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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.
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Details
1 University of Freiburg, Department of Cardiology and Angiology I, University Heart Center Freiburg – Bad Krozingen, Faculty of Medicine, Freiburg, Germany (GRID:grid.5963.9)
2 Baker Heart and Diabetes Institute, Atherothrombosis and Vascular Biology Laboratory, Melbourne, Australia (GRID:grid.1051.5) (ISNI:0000 0000 9760 5620); Monash University, Department of Medicine, Central Clinical School, Melbourne, Australia (GRID:grid.1002.3) (ISNI:0000 0004 1936 7857); University of Melbourne, Department of Cardiometabolic Health, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X)