Effects of Thrombomodulin in Reducing Lethality and Suppressing Neutrophil Extracellular Trap Formation in the Lungs and Liver in a Lipopolysaccharide-Induced Murine Septic Shock Model.

Yu Kato,Takanori Onouchi,Takahiro Kawaji,Yasuyo Shimomura,Osamu Nishida,Naohide Kuriyama,Tomoyuki Nakamura,Daisuke Hasegawa

doi:10.3390/ijms22094933

Abstract

Neutrophil extracellular trap (NET) formation, an innate immune system response, is associated with thrombogenesis and vascular endothelial injury. Circulatory disorders due to microvascular thrombogenesis are one of the principal causes of organ damage. NET formation in organs contributes to the exacerbation of sepsis, which is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. We have previously reported that recombinant human soluble thrombomodulin (rTM) reduces lipopolysaccharide (LPS)-induced NET formation in vitro. Here, we aimed to show that thrombomodulin (TM)-mediated suppression of NET formation protects against organ damage in sepsis. Mice were injected intraperitoneally (i.p.) with 10 mg/kg LPS. rTM (6 mg/kg/day) or saline was administered i.p. 1 h after LPS injection. In the LPS-induced murine septic shock model, extracellular histones, which are components of NETs, were observed in the liver and lungs. In addition, the serum cytokine (interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), macrophage chemotactic protein-1 (MCP-1), and interleukin-10 (IL-10)) levels were increased. The administration of rTM in this model prevented NET formation in the organs and suppressed the increase in the levels of all cytokines except IL-1β. Furthermore, the survival rate improved. We provide a novel role of TM in treating inflammation and NETs in organs during sepsis.

Highlights

Recent studies have reported the formation of neutrophil extracellular traps (NETs) by neutrophils, which presents a new type of innate immune response [1]
NET formation plays an important role in confining infections to small areas via its involvement in coagulation and thrombogenesis
Using an in vitro study involving human neutrophil and platelet cultures, we have reported that recombinant human soluble thrombomodulin suppresses lipopolysaccharide (LPS)-induced NET formation [14], and we have hypothesized that by suppressing

Summary

Introduction

Recent studies have reported the formation of neutrophil extracellular traps (NETs) by neutrophils, which presents a new type of innate immune response [1]. NETs are reticular structures composed of various intracellular neutrophil components such as histones and nuclear DNA, and cytoplasmic antibacterial proteins such as elastase and myeloperoxidase. These structures are released by neutrophils to capture and kill cells [1]. The role of NET formation in immunothrombosis has attracted attention [2]. NET formation induces vascular endothelial injury and microvascular circulation disorders [3,4]. In rapidly progressing systemic inflammation, such as sepsis, this immune response is induced in the local infection region, and in the non-infection region, and develops into organ failure

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