| Autor: |
Kasetty G; Respiratory Medicine & Allergology, Lund University and Skåne University Hospital, Lund, Sweden. Gopinath.Kasetty@med.lu.se., Papareddy P; Infection Medicine, Department of Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden., Bhongir RKV; Respiratory Medicine & Allergology, Lund University and Skåne University Hospital, Lund, Sweden., Ali MN; Respiratory Medicine & Allergology, Lund University and Skåne University Hospital, Lund, Sweden., Mori M; Department of Experimental Medical Science, Lund University and Skåne University Hospital, Lund, Sweden., Wygrecka M; Department of Biochemistry, German Center of Lung Research, University of Giessen, Giessen, Germany., Erjefält JS; Department of Experimental Medical Science, Lund University and Skåne University Hospital, Lund, Sweden., Hultgårdh-Nilsson A; Department of Experimental Medical Science, Lund University and Skåne University Hospital, Lund, Sweden., Palmberg L; Work Environment Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Solna, Sweden., Herwald H; Infection Medicine, Department of Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden., Egesten A; Respiratory Medicine & Allergology, Lund University and Skåne University Hospital, Lund, Sweden. |
| Abstrakt: |
Extracellular histones are present in the airways because of cell death occurring during inflammation. They promote inflammation and cause tissue damage due to their cationic nature. The anionic phosphoglycoprotein osteopontin (OPN) is expressed at high levels during airway inflammation and has been ascribed both pro- and anti-inflammatory roles. In this study, it was hypothesized that OPN may neutralize the harmful activities of extracellular histones at the airway mucosal surface. In a model of histone-induced acute lung injury, OPN -/- mice showed increased inflammation and tissue injury, and succumbed within 24 h, whereas wild-type mice showed lower degrees of inflammation and no mortality. In lipopolysaccharide-induced acute lung injury, wild-type mice showed less inflammation and tissue injury than OPN -/- mice. In bronchoalveolar lavage fluid from ARDS patients, high levels of OPN and also histone-OPN complexes were detected. In addition, OPN bound to histones with high affinity in vitro, resulting in less cytotoxicity and reduced formation of tissue-damaging neutrophil extracellular traps (NETs). The interaction between OPN and histones was dependent on posttranslational modification of OPN, i.e., phosphorylation. The findings demonstrate a novel role for OPN, modulating the pro-inflammatory and cytotoxic properties of free histones. |
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