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 Escherichia coli (E. coli) pneumosepsis and to enhance human macrophage function. Pneumonia was induced in rats by intratracheal instillation of E. coli ((2.0-3.0) x 10(9) Colony forming units (CFU)/kg). One hour later, animals were randomized to receive (a) vehicle; (b) naive UC-MSCs; or (c) IL-10 overexpressing UC-MSCs (1 x 10(7) cells/kg). Lung injury severity, cellular infiltration, and E. coli 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 naive (11/12 (91%)) UC-MSCs compared to vehicle (9/15 (60%, p = 0.03). IL-10 UC-MSCs-but not naive UC-MSCs-significantly decreased the alveolar arterial gradient (455 +/- 93 and 520 +/- 81, mmHg, respectively) compared to that of vehicle animals (544 +/- 52, p = 0.02). Lung tissue bacterial counts were significantly increased in vehicle- and naive-UC-MSC-treated animals but were not different from sham animals in those treated with IL-10 overexpressing UC-MSCs. IL-10 (but not naive) UC-MSCs decreased alveolar neutrophils and increased alveolar macrophage percentages compared to vehicle. IL-10 UC-MSCs decreased structural lung injury compared to naive 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 E. coli 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).