• 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, and RoccoPatricia Rieken MacedoPRMLaboratory of Pulmonary Investigation, Carlos Chagas Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, B.
• Laboratory of Pulmonary Investigation, Carlos Chagas Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
• Crit. Care Med. 2021 Sep 1; 49 (9): e880e890e880-e890.

ObjectivesTo ascertain whether systemic administration of mitochondria-rich fraction isolated from mesenchymal stromal cells would reduce lung, kidney, and liver injury in experimental sepsis.DesignAnimal study.SettingLaboratory investigation.SubjectsSixty C57BL/6 male mice.InterventionsSepsis 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 ResultsIn 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.ConclusionsMitotherapy decreased lung, liver, and kidney injury and increased survival rate in cecal ligation and puncture-induced sepsis.Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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