Thymosin β4 attenuates microcirculatory and hemodynamic destabilization in sepsis

Abstract

Objective: The actin polymerization regulator Thymosin β4 (Tβ4) has been shown to be involved in angiogenesis, wound healing, cell survival and anti-inflammatory responses. We have previously shown that Tβ4 is capable of recruiting pericytes, thus stabilizing the endothelial barrier function. Here, we analyzed whether treatment with Tβ4 is able to reduce the pericytes loss in lipopolysaccharides (LPS)-induced sepsis and to improve the hemodynamic function and survival in C57BL/6 mice.

Methods: Fourteen days before LPS injection, the mice were injected with an adeno-associated virus carrying the Tβ4 (rAAV.Tβ4) or LacZ gene (rAAV.LacZ). A sepsis-severity score was assessed, and non-invasive hemodynamic and permeability measurements were performed. Heart and muscle samples were analyzed for PECAM-1⁺ capillaries and NG2⁺pericytes.

Results: At 36 h, there was a decrease of sepsis severity score in rAAV.Tβ4-treated animals as compared to rAAV.LacZ-treated control. rAAV.Tβ4-treated animals displayed lower perivascular leakage and higher blood pressure compared to control. Of note, the rAAV.Tβ4 group showed a higher pericyte count in heart and peripheral muscle samples. Finally, Tβ4-treatment reduced mortality compared to control.

Conclusion: The data indicate a preventive role of Tβ4 in septic hypercirculation and highlight Tβ4 as a potential therapeutic target in severe sepsis.

Keywords:

• pericytes
• septic shock
• severe sepsis
• thymosin β4

Acknowledgments

We thank Tien Cuong Kieu and Elisabeth Raatz for their excellent technical assistance.

Declaration of interest

This paper is part of a supplemental issue, sponsored by SciClone. This work was supported by the LegerlotzStiftung (C.K) and the German Ministry of Education and Research (BMBF) (C.K. and R.H.), and FöFoLe grants of the Ludwig-Maximilians-University T Ziegler, C Kupatt, R Hinkel. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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