Abstract
In sepsis, the severity-dependent decrease of von Willebrand factor (VWF)-inactivating protease, a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13), results in platelet aggregation and consumption, leading to sepsis-associated thrombotic microangiopathy (TMA) and organ failure. Previous reports assessing its functional deficiency have pinpointed involvement of autoantibodies or mutations to propagate thrombotic thrombocytopenic purpura (TTP). However, mechanisms of acquired ADAMTS13 deficiency during host response remain unclear. To enhance understanding of ADAMTS13 deficiency in sepsis, we evaluated changes in expression of mRNA coding ADAMTS13 during septic conditions using primary cellular sources of the protease. We hypothesized that proinflammatory cytokines and constituents of serum from septic patients affect the transcriptional level of ADAMTS13 in vitro, and previously recommended therapeutic agents as adjunctive therapy for sepsis interact therewith. Cultured hepatic stellate cells (HSCs), endothelial cells (HMEC) and human precision-cut liver slices as an ex vivo model were stimulated with sepsis prototypic cytokines, bacterial endotoxin and pooled serum obtained from septic patients. Stimulation resulted in a significant decrease in ADAMTS13 mRNA between 10% and 80% of basal transcriptional rates. Costimulation of selenite or recombinant activated protein C (APC) with serum prevented ADAMTS13 decrease in HSCs and increased ADAMTS13 transcripts in HMEC. In archived clinical samples, the activity of ADAMTS13 in septic patients treated with APC (n = 5) increased with an accompanying decrease in VWF propeptide as surrogate for improved endothelial function. In conclusion, proinflammatory conditions of sepsis repress mRNA coding ADAMTS13 and the ameliorating effect by selenite and APC may support the concept for identification of beneficial mechanisms triggered by these drugs at a molecular level.
Highlights
Despite therapy with appropriate antibiotics and intensive supportive care, sepsis carries a persistently high morbidity and mortality [1,2,3,4]
To gain insight into mechanisms of ADAMTS13 deficiency in systemic inflammation and sepsis, we investigated the effects of proinflammatory cytokines, endotoxins and constituents of serum obtained from septic patients on ADAMTS13 expression on a transcriptional level
We report that the dysbalance ratio between von Willebrand factor (VWF) and ADAMTS13 might be governed by treatment of endothelial dysfunction with activated protein C (APC)
Summary
Despite therapy with appropriate antibiotics and intensive supportive care, sepsis carries a persistently high morbidity and mortality [1,2,3,4]. Sepsis is a progressive injurious process aggravating from a systemic inflammatory response to infection [5]. The continuum of sepsis pathophysiology involves a complex integrated response involving immune cell activation, inflammatory mediators and the coagulation system. Central to these responses are alterations in endothelial cell function and a shift to a proinflammatory and procoagulant surface, which amplifies the initial signal intensity [6,7]. Alterations in microcirculation and microvascular permeability precede early tissue injury and organ failure [8]. Pathogenic mechanisms and messengers involved in processes resulting in remote organ injury require further investigation
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