Overexpression of IL-10 Enhances the Efficacy of Human Umbilical-Cord-Derived Mesenchymal Stromal Cells in E. coli Pneumosepsis

Enhancing the immunomodulatory effects of mesenchymal stromal cells (MSCs) may increase their effects in sepsis. We tested the potential for overexpression of Interleukin-10 (IL-10) in human umbilical cord (UC) MSCs to increase MSC efficacy in <i>Escherichia coli</i> <i>(E. coli)</i> pneumosepsis and to enhance human macrophage function. Pneumonia was induced in rats by intratracheal instillation of <i>E. coli</i> ((2.0&ndash;3.0) &times; 10⁹Colony forming units (CFU)/kg). One hour later, animals were randomized to receive (a) vehicle; (b) na&iuml;ve UC-MSCs; or (c) IL-10 overexpressing UC-MSCs (1 &times; 10⁷ cells/kg). Lung injury severity, cellular infiltration, and <i>E. coli</i> colony counts were assessed after 48 h. The effects and mechanisms of action of IL-10 UC-MSCs on macrophage function in septic rodents and in humans were subsequently assessed. Survival increased with IL-10 (9/11 (82%)) and na&iuml;ve (11/12 (91%)) UC-MSCs compared to vehicle (9/15 (60%, <i>p </i>= 0.03). IL-10 UC-MSCs&mdash;but not na&iuml;ve UC-MSCs&mdash;significantly decreased the alveolar arterial gradient (455 93 and 520 81, mmHg, respectively) compared to that of vehicle animals (544 52, <i>p </i>= 0.02). Lung tissue bacterial counts were significantly increased in vehicle- and na&iuml;ve-UC-MSC-treated animals but were not different from sham animals in those treated with IL-10 overexpressing UC-MSCs. IL-10 (but not na&iuml;ve) UC-MSCs decreased alveolar neutrophils and increased alveolar macrophage percentages compared to vehicle. IL-10 UC-MSCs decreased structural lung injury compared to na&iuml;ve UC-MSC or vehicle therapy. Alveolar macrophages from IL-10-UC-MSC-treated rats and from human volunteers demonstrated enhanced phagocytic capacity. This was mediated via increased macrophage hemeoxygenase-1, an effect blocked by prostaglandin E2 and lipoxygenase A4 blockade. IL-10 overexpression in UC-MSCs enhanced their effects in <em>E. coli</em> pneumosepsis and increased macrophage function. IL-10 UC-MSCs similarly enhanced human macrophage function, illustrating their therapeutic potential for infection-induced acute respiratory distress syndrome (ARDS)