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313 results on '"Wurm, Florian M."'

5. Alpha1-antitrypsin improves survival in murine abdominal sepsis model by decreasing inflammation and sequestration of free heme.

Author

Zemtsovski, Jan D., Tumpara, Srinu, Schmidt, Sonja, Vijayan, Vijith, Klos, Andreas, Laudeley, Robert, Held, Julia, Immenschuh, Stephan, Wurm, Florian M., Welte, Tobias, Haller, Hermann, Janciauskiene, Sabina, and Shushakova, Nelli

Subjects
ACUTE phase proteins, HEME, HEMOPROTEINS, SEPSIS, BLOOD lactate
Abstract

Background: Excessive inflammation, hemolysis, and accumulation of labile heme play an essential role in the pathophysiology of multi-organ dysfunction syndrome (MODS) in sepsis. Alpha1-antitrypsin (AAT), an acute phase protein with heme binding capacity, is one of the essential modulators of host responses to inflammation. In this study, we evaluate the putative protective effect of AAT against MODS and mortality in a mouse model of polymicrobial abdominal sepsis. Methods: Polymicrobial abdominal sepsis was induced in C57BL/6N mice by cecal ligation and puncture (CLP). Immediately after CLP surgery, mice were treated intraperitoneally with three different forms of human AAT--plasmaderived native (nAAT), oxidized nAAT (oxAAT), or recombinant AAT (recAAT)-- or were injected with vehicle. Sham-operated mice served as controls. Mouse survival, bacterial load, kidney and liver function, immune cell profiles, cytokines/chemokines, and free (labile) heme levels were assessed. In parallel, in vitro experiments were carried out with resident peritoneal macrophages (MPMF) and mouse peritoneal mesothelial cells (MPMC). Results: All AAT preparations used reduced mortality in septic mice. Treatment with AAT significantly reduced plasma lactate dehydrogenase and s-creatinine levels, vascular leakage, and systemic inflammation. Specifically, AAT reduced intraperitoneal accumulation of free heme, production of cytokines/chemokines, and neutrophil infiltration into the peritoneal cavity compared to septic mice not treated with AAT. In vitro experiments performed using MPMC and primary MPMF confirmed that AAT not only significantly decreases lipopolysaccharide (LPS)-induced pro-inflammatory cell activation but also prevents the enhancement of cellular responses to LPS by free heme. In addition, AAT inhibits cell death caused by free heme in vitro. Conclusion: Data from the septic CLP mouse model suggest that intraperitoneal AAT treatment alone is sufficient to improve sepsis-associated organ dysfunctions, preserve endothelial barrier function, and reduce mortality, likely by preventing hyper-inflammatory responses and by neutralizing free heme. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Human PBMCs Form Lipid Droplets in Response to Spike Proteins.

Author

Sivaraman, Kokilavani, Pino, Paco, Raussin, Guillaume, Anchisi, Stephanie, Metayer, Charles, Dagany, Nicolas, Held, Julia, Wrenger, Sabine, Welte, Tobias, Wurm, Maria J., Wurm, Florian M., Olejnicka, Beata, and Janciauskiene, Sabina

Subjects
MONONUCLEAR leukocytes, ENDOTOXINS, STAINS & staining (Microscopy), LIPIDS, LIPID metabolism, GENE expression
Abstract

Intracellular lipid droplets (LDs) can accumulate in response to inflammation, metabolic stresses, and other physiological/pathological processes. Herein, we investigated whether spike proteins of SARS-CoV-2 induce LDs in human peripheral blood mononuclear cells (PBMCs) and in pulmonary microvascular endothelial cells (HPMECs). PBMCs or HPMECs were incubated alone or with endotoxin-free recombinant variants of trimeric spike glycoproteins (Alpha, Beta, Delta, and Omicron, 12 µg/mL). Afterward, cells were stained with Oil Red O for LDs, cytokine release was determined through ELISA, and the gene expression was analyzed through real-time PCR using TaqMan assays. Our data show that spikes induce LDs in PBMCs but not in HPMECs. In line with this, in PBMCs, spike proteins lower the expression of genes involving lipid metabolism and LD formation, such as SREBF1, HMGCS1, LDLR, and CD36. On the other hand, PBMCs exposed to spikes for 6 or 18 h did not increase in IL-1β, IL-6, IL-8, MCP-1, and TNFα release or expression as compared to non-treated controls. Thus, spike-induced LD formation in PBMCs seems to not be related to cell inflammatory activation. Further detailed studies are warranted to investigate in which specific immune cells spikes induce LDs, and what are the pathophysiological mechanisms and consequences of this induction in vivo. [ABSTRACT FROM AUTHOR]

Published
2023
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16. A new T‐antigen negative HEK293 cell line with improved AAV productivity.

Author

Croissant, Coralie, Armitano, Joshua, Lazuech, Bertrand, Švec, Danijel, Pugin, Cyril, Guesdon, Anaïs, Bryan, Louise, Castro, Antonio, Neuhaus, Léa, Fonti, Giulia, Martinis, Jacopo, Wurm, Maria J., Wurm, Florian M., and Pino, Paco

Abstract

Viral vectors for gene therapy, such as recombinant adeno‐associated viruses, are produced in human embryonic kidney (HEK) 293 cells. However, the presence of the SV40 T‐antigen‐encoding CDS SV40GP6 and SV40GP7 in the HEK293T genome raises safety issues when these cells are used in manufacturing for clinical purposes. We developed a new T‐antigen‐negative HEK cell line from ExcellGene's proprietary HEKExpress,® using the CRISPR‐Cas9 strategy. We obtained a high number of clonally‐derived cell populations and all of them were demonstrated T‐antigen negative. Stability study and AAV production evaluation showed that the deletion of the T‐antigen‐encoding locus did not impact neither cell growth nor viability nor productivity. The resulting CMC‐compliant cell line, named HEKzeroT,® is able to produce high AAV titers, from small to large scale. [ABSTRACT FROM AUTHOR]

Published
2023
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