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Rac1 regulates bacterial toxin-induced thrombin generation

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Abstract

Objective

Systemic inflammatory response syndrome is associated with severe coagulopathy. The purpose of this study was to examine thrombin generation in systemic inflammation triggered by the endotoxin lipopolysaccharide (LPS) and the exotoxin streptococcal M1 protein.

Methods

Thrombin generation, lung histology and myeloperoxidase (MPO) activity were determined 6 and 24 h after induction of systemic inflammation. Male C57BL/6 mice received the Rac1 inhibitor NSC23766 prior to challenge with bacterial toxins.

Results

LPS and M1 protein challenge increased neutrophil infiltration and caused damage in the lung. Time to peak thrombin formation was increased and peak and total generation of thrombin were decreased in plasma from LPS- and M1 protein-treated mice. Coincubation of samples from mice exposed to bacterial toxins with platelet poor plasma from healthy mice completely reversed the inhibitory effect of LPS and M1 protein on thrombin generation, suggesting that bacterial toxins decreased levels of plasma factors explaining the reduction of thrombin generating capacity of plasma from septic animals. NSC23766 treatment not only decreased LPS- and M1 protein-induced neutrophil accumulation as well as levels of interleukin-6 and CXCL2 in the lung, but also abolished bacterial toxin-induced changes in thrombin generation. For example, NSC23766 increased peak formation by 57 % and total thrombin generation by 48 % in LPS-treated animals at 6 h.

Conclusions

Taken together, our novel findings show that bacterial toxins increase thrombin generation via consumption of plasma factors and that Rac1 signaling plays an important role in thrombin generation in response to bacterial toxins. Thus, targeting Rac1 activity might be a useful way not only to ameliorate pulmonary inflammation, but also inhibit pathological changes in coagulation in bacterial infections.

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Acknowledgments

This work was supported by grants from the Swedish Medical Research Council (2012-3685), Yongzhi Wang is supported by a Grant from China Scholarship Council (2010631095).

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Authors and Affiliations

  1. Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Skåne University Hospital, 205 02, Malmö, Sweden

    Yongzhi Wang, Rundk Hwaiz, Lingtao Luo & Henrik Thorlacius

  2. Department of Clinical Sciences, Lund, Section of Cardiology, Lund University, Lund, Sweden

    Oscar Ö. Braun

  3. Department of Laboratory Medicine, Malmö, Section of Clinical Chemistry, Lund University, Lund, Sweden

    Eva Norström

Authors
  1. Yongzhi Wang
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  2. Rundk Hwaiz
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  3. Lingtao Luo
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  6. Henrik Thorlacius
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Correspondence to Henrik Thorlacius.

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Responsible Editor: John Di Battista.

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Wang, Y., Hwaiz, R., Luo, L. et al. Rac1 regulates bacterial toxin-induced thrombin generation. Inflamm. Res. 65, 405–413 (2016). https://doi.org/10.1007/s00011-016-0924-3

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  • DOI: https://doi.org/10.1007/s00011-016-0924-3

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