Antithrombin III improved neutrophil extracellular traps in lung after the onset of endotoxemia

Abstract

Background: Coagulation and inflammation are closely linked during acute inflammatory conditions, such as sepsis. Antithrombin (AT) is an anticoagulant that also has anti-inflammatory activities. The effects of therapeutically administering AT III after the onset of endotoxemia or sepsis were not clear. Here, we studied the effects of administering AT III after inducing lethal endotoxemia in mice.

Methods: Mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce endotoxemia. AT III was administered 3 h later. We assessed survival and the severity of endotoxemia and quantified plasma cytokine levels and biochemical markers of liver and kidney function. In the lungs, we examined neutrophil accumulation, neutrophil extracellular traps, alveolar wall thickness, and chemokine (C-X-C motif) ligand 1 (cxcl-1), cxcl-2, and high mobility group box 1 expression.

Results: Administering AT III reduced the severity and mortality of LPS-induced endotoxemia as indicated by 24-h survival of 84% of the mice that received LPS + AT III and only 53% of mice given LPS alone (P < 0.05). AT III treatment attenuated several changes induced in the lungs by endotoxemia including cxcl-2 mRNA expression, high mobility group box 1 protein expression, neutrophil accumulation, alveolar septal thickening, and neutrophil extracellular trap formation. AT III did not decrease plasma cytokine levels or plasma urea nitrogen levels that were upregulated as a result of LPS-induced endotoxemia.

Conclusions: Administration of AT III after the onset of endotoxemia improved outcomes in a mouse model. The attenuation of lung inflammation may have a large impact on mortality and morbidity. Because lung inflammation increases the likelihood of mortality from sepsis, AT III could be a useful agent in septic patients.

Keywords: Anti-Inflammation; Antithrombin; HMGB-1; Lung; Neutrophil extracellular traps; Sepsis.