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A7406 - Eicosapentaenoic Acid Enhances the Effects of Adipose-Derived Mesenchymal Stromal Cells in Experimental Sepsis
Author Block: J. Silva1, L. Castro1, J. Z. Kitoko2, S. Trivelin2, N. Amorim3, M. M. Morales4, S. Souza5, V. L. Capelozzi6, B. L. Diaz3, P. R. Rocco3; 1Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, 2Carlos Chagas Filho Institute of Biophysics, Laboratory of Pulmonary Investigation, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, 3Carlos Chagas Filho Institute of Biophysics, Laboratory of Inflammation, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, 4Carlos Chagas Filho Institute of Biophysics, Laboratory of Cellular and Molecular Physiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, 5Department of Radiology, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, 6Department of Pathology, University of Sao Paulo, Sao Paulo, Brazil.
RATIONALE: Sepsis is a life-threatening condition caused by an exacerbated immune response to an infection, most commonly of bacterial etiology. Sepsis can lead to multiorgan failure and death. Even though treatment with mesenchymal stromal cells (MSCs) has been demonstrated to alleviate sepsis-associated lung and distal organ damage and improve survival in mouse models of polymicrobial sepsis, mortality rates remain high. Eicosapentaenoic acid (EPA) serves as a substrate for production of anti-inflammatory mediators such as eicosanoids and resolvins during cellular stress. We hypothesized that MSC exposure to EPA might potentiate their effects in experimental sepsis by further reducing systemic inflammation and lung and distal organ damage, thus mitigating sepsis severity and improving survival. METHODS: Twenty-Four C57BL/6 mice were randomly allocated to undergo sham surgery or cecal ligation and puncture (CLP) to induce sepsis. Twenty-four hours after CLP, animals were further randomized to receive saline (50μL, SAL, n=6/each), adipose tissue-derived MSCs (105, AD-MSCs, n=6/each), or adipose tissue-derived MSCs stimulated with EPA (105, AD-MSC-EPA, n=6/each), for 6h, intravenously. Twenty-four hours after treatment, survival rate, sepsis severity, lung mechanics, lung and distal organ histology, pro- and anti-inflammatory biomarkers in bronchoalveolar lavage fluid (BALF) and blood, bacterial phagocytosis, and MSC biodistribution (by technetium-99m tagging) were analyzed. RESULTS: Non-stimulated and EPA-stimulated MSCs exhibit similar viability and differentiation capacity, accumulated mainly in lungs and kidney, reduced static lung elastance, total and differential cell counts in BALF, transforming growth factor-β and proinflammatory mediators (IL-6, IL-1β, murine IL-8 homologue KC, TNF-α) in lung tissue, and damage to heart, spleen, and small intestine. Furthermore, compared to nonstimulated MSCs, EPA-stimulated MSCs produced superior improvement in clinical sepsis score, alveolar collapse, neutrophil counts in lung tissue, collagen fiber content in alveolar septa, and total leukocyte counts in blood; greater reductions in damage to lung (alveolar edema and inflammation), kidney (tubular acute necrosis), and liver (hepatocyte disarrangement and Kupffer cell hyperplasia); and enhanced phagocytic activity and the size of extracellular vesicles. CONCLUSIONS: In CLP-induced experimental sepsis, EPA potentiation of MSCs yielded further reductions in lung inflammation and remodeling and mitigated lung and distal organ damage. This strategy may hold promise for clinical application.