An activation specific anti-Mac-1 designed ankyrin repeat protein improves survival in a mouse model of acute lung injury
Abstract The acute respiratory distress syndrome (ARDS) is a life-threatening clinical condition. The number of ARDS cases has risen dramatically recently but specific treatment options are limited. ARDS is associated with an overshooting inflammatory response and neutrophils play a central role in...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-10090-6 |
| _version_ | 1818022518311616512 |
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| author | Patrick M. Siegel Anne-Sophie Przewosnik Jan Wrobel Timo Heidt Martin Moser Karlheinz Peter Christoph Bode Philipp Diehl István Bojti |
| author_facet | Patrick M. Siegel Anne-Sophie Przewosnik Jan Wrobel Timo Heidt Martin Moser Karlheinz Peter Christoph Bode Philipp Diehl István Bojti |
| author_sort | Patrick M. Siegel |
| collection | DOAJ |
| description | Abstract The acute respiratory distress syndrome (ARDS) is a life-threatening clinical condition. The number of ARDS cases has risen dramatically recently but specific treatment options are limited. ARDS is associated with an overshooting inflammatory response and neutrophils play a central role in its pathogenesis. Neutrophils express the integrin Mac-1 on their surface which adopts a resting and activated conformation depending on leukocyte activation. The aim of this study was to investigate the anti-inflammatory effects of the unique activation-specific anti-Mac-1 DARPin ‘F7’ in a mouse model of ARDS. ARDS was induced by intratracheal lipopolysaccharide (LPS) instillation and the acute (day 1–4) and chronic phase (day 5–10) were studied. After expression and purification, F7, a control DARPin and PBS, were applied daily via the intraperitoneal route. Survival and weight loss were recorded. Histological analysis of lung sections, flow cytometric leukocyte analysis of blood and bronchioalveolar lavage (BALF) were performed. Moreover, protein concentration and cytokine levels were determined in the BALF. Treatment with F7 improved survival and reduced weight loss significantly compared to treatment with the control DARPin or PBS. Neutrophil count in the BALF and peripheral blood were significantly reduced in mice treated with F7. Histology revealed significantly reduced pulmonary inflammation in the F7 treated group. Treatment with DARPin F7 inhibited neutrophil accumulation, reduced signs of local and systemic inflammation and improved survival in a mouse model of ARDS. F7 may be a novel anti-inflammatory drug candidate for the treatment of severe ARDS. |
| first_indexed | 2024-12-10T03:29:42Z |
| format | Article |
| id | doaj.art-05fd4a7a855f4fb4af21e180d27a65b3 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-10T03:29:42Z |
| publishDate | 2022-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-05fd4a7a855f4fb4af21e180d27a65b32022-12-22T02:03:50ZengNature PortfolioScientific Reports2045-23222022-04-0112111410.1038/s41598-022-10090-6An activation specific anti-Mac-1 designed ankyrin repeat protein improves survival in a mouse model of acute lung injuryPatrick M. Siegel0Anne-Sophie Przewosnik1Jan Wrobel2Timo Heidt3Martin Moser4Karlheinz Peter5Christoph Bode6Philipp Diehl7István Bojti8Department of Cardiology and Angiology I, University Heart Center Freiburg – Bad Krozingen, Faculty of Medicine, University of FreiburgDepartment of Cardiology and Angiology I, University Heart Center Freiburg – Bad Krozingen, Faculty of Medicine, University of FreiburgDepartment of Cardiology and Angiology I, University Heart Center Freiburg – Bad Krozingen, Faculty of Medicine, University of FreiburgDepartment of Cardiology and Angiology I, University Heart Center Freiburg – Bad Krozingen, Faculty of Medicine, University of FreiburgDepartment of Cardiology and Angiology I, University Heart Center Freiburg – Bad Krozingen, Faculty of Medicine, University of FreiburgAtherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes InstituteDepartment of Cardiology and Angiology I, University Heart Center Freiburg – Bad Krozingen, Faculty of Medicine, University of FreiburgDepartment of Cardiology and Angiology I, University Heart Center Freiburg – Bad Krozingen, Faculty of Medicine, University of FreiburgDepartment of Cardiology and Angiology I, University Heart Center Freiburg – Bad Krozingen, Faculty of Medicine, University of FreiburgAbstract The acute respiratory distress syndrome (ARDS) is a life-threatening clinical condition. The number of ARDS cases has risen dramatically recently but specific treatment options are limited. ARDS is associated with an overshooting inflammatory response and neutrophils play a central role in its pathogenesis. Neutrophils express the integrin Mac-1 on their surface which adopts a resting and activated conformation depending on leukocyte activation. The aim of this study was to investigate the anti-inflammatory effects of the unique activation-specific anti-Mac-1 DARPin ‘F7’ in a mouse model of ARDS. ARDS was induced by intratracheal lipopolysaccharide (LPS) instillation and the acute (day 1–4) and chronic phase (day 5–10) were studied. After expression and purification, F7, a control DARPin and PBS, were applied daily via the intraperitoneal route. Survival and weight loss were recorded. Histological analysis of lung sections, flow cytometric leukocyte analysis of blood and bronchioalveolar lavage (BALF) were performed. Moreover, protein concentration and cytokine levels were determined in the BALF. Treatment with F7 improved survival and reduced weight loss significantly compared to treatment with the control DARPin or PBS. Neutrophil count in the BALF and peripheral blood were significantly reduced in mice treated with F7. Histology revealed significantly reduced pulmonary inflammation in the F7 treated group. Treatment with DARPin F7 inhibited neutrophil accumulation, reduced signs of local and systemic inflammation and improved survival in a mouse model of ARDS. F7 may be a novel anti-inflammatory drug candidate for the treatment of severe ARDS.https://doi.org/10.1038/s41598-022-10090-6 |
| spellingShingle | Patrick M. Siegel Anne-Sophie Przewosnik Jan Wrobel Timo Heidt Martin Moser Karlheinz Peter Christoph Bode Philipp Diehl István Bojti An activation specific anti-Mac-1 designed ankyrin repeat protein improves survival in a mouse model of acute lung injury Scientific Reports |
| title | An activation specific anti-Mac-1 designed ankyrin repeat protein improves survival in a mouse model of acute lung injury |
| title_full | An activation specific anti-Mac-1 designed ankyrin repeat protein improves survival in a mouse model of acute lung injury |
| title_fullStr | An activation specific anti-Mac-1 designed ankyrin repeat protein improves survival in a mouse model of acute lung injury |
| title_full_unstemmed | An activation specific anti-Mac-1 designed ankyrin repeat protein improves survival in a mouse model of acute lung injury |
| title_short | An activation specific anti-Mac-1 designed ankyrin repeat protein improves survival in a mouse model of acute lung injury |
| title_sort | activation specific anti mac 1 designed ankyrin repeat protein improves survival in a mouse model of acute lung injury |
| url | https://doi.org/10.1038/s41598-022-10090-6 |
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