Eicosapentaenoic acid potentiates the therapeutic effects of adipose tissue-derived mesenchymal stromal cells on lung and distal organ injury in experimental sepsis.
BACKGROUND
Even though mesenchymal stromal cells (MSCs) mitigate lung and distal organ damage in experimental polymicrobial sepsis, mortality remains high. We investigated whether preconditioning with eicosapentaenoic acid (EPA) would potentiate MSC actions in experimental sepsis by further decreasing lung and distal organ injury, thereby improving survival.


METHODS
In C57BL/6 mice, sepsis was induced by cecal hligation and puncture (CLP); sham-operated animals were used as control. Twenty-four hours after surgery, CLP mice were further randomized to receive saline, adipose tissue-derived (AD)-MSCs (105, nonpreconditioned), or AD-MSCs preconditioned with EPA for 6 h (105, EPA-preconditioned MSCs) intravenously. After 24 h, survival rate, sepsis severity score, lung mechanics and histology, protein level of selected biomarkers in lung tissue, cellularity in blood, distal organ damage, and MSC distribution (by technetium-99m tagging) were analyzed. Additionally, the effects of EPA on the secretion of resolvin-D1 (RvD1), prostaglandin E2 (PGE2), interleukin (IL)-10, and transforming growth factor (TGF)-β1 by MSCs were evaluated in vitro.


RESULTS
Nonpreconditioned and EPA-preconditioned AD-MSCs exhibited similar viability and differentiation capacity, accumulated mainly in the lungs and kidneys following systemic administration. Compared to nonpreconditioned AD-MSCs, EPA-preconditioned AD-MSCs further reduced static lung elastance, alveolar collapse, interstitial edema, alveolar septal inflammation, collagen fiber content, neutrophil cell count as well as protein levels of interleukin-1β and keratinocyte chemoattractant in lung tissue, and morphological abnormalities in the heart (cardiac myocyte architecture), liver (hepatocyte disarrangement and Kupffer cell hyperplasia), kidney (acute tubular necrosis), spleen (increased number of megakaryocytes and lymphocytes), and small bowel (villi architecture disorganization). EPA preconditioning of MSCs resulted in increased secretion of pro-resolution and anti-inflammatory mediators (RvD1, PGE2, IL-10, and TGF-β).


CONCLUSIONS
Compared to nonpreconditioned cells, EPA-preconditioned AD-MSCs yielded further reductions in the lung and distal organ injury, resulting in greater improvement in sepsis severity score and higher survival rate in CLP-induced experimental sepsis. This may be a promising therapeutic approach to improve outcome in septic patients.
['Silva|Johnatas D|JD|', 'Lopes-Pacheco|Miquéias|M|', 'de Castro|Ligia L|LL|', 'Kitoko|Jamil Z|JZ|', 'Trivelin|Stefano A|SA|', 'Amorim|Natália R|NR|', 'Capelozzi|Vera L|VL|', 'Morales|Marcelo M|MM|', 'Gutfilen|Bianca|B|', 'de Souza|Sergio A L|SAL|', 'Weiss|Daniel J|DJ|', 'Diaz|Bruno L|BL|', 'Rocco|Patricia R M|PRM|0000-0003-1412-7136']
D000273:Adipose Tissue D000818:Animals D003131:Combined Modality Therapy D016207:Cytokines D015118:Eicosapentaenoic Acid D018836:Inflammation Mediators D055370:Lung Injury D008297:Male D045164:Mesenchymal Stem Cell Transplantation D059630:Mesenchymal Stem Cells D051379:Mice D008810:Mice, Inbred C57BL D018805:Sepsis
Eicosapentaenoic acid Mesenchymal stromal cells Sepsis Preconditioning Inflammation Macrophages