Mitochondria-Rich Fraction Isolated from Mesenchymal Stromal Cells Reduces Lung and Distal Organ Injury in Experimental Sepsis∗

Luiza Rachel Pinheiro De Carvalho, Soraia Carvalho Abreu, Ligia Lins De Castro, Luísa Helena Andrade Da Silva, Paula Matos Silva, Juliana Borges Vieira, Renata Trabach Santos, Marianna Ribeiro Cabral, Maroun Khoury, Daniel J. Weiss, Miquéias Lopes-Pacheco, Pedro Leme Silva, Fernanda Ferreira Cruz, Patricia Rieken Macedo Rocco

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

OBJECTIVES: To ascertain whether systemic administration of mitochondria-rich fraction isolated from mesenchymal stromal cells would reduce lung, kidney, and liver injury in experimental sepsis. DESIGN: Animal study. SETTING: Laboratory investigation. SUBJECTS: Sixty C57BL/6 male mice. INTERVENTIONS: Sepsis was induced by cecal ligation and puncture; sham-operated animals were used as control. At 24 hours after surgery, cecal ligation and puncture and Sham animals were further randomized to receive saline or mitochondria-rich fraction isolated from mesenchymal stromal cells (3 × 106) IV. At 48 hours, survival, peritoneal bacterial load, lung, kidney, and liver injury were analyzed. Furthermore, the effects of mitochondria on oxygen consumption rate and reactive oxygen species production of lung epithelial and endothelial cells were evaluated in vitro. MEASUREMENTS AND MAIN RESULTS: In vitro exposure of lung epithelial and endothelial cells from cecal ligation and puncture animals to mitochondria-rich fraction isolated from mesenchymal stromal cells restored oxygen consumption rate and reduced total reactive oxygen species production. Infusion of exogenous mitochondria-rich fraction from mesenchymal stromal cells (mitotherapy) reduced peritoneal bacterial load, improved lung mechanics and histology, and decreased the expression of interleukin-1β, keratinocyte chemoattractant, indoleamine 2,3-dioxygenase-2, and programmed cell death protein 1 in lung tissue, while increasing keratinocyte growth factor expression and survival rate in cecal ligation and puncture-induced sepsis. Mitotherapy also reduced kidney and liver injury, plasma creatinine levels, and messenger RNA expressions of interleukin-18 in kidney, interleukin-6, indoleamine 2,3-dioxygenase-2, and programmed cell death protein 1 in liver, while increasing nuclear factor erythroid 2-related factor-2 and superoxide dismutase-2 in kidney and interleukin-10 in liver. CONCLUSIONS: Mitotherapy decreased lung, liver, and kidney injury and increased survival rate in cecal ligation and puncture-induced sepsis.

Original languageEnglish
Pages (from-to)E880-E890
JournalCritical Care Medicine
DOIs
StateAccepted/In press - 2021

Bibliographical note

Publisher Copyright:
© 2021 Lippincott Williams and Wilkins. All rights reserved.

Keywords

  • animal model
  • critical illness
  • inflammation
  • mitotherapy
  • oxidative stress
  • remodeling

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