor rats to recipient male Fisher 344 rats. Rat BMSC-sec was introduced intratracheally in the recipient every day after the transplant until the day the animal was sacrificed. Group A (n = 5) received control medium and cyclosporine A (2.5 mg/kg body weight intraperitoneally) for 5 days post-transplant and group B (n = 5) received BMSC-sec and cyclosporine A. Blood gas analysis was performed to assess graft function at day 5 only from the graft, and the tissue was sampled for measurement of the wet/dry ratio and histological grading of rejection. RESULTS All control animals (group A) showed severe signs of rejection. At day 5 grafts in group B showed improved gas exchange (i.e. mean PaO2 mmHg 237.9 ± 130 mmHg vs 24.9 ± 7.8 mmHg in group A). Histological examination according to the International Society of Heart and Lung Transplantation (ISHLT) revealed moderate to severe rejection in all animals in group A (III B) and a significant improvement in group B (I-IIA). The wet/dry ratio was also reduced in group B to 6.19 ± 0.6 compared to 9.36 ± 2 in group A. Furthermore, in vitro T-cell proliferation was reduced after treatment with BMSC-sec for CD 3 cells (69.55 ± 07 vs 73 ± 0.84), for CD 4 (24.95 ± 1.2 vs 27.75 ± 0.21) and for CD 8 cells (3.75 ± 0.2 vs 5.68 ± 0.02). CONCLUSIONS The BMSC-sec is a promising novel cell-based therapeutic option for acute rejection in a rat lung allograft model.
- Published
- 2018
43. LRR protein RNH1 dampens the inflammasome activation and is associated with adverse clinical outcomes in COVID-19 patients
- Author
-
Nicolas Bonadies, Joerg C. Schefold, Aubry Tardivel, Eric Chi-Wang Yu, Vedat Burak Ozan, Thibaud Spinetti, Esther Youd, Amiq Gazdhar, Kendle M. Maslowski, Ramanjaneyulu Allam, Pascal Schneider, Cédric Hirzel, Matthew Pugh, Mayuresh Anant Sarangdhar, Anne Angelillo-Scherrer, Giuseppe Bombaci, Graham S. Taylor, Yara Banz, Gillian M Mackie, and Nicola Andina
- Subjects
Innate immune system ,business.industry ,Ribonuclease inhibitor ,Regulator ,Peritonitis ,Inflammation ,Inflammasome ,Leucine-rich repeat ,medicine.disease ,Cytosol ,Immunology ,medicine ,medicine.symptom ,business ,medicine.drug - Abstract
Inflammasomes are cytosolic innate immune sensors of pathogen infection and cellular damage that induce caspase-1 mediated inflammation upon activation. Although inflammation is protective, uncontrolled excessive inflammation can cause inflammatory diseases and can be detrimental, such as in COVID-19. However, the underlying mechanisms that control inflammasome activation are incompletely understood. Here we report that the leucine rich repeat (LRR) protein Ribonuclease inhibitor (RNH1), which shares homology with LRRs of NLRP proteins, attenuates inflammasome activation. Deletion of RNH1 in macrophages increases IL-1β production and caspase-1 activation for inflammasome stimuli. Mechanistically, RNH1 decreases pro-IL-1β expression and induces proteasome-mediated caspase-1 degradation. Corroborating this, mouse models of monosodium urate (MSU)-induced peritonitis and LPS-induced endotoxemia, which are dependent on caspase-1, respectively show increased neutrophil infiltration and lethality in Rnh1-/- mice compared to WT mice. Furthermore, RNH1 protein levels are negatively correlated with inflammation and disease severity in hospitalized COVID-19 patients. We propose that RNH1 is a new inflammasome regulator with relevance to COVID-19 severity.
- Published
- 2021
44. In Vivo Electroporation-Mediated Gene Delivery to the Beating Heart
- Author
-
Tevaearai, Hendrik T., primary, Gazdhar, Amiq, additional, Giraud, Marie-Noëlle, additional, and Flück, Martin, additional
- Published
- 2014
- Full Text
- View/download PDF
45. Interactome Analysis of iPSC Secretome and Its Effect on Macrophages In Vitro
- Author
-
Anis Feki, Izabela Nita, Luca Tamò, Kleanthis Fytianos, Fabienne Caldana, Cedric Simillion, Thomas Geiser, Amiq Gazdhar, and Manfred Heller
- Subjects
Proteome ,induced pluripotent stem cells ,610 Medicine & health ,Interactome ,Catalysis ,Article ,Flow cytometry ,Inorganic Chemistry ,lcsh:Chemistry ,03 medical and health sciences ,0302 clinical medicine ,Gene expression ,Amyloid precursor protein ,medicine ,Macrophage ,Humans ,Protein Interaction Maps ,Physical and Theoretical Chemistry ,Induced pluripotent stem cell ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,biology ,medicine.diagnostic_test ,Regeneration (biology) ,lung repair and regeneration ,Gene Expression Profiling ,Macrophages ,Organic Chemistry ,lung fibrosis ,Cell Differentiation ,General Medicine ,Phenotype ,Computer Science Applications ,Cell biology ,stem cells secretome ,lcsh:Biology (General) ,lcsh:QD1-999 ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Culture Media, Conditioned ,biology.protein ,Leukocytes, Mononuclear - Abstract
Simple Summary Macrophages play essential role in repair, regeneration and tissue remodeling. Role of macrophages in progression of lung fibrosis is established. Secretome of Induced pluripotent stem cells (iPSC-CM) has shown to reduce lung fibrosis and regulate macrophage phenotype, however exact mechanism is not known. Using advanced bioinformatics analysis by gene network analysis in this study we identified two components AAP and ELAVL-1 present in the iPSC-CM playing important role in regulation of macrophage phenotype. In this invitro study we confirmed experimentally that AAP and ELAVL1 play essential role by changing the profibrotic phenotype of the macrophages to pro resolution macrophages. We demonstrate reduction in gene expression and cytokine secretion of profibrotic macrophages after iPSC-CM treatment. Our study confirms antifibrotic and regenerative potential of iPSC-CM. Abstract Induced pluripotent stem cell secretome (iPSC-CM) mitigate organ injury and help in repair. Macrophages play a critical role in tissue repair and regeneration and can be directed to promote tissue repair by iPSC-CM, although the exact mechanisms are not known. In the current investigative study, we evaluated the possible mechanism by which iPSC-CM regulates the phenotype and secretory pattern of macrophages in vitro. Macrophages were obtained from human peripheral blood mononuclear cells and differentiated to various subpopulations and treated with either iPSC-CM or control media in vitro. Macrophage phenotype was assessed by flow cytometry, gene expression changes by qRT PCR and secretory pattern by multiplex protein analysis. The protein and gene interaction network revealed the involvement of Amyloid precursor protein (APP) and ELAV-like protein 1 (ELAVL-1) both present in the iPSC-CM to play an important role in regulating the macrophage phenotype and their secretory pattern. This exploratory study reveals, in part, the possible mechanism and identifies two potential targets by which iPSC-CM regulate macrophages and help in repair and regeneration.
- Published
- 2021
46. LRR protein RNH1 dampens the inflammasome activation and is associated with adverse clinical outcomes in COVID-19 patients
- Author
-
Bombaci, Giuseppe, Sarangdhar, Mayuresh Anant, Andina, Nicola, Tardivel, Aubry Bernard Maurice, Chi-Wang Yu, Eric, Mackie, Gillian M., Pugh, Matthew, Ozan, Vedat Burak, Banz, Yara, Spinetti, Thibaud, Hirzel, C��dric, Youd, Esther, Schefold, Joerg C., Taylor, Graham, Gazdhar, Amiq, Bonadies, Nicolas, Angelillo-Scherrer, Anne, Schneider, Pascal, Maslowski, Kendle M., and Allam, Ramanjaneyulu
- Subjects
570 Life sciences ,biology ,610 Medicine & health - Abstract
Inflammasomes are cytosolic innate immune sensors of pathogen infection and cellular damage that induce caspase-1 mediated inflammation upon activation. Although inflammation is protective, uncontrolled excessive inflammation can cause inflammatory diseases and can be detrimental, such as in COVID-19. However, the underlying mechanisms that control inflammasome activation are incompletely understood. Here we report that the leucine rich repeat (LRR) protein Ribonuclease inhibitor (RNH1), which shares homology with LRRs of NLRP proteins, attenuates inflammasome activation. Deletion of RNH1 in macrophages increases IL-1b production and caspase-1 activation for inflammasome stimuli. Mechanistically, RNH1 decreases pro-IL-1b expression and induces proteasome-mediated caspase-1 degradation. Corroborating this, mouse models of monosodium urate (MSU)-induced peritonitis and LPS-induced endotoxemia, which are dependent on caspase-1, respectively show increased neutrophil infiltration and lethality in Rnh1-/- mice compared to WT mice. Furthermore, RNH1 protein levels are negatively correlated with inflammation and disease severity in hospitalized COVID-19 patients. We propose that RNH1 is a new inflammasome regulator with relevance to COVID-19 severity
- Published
- 2021
- Full Text
- View/download PDF
47. Efficacy of Combined
- Author
-
S. Morteza Seyed Jafari, Fabian Blank, Hallie E. Ramser, Alan E. Woessner, Maziar Shafighi, Thomas Geiser, Kyle P. Quinn, Robert E. Hunger, and Amiq Gazdhar
- Subjects
Necrosis ,Genetic enhancement ,lcsh:Surgery ,610 Medicine & health ,Gene delivery ,Pharmacology ,030207 dermatology & venereal diseases ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,cell metabolism ,In vivo ,Medicine ,HGF ,gene delivery ,Original Research ,business.industry ,Electroporation ,lcsh:RD1-811 ,VEGF ,Vascular endothelial growth factor ,label free fluorescence lifetime imaging ,chemistry ,030220 oncology & carcinogenesis ,flap survival ,IL-10 ,Hepatocyte growth factor ,Surgery ,medicine.symptom ,business ,Perfusion ,in-vivo electroporation ,medicine.drug - Abstract
Preventing surgical flaps necrosis remains challenging. Laser Doppler imaging and ultrasound can monitor blood flow in flap regions, but they do not directly measure the cellular response to ischemia. The study aimed to investigate the efficacy of synergistic in-vivo electroporation-mediated gene transfer of interleukin 10 (IL-10) with either hepatocyte growth factor (HGF) or vascular endothelial growth factor (VEGF) on the survival of a modified McFarlane flap, and to evaluate the effect of the treatment on cell metabolism, using label-free fluorescence lifetime imaging. Fifteen male Wistar rats (290–320 g) were randomly divided in three groups: group-A (control group) underwent surgery and received no gene transfer. Group-B received electroporation mediated hIL-10 gene delivery 24 h before and VEGF gene delivery 24 h after surgery. Group-C received electroporation mediated hIL-10 gene delivery 24 h before and hHGF gene delivery 24 h after surgery. The animals were assessed clinically and histologically. In addition, label-free fluorescence lifetime imaging was performed on the flap. Synergistic electroporation mediated gene delivery significantly decreased flap necrosis (P = 0.0079) and increased mean vessel density (P = 0.0079) in treatment groups B and C compared to control group-A. NADH fluorescence lifetime analysis indicated an increase in oxidative phosphorylation in the epidermis of the group-B (P = 0.039) relative to controls. These findings suggested synergistic in-vivo electroporation-mediated gene transfer as a promising therapeutic approach to enhance viability and vascularity of skin flap. Furthermore, the study showed that combinational gene therapy promoted an increase in tissue perfusion and a relative increase in oxidative metabolism within the epithelium.
- Published
- 2020
48. HGF Expressing Stem Cells in Usual Interstitial Pneumonia Originate from the Bone Marrow and Are Antifibrotic.
- Author
-
Amiq Gazdhar, Njomeza Susuri, Katrin Hostettler, Mathias Gugger, Lars Knudsen, Michael Roth, Matthias Ochs, and Thomas Geiser
- Subjects
Medicine ,Science - Abstract
Pulmonary fibrosis may result from abnormal alveolar wound repair after injury. Hepatocyte growth factor (HGF) improves alveolar epithelial wound repair in the lung. Stem cells were shown to play a major role in lung injury, repair and fibrosis. We studied the presence, origin and antifibrotic properties of HGF-expressing stem cells in usual interstitial pneumonia.Immunohistochemistry was performed in lung tissue sections and primary alveolar epithelial cells obtained from patients with usual interstitial pneumonia (UIP, n = 7). Bone marrow derived stromal cells (BMSC) from adult male rats were transfected with HGF, instilled intratracheally into bleomycin injured rat lungs and analyzed 7 and 14 days later.In UIP, HGF was expressed in specific cells mainly located in fibrotic areas close to the hyperplastic alveolar epithelium. HGF-positive cells showed strong co-staining for the mesenchymal stem cell markers CD44, CD29, CD105 and CD90, indicating stem cell origin. HGF-positive cells also co-stained for CXCR4 (HGF+/CXCR4+) indicating that they originate from the bone marrow. The stem cell characteristics were confirmed in HGF secreting cells isolated from UIP lung biopsies. In vivo experiments showed that HGF-expressing BMSC attenuated bleomycin induced pulmonary fibrosis in the rat, indicating a beneficial role of bone marrow derived, HGF secreting stem cells in lung fibrosis.HGF-positive stem cells are present in human fibrotic lung tissue (UIP) and originate from the bone marrow. Since HGF-transfected BMSC reduce bleomycin induced lung fibrosis in the bleomycin lung injury and fibrosis model, we assume that HGF-expressing, bone-marrow derived stem cells in UIP have antifibrotic properties.
- Published
- 2013
- Full Text
- View/download PDF
49. Nonviral Gene Delivery of Growth and Differentiation Factor 5 to Human Mesenchymal Stem Cells Injected into a 3D Bovine Intervertebral Disc Organ Culture System
- Author
-
Christian Bucher, Amiq Gazdhar, Lorin M. Benneker, Thomas Geiser, and Benjamin Gantenbein-Ritter
- Subjects
Internal medicine ,RC31-1245 - Abstract
Intervertebral disc (IVD) cell therapy with unconditioned 2D expanded mesenchymal stem cells (MSC) is a promising concept yet challenging to realize. Differentiation of MSCs by nonviral gene delivery of growth and differentiation factor 5 (GDF5) by electroporation mediated gene transfer could be an excellent source for cell transplantation. Human MSCs were harvested from bone marrow aspirate and GDF5 gene transfer was achieved by in vitro electroporation. Transfected cells were cultured as monolayers and as 3D cultures in 1.2% alginate bead culture. MSC expressed GDF5 efficiently for up to 21 days. The combination of GDF5 gene transfer and 3D culture in alginate showed an upregulation of aggrecan and SOX9, two markers for chondrogenesis, and KRT19 as a marker for discogenesis compared to untransfected cells. The cells encapsulated in alginate produced more proteoglycans expressed in GAG/DNA ratio. Furthermore, GDF5 transfected MCS injected into an IVD papain degeneration organ culture model showed a partial recovery of the GAG/DNA ratio after 7 days. In this study we demonstrate the potential of GDF5 transfected MSC as a promising approach for clinical translation for disc regeneration.
- Published
- 2013
- Full Text
- View/download PDF
50. Electrospray Mediated Localized and Targeted Chemotherapy in a Mouse Model of Lung Cancer
- Author
-
Ruzgys, Paulius, primary, Böhringer, Stephan, additional, Dokumaci, Ayse Sila, additional, Hari, Yvonne, additional, Schürch, Christian M., additional, Brühl, Frido, additional, Schürch, Stefan, additional, Szidat, Sönke, additional, Riether, Carsten, additional, Šatkauskas, Saulius, additional, Geiser, Thomas, additional, Hradetzky, David, additional, and Gazdhar, Amiq, additional
- Published
- 2021
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.