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The Amide Local Anesthetic Ropivacaine Attenuates Acute Rejection After Allogeneic Mouse Lung Transplantation

  • Tatsuo Maeyashiki
  • Jae-Hwi Jang
  • Florian Janker
  • Yoshito Yamada
  • Ilhan Inci
  • Walter Weder
  • Tobias PiegelerEmail author
  • Wolfgang Jungraithmayr
Acute Lung Injury
  • 16 Downloads

Abstract

Purpose

Acute allograft rejection after lung transplantation remains an unsolved hurdle. The pathogenesis includes an inflammatory response during and after transplantation. Ropivacaine, an amide-linked local anesthetic, has been shown to attenuate lung injury due to its anti-inflammatory effects. We hypothesized that the drug would also be able to attenuate acute rejection (AR) after allogeneic lung transplantation.

Methods

Allogeneic, orthotopic, single left lung transplantation was performed between BALB/c (donors) and C57BL/6 (recipients) mice. Prior to explantation, lungs were flushed with normal saline with or without ropivacaine (final concentration 1 µM). Plasma levels of tumor necrosis factor-α and interleukins − 6 and − 10 were measured 3 h after transplantation by ELISA. Lung function was assessed on postoperative day five and transplanted lungs were analyzed using histology (AR), immunohistochemistry (infiltrating leukocytes) and Western blot (phosphorylation and expression of Src and caveolin-1).

Results

Ropivacaine pre-treatment significantly reduced AR scores (median 3 [minimum–maximum 2–4] for control vs. 2 [1–2] for ropivacaine, p < 0.001) and plasma levels of tumor necrosis factor-α (p = 0.01) compared to control, whereas plasma concentrations of interleukin − 6 (p = 0.008) and − 10 (p < 0.001) were increased by ropivacaine. The number of T-lymphocytes infiltrating the transplanted lung was attenuated (p = 0.02), while no differences in macrophage or B-lymphocyte numbers could be observed after ropivacaine pre-treatment. Caveolin-1 phosphorylation in ropivacaine-treated lungs was diminished (p = 0.004).

Conclusions

Pre-treatment of donor lungs with the local anesthetic ropivacaine diminished histological signs of AR after orthotopic left lung transplantation in mice, most likely due to reduced infiltration of T-lymphocytes into the graft.

Keywords

Local anesthetics Lung transplantation Inflammation Endothelium T-lymphocytes 

Notes

Acknowledgements

The authors thank Dr. Volker Eulenburg (Department of Anesthesiology and Intensive Care Medicine, University Hospital Leipzig, Leipzig, Germany) for his assistance with the Western blot analyses.

Funding

This study was supported by the Hartmann-Müller-Foundation Zurich, Switzerland (Grant No. 1773).

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable international, national, and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Supplementary material

408_2019_197_MOESM1_ESM.docx (25 kb)
Supplementary material 1 (DOCX 24 KB)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Thoracic SurgeryUniversity Hospital ZurichZurichSwitzerland
  2. 2.Department of Anesthesiology and Intensive Care MedicineUniversity Hospital LeipzigLeipzigGermany
  3. 3.Department of Thoracic SurgeryUniversity Hospital RostockRostockGermany

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